Evaluation of asbestos-exposure, clinical diagnosis and treatment of MPM

Transcription

1 Evaluation of asbestos-exposure, clinical diagnosis and treatment of MPM Aija Knuuttila, MD, PhD Dept. of Pulmonary Medicine Helsinki University Central Hospital, Finland

2 Malignant pleural mesothelioma new cases yearly in Finland! yearly diagnosed /referred to Helsinki Univ. Hospital 80-90% have an occupational asbestos-exposure clinical presentation unilateral pleural effusion in 80-90% chest pain in! 70% dyspnoe in! 60% weight loss, fatigue, fever, CRP " metastases rare, occur late, rarely clinical morbidity median survival after dg: 9-12mos (6 17) 2yr survival! 20% (Herndon et al. 1998, Boutin et al. 1998)

3 Evaluation of asbestos-exposure in MPM any amount of occupational exposure > 10 yrs earlier # occupational disease entitled to compensation risk occupations (ship yard industry, plummers, electricians, mechanicians etc) occupational history - surveyed in detail with a social worker medical statement for the insurance company (employer s) all the treatment given is paid by the insurance company no additional examinations required (eg. BAL, tissue samples) to prove the exposure if accepted cepted/suspected occupational disease post-mortem forensic autopsy required

4 Clinical presentation of MPM

5 Radiological diagnostics chest X-ray diagnosis of pleural effusion, in clinical follow- up (amount of the effusion) CT (chest-abdomen) sometimes pleural effusion only, diffuse pleural tumours, thickening of interlobar fissures in 80%, pleural plaques as marker of asbestos-exposure MRI shows the local invasive growth, demonstration of diaphragmatic growth if radical surgery considered PET-CT large number of MPMs are FDG-PET positive, exclusion of metastases if surgery considered, the role in defining the local invasion still open

6 Growth pattern of MPM originates from parietal pleura, grows platelike over the lung surfaces and lobes, tracks along interlobar fissures, encases the lung - affision of contralat. lung and/or peritoneum! 10-20%

7 The role of serum markers in diagnostics not yet used; ; histological samples needed! S-CA125 sometimes positive (eg. pleural metastases of ovarian ca) in follow-up? S-osteopontin (Pass et al. NEJM 2005) upregulated by asbestos- exposure, does not correlate to stage or to histology S-mesotelin (Pf-mesotelin) (SMRP-soluble mesothelin related peptides) Mesomark (Robinson et al. Lancet 2003) - surface glycoprotein of mesothelial cells, no expression from other cells, correlates with tumour size and increases in tumour progression - increased concentrations: in 84% of MPMs and in less than 2% in other pleural abnormalities (sensitivity 84%, spesificity 99%) - diagnostic use/follow up of treatment?

8 Other clinical diagnostics anemia, trombocytosis, LD",, CRP",, hypersedimentation, elevated transaminases, hypoalbuminemia common findings in advanced stages of MPM Spirometry - the amount of pleural effusion affects, otherwise the change in FVC relates to regression/progression - not used in clinical practice bronchoscopy+bal: no use in diagnostics, sometimes the evaluation of asbestos-exposure

9 TNM staging IMIG (Intl Mesothelioma Interest Group 1994) stage I - IV ~ surgical stage T: involvement of parietal pleural - ( T1a); visceral pleura (T1b-T2), adjacent structures (T3-4) N- ja M- factors as in NSCLC No special use in diagnostics or when evaluating chemotherapy response Important when assessing operability (stages Ia, Ib, II)

10 Prognostic factors male gender, low performance status, advanced stage (Herndon et al. Chest 1998) sarcomatous subtype, leukocytosis, trombocytosis, anemia, high SUVs in FDG-PET (Pass NEJM 2005, O Byrne et al. Lung Cancer 2004) three phase III consecutive trials (Fennell et al. JCO 2005) vinorelbine single (28 pts), vinorelbine - oxaliplatin (70 pts) irinotecan-cisplatin-mitomycin (47 pts) poor prognostic factors were : elevated leukocytes, poor PS, sarcomatous subtype prognostic factors in the treatment (945pts) histology, gender,, smoking, asbestos-exposure, laterality, surgical resection (Flores et al. J Thoracic Oncol 2007)

11 Surgery in MPM surgical procedures alone no survival effect int l consensus: recommended as a part of combination therapy (Waller et al. Lung Cancer 2004) extrapleural pneumonectomy (EPP) in trimodality therapy (183pts) 2 yr survival 38%, 5 yr survival 15% prognostic factors: epithelial, N0 (Sugarbaker et al.j Th Cardiovasc Surg 1999) pleurectomy/decortication good control of pleural effusion, obvious pleural disease removal thoracoscopy with talc pleurodesis fairly good control of pleural effusion long-term tunnelled pleural catheter ( Denver( Denver ) as effective as thoracoscopy with pleurodesis (?)

12 Radiotherapy in MPM has not been shown to alter the survival radiosensitivity of MPM only modest difficult to evaluate; mostly given in treatment combinations profylactic RT prevents tumour seeding along biopsy/chest tube tracts and wounds (Boutin et al. Chest 1995) no survival benefit, not in clinical use Cochrane-review 2006: RT alone vs. chemotherapy/surgery/bsc there are no randomized, validated studies not possible to make conclusions Ung et al. Radiother and Oncol 2006 review - 3 trials, postoperative RT to surgical wounds vs. no RT, no difference in tumour growth - 4 non-randomized trials, hemithx-rt - toxicity" palliative RT to limited fields (less than hemithx) can provide pain relief in 50-70%

13 Chemotherapy in MPM most of the modern chemotherapy agents have been tested mainly small phase II non-randomized trials palliative effect at the most, curative treatment not known cisplatin and antracyclins as single-agents antifolates have shown most effect methotrexate (Solheim Halme et al. 1999), pemetrexed, raltitrexed Solheim et al. 1992, Vogelzang et al. JCO 2003: : phase III randomized trial 448 pts cisplatin 75mg/m!+pemetrexed 500mg/m! vs. cisplatin RRs 41% vs. 17%

14 100 Survival: All Eligible Patients Pemetrexed + Cisplatin (n=226) Cisplatin (n=222) 75 % Alive MST = 9.3 mos HR 0.77 Logrank p-value MST = 12.1 mos Months Method: Kaplan-Meier

15 Patient treated with cisplatin + pemetrexed Baseline Visit 4

16 Chemotherapy in MPM (cont.) phase III; raltitrexed+cis vs. cis 250 pts; RR 24% vs.14%, MS 11.4mo vs. 8.8mo (van Meerbeeck et al. JCO 2005) phase II; carbo+pemetrexed; ; 102 pts, RR 18.6%, SD 47%, MS 12.7mo (Ceresoli et al. JCO 2006) cis+gemcitabine 2 trials; RRs 33% and 48%, alleviation of symptoms, quality of life benefit review 119 trials (8 phase III, 111 phase II, no placebocontr. ) combinations achieve better RRs than single-chemotherapy cisplatin+pemetrexed (or raltitrexed) # recommended for first-line treatment ( Ellis et al. J Thorac Oncol 2006)

17 Chemotherapy in MPM (cont.) Manegold C et al. (IASLC 2007 abstr.) Expanded Access Program (EAP) pemetrexed vs. Cis+pem vs. Carbo+pem PRs: : 10.1% vs. 24.3% vs. 20.7% median time to PD: 6.0mo vs. 7.0mo vs 6.9mo 1year survival: 58.6% vs. 63.1% vs. 64.0% toxicity was feasible in all treatment groups, but in carbo-pem group experienced gr 3-4 toxicity most frequently

18 Chemotherapy in MPM (cont.) Gem+Cis ± bevacizumab in first line treatment Kindler H et al. (ASCO( 2007 abstr.) 53 and 55 patients epithelial subtype: 74% (bevacizumab( bevacizumab-group) vs. 67% median PFS: 6.9mo vs. 6.0mo median survivals: 15.6mo vs. 14.7mo 1y survival: 59% vs. 57% combination of bevacizumab did not give additional effect compared to chemotherapy alone bevacizumab-group if VEGF-level initially low; longer PFS and survival

19 Second-line chemotherapy - no placebo-controlled trials Porta et al. Lung Cancer 2006 Giaccone et al. Eur J Cancer 2002 Fennell et al. Lung Cancer (abstr.) 2003 chemotherapy n RR (%) raltitrexed- oxaliplatin OS (mo) ZD irino-cis-mitomycin cis+pemetrexed EAP-trial (subgroup analysis); ; 153 pts received 2nd or 3rd line treatment; ORR 20%; - cis+pemetrexed (80 pts), OS 7.6 mo (95%CI, mo) or - pemetrexed-single (73pts), OS 4.1 mo (95% CI, 3.2 N/A) (Jänne et al. J Thorac Oncol 2006)

20 Is chemotherapy beneficial in MPM?? no placebo-controlled, randomized trials (1 abstract) natural course of the disease varies (2y-survival! 20% despite treatment?) controlling the pleural effusion already gives marked clinical benefit sarcomatous subtype any benefit?? trial results difficult to evaluate (all subtypes included) MSO1-trial (Muers et. al, ASCO 2007 abstr.) MSO1-trial The role of chemotherapy in MPM BSC vs. BSC+MVP vs. BSC+vinorelbine - no clear evidence that chemotherapy improved survival compared to BSC alone

21 MPM patients in HUCH/ Pulmonary Department evaluation of patients diagnosed new MPM patients male / female: 33 / 6 median age 66yrs (range 51-83yrs) occupational asbestos-exposure 29 (no 5, not known 5) epithelial 27, mixed 3, sarcomatous 5, not defined 4 chemotherapy to 23 patients; (23/39 = 59%) median number of chemotherapy cycles 4 Treatment n cis + pemetrexed 10 carbo + pemetrexed 9 pemetrexed-single 3 carbo + gemcitabine + doxorubicin 1 no chemotherapy 13 did not want chemotherapy 3

22 HUCH Pulmonary Department -clinical experience (cont.) surgical procedures to control the pleural effusion 15/39 patients pleurectomy + decortication 6 indwelled, tunneled pleural catheter 5 talc pleurodesis 2 extrapleural pneumonectomy 2

23 HUCH Pulmonary Department -clinical experience (cont.) responses to chemotherapy (radiological+clinical) PR 5/23 (22%) first line treatment - 3 cis+pem, 1 Cb+pem, 1 pem-single - all were epithelial subtype - survivals : 9mo, 30mo, 34mo, 36mo+,49mo+ SD 10/23 (43%) - 8 epithelial, 1 mixed, 1 sarcomatous - median survival 12mo; 2 still alive > 40mos MPMs diagnosed (all 39pts) - median survival 12 mos (range 2 mos 54mos+) - 2-year survival 26% (10/39)

24 How to proceed in the clinic? adequate verification of mesothelioma (histology, consultation of Inst. Occup. of Health mesothelioma panel if needed) subtype? is there occupational asbestos-exposure (>10 years earlier) statement of the occupational diasese for the insurance company

25 the possibility for radical surgery (EPP) should be evaluated, in combination with chemotherapy ( cis-pem pem?)/rt? good control of pleural effusion for all (decortication /tunnelled pleural catheter)! adequate pain medication chemotherapy when feasible (cis/carbo - pemetrexed x 3-6 or pemetrexed-single) second-line chemotherapy after progression, if PR/SD achieved in first-line (reintroduction of pemetrexed±platinum ±platinum, vinorelbin?, gemcitabine?) targeted therapy (eg. bevacizumab, EGFR-inhibitors etc.) have not yet shown additional benefit

26 Response assessment WHO criteria: feasible in bidimensional measurements modified RECIST-criteria for MPM (Byrne et al. Ann Oncol 2004) - longest unidimensional diameter creates difficulties within curved structures of the thorax ## three axial CT-levels; two thickest tumour lesions are measured (perpendicular to the thoracic wall) sum of these six measurements (PR"30%, PD#20%)