RECENT MEDICAL RESEARCH ON MESOTHELIOMA IN AUSTRALIA

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1 RECENT MEDICAL RESEARCH ON MESOTHELIOMA IN AUSTRALIA MANY GOOD QUESTIONS, FEW GOOD ANSWERS Dr Malcolm Feigen Radiation Oncology Centre Melbourne, Victoria

2 QUESTIONS Can mesothelioma be diagnosed in its early stages? How soon should treatment be started? What therapy works best? Which patients benefit from surgery? What surgical procedure works best? Which chemotherapy is best? Does radiotherapy offer any benefit? How can my pain be best controlled?

3 PERTH Epidemiological studies Wittenoom Mesothelin 2003 NCARD* 2006 Metabolic response analysis of FDG-PET scans 2007 * National Centre for Asbestos Related Diseases

4 Epidemiological studies, staging, CT scans, modified RECIST, MRI scans, 18 FDG-PET scans, mesothelin, MFISH, microarrays, proteomics, gene microarrays, immune activation, T cell immunotherapy, apoptosis, syndecans, proteoglycans, adenovirus gene therapy, SV40, BCL-2, anti-cd40, SNPs, TGF, GM-CSF, interleukin-2 and 4, telomeres, NS enolase, antisense oligonucleotides, heat shock proteins, vitamins A and E, cisplatin/ gemcitabine, tomudex, irinotecan, EGFR, iressa, thalidomide, extrapleural pneumonectomy, photodynamic therapy, pleurectomy/decortication, intensity-modulated radiotherapy

5 Vol 366 July 30, 2005 Malignant mesothelioma Bruce W S Robinson, Arthur W Musk, Richard A Lake Vol 366 July 30, 2005 Lancet 2005;366:

6 EARLY DIAGNOSIS Mesothelin-family proteins and diagnosis of mesothelioma BWS Robinson, J Creaney, R Lake, AW Musk, N de Klerk, P Winzell, KE Hellstrom, I Hellstrom Lancet 2003;362:

7 INCREASED MESOTHELIN LEVELS PRIOR TO DIAGNOSIS OF MESOTHELIOMA STUDY NO. POSITIVE COMMENT Roe 2008 Norway 1/77 1% Retrospective Creaney 2010 Perth 17/106 16% Retrospective Gube 2011 Germany 2/20 10% Retrospective Hollovoet 2011 Belgium 0/137 0% Prospective TOTAL 20/340 6%

8 Predicting survival in malignant mesothelioma AW Musk, N Olsen, H Alfonso, A Reid, P Franklin, J Sleith, N Hammond, T Threlfall, KB Shifkin, NH de Klerk European Respiratory Journal 2011;38: Western Australian Mesothelioma Registry database of 1,362 cases Survival = exp (-t0/97exp((-1.04)( (a/10) (a/10)3 ln (a/10)+0.41f-0.40p-0.15l-0.16r -0.52s+0.22e 0.17b+0.51d1980s+0.61d1990s+0.76d2000s)))

9 Increasing incidence of malignant mesothelioma after exposure to asbestos during home maintenance and renovation NJ Olsen, PJ Franklin, A Reid, N de Klerk, TJ Threlfall, K Shilkin, B Musk Medical Journal of Australia 2011;195:271-4

10 Outcome for Patients with Malignant Pleural Mesothelioma referred for Trimodality Therapy in Western Australia A Hasani, JA Alvarez. JM Wyatt, S Bydder, M Millward, M Byrne, AW Musk, AK Nowak Journal of Thoracic Oncology 2009;4: patients Operative mortality 11%

11 Early Prediction of Response to Chemotherapy and Survival in Malignant Pleural Mesothelioma using a Novel Semiautomated 3-Dimensional Volume- Based Analysis of Serial 18 F-FDG PET Scans RJ Francis, MJ Byrne, AA van der Schaal, JA Boucek, AK Nowak, M Phillips, R Price, AP Patrikeos, AW Musk, MJ Millward Journal of Nuclear Medicine 2007:48: FDG-PET scans before and after one cycle of chemotherapy (A,B), with Total Glycolytic Volume (TGV) assessment of tumour activity (C,D) using software program developed at Sir Charles Gairdner Hospital in Perth.

12 A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma S Bydder, M Phillips, DJ Joseph, N Spry, Y DeMelker, AW Musk British Journal of Cancer 2004;91:9-10 Metastases on followup 2 (7%) 3 (10%) N.S. 7/43 patients alive at 8.7 mths median from randomisation

13 CHEMOTHERAPY FOR MESOTHELIOMA

14 MESOTHELIOMA PHASE III TRIALS OF SECOND LINE CHEMOTHERAPY A. 222 Dutch and Australian (n 14) patients randomised after 4-6 cycles of cisplatin/carboplatinum and pemetrexed to maintenance therapy with thalidomide or placebo B. 661 patients from 23 countries randomised after relapse from 4-6 cycles of cisplatin/carboplatinum and pemetrexed to vorinostat or placebo Vorinostat Median 7.2 mths Placebo Median 6.3 mths HR = p=0.858 Overall Survival Overall Survival Time (mths) Time (mths)

15 SURGERY AND RADIOTHERAPY FOR MESOTHELIOMA

16 LOCAL THERAPIES FOR MESOTHELIOMA Pleurodesis fusion of two sides of pleura with talc 4 2. Pleurectomy/Decortication surgery to remove all the pleura 2 3. Extrapleural Pneumonectomy surgery to remove the whole lung with pleura and lymph nodes, replacing diaphragm and heart membrane with synthetic mesh 3 4. Radiation Pneumonectomy high-dose radiotherapy to entire hemithorax (IMRT recommended), surgery and chemotherapy optional

17 SYDNEY Extrapleural Pneumonectomy ADRI* 2009 *Asbestos Diseases Research Institute

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19 SURGERY FOR MESOTHELIOMA Survival in relation to the type of surgical procedure, curative versus palliative intent. (95% confidence interval) Survival for patients managed with curative-intent surgery only versus those managed with multimodality therapy. Rusch IASLC Mesothelioma Database J Thoracic Oncology 2012;7:1631-9

20 SURGICAL OPTIONS FOR MESOTHELIOMA PLEURECTOMY/ DECORTICATION EXTRAPLEURAL PNEUMONECTOMY

21 Extrapleural pneumonectomy for malignant pleural mesothelioma : Outcomes of treatment and prognostic factors TD Yan, M Boyer, MM Tin, D Wong, C Kennedy, J Maclean, PG Bannon, BC McCaughan Journal of Thoracic and Cardiovascular Surgery 2009;138: patients Operative mortality 5.7% Morbidity 37% 6 had chemotherapy prior to surgery

22 Improving survival results after surgical management of malignant pleural mesothelioma: an Australian institution experience TD Yan, CQ Cao, M Boyer, MM Tin, D Wong, C Kennedy, J Maclean, PG Bannon, BC McCaughan Annals of Thoracic and Cardiovascular Surgery 2011;17: cases

23 MELBOURNE Pleurectomy/decortication ± PDT 2006 PET/CT scans followup 2009 Radiation Pneumonectomy 2012

24 PLEURECTOMY/DECORTICATION + PHOTOTHERAPY Management of Malignant Mesothelioma by Decortication and Adjunct Phototherapy CP Clarke, SR Knight, FJ Daniels, S Seevanayagam Asian Cardiovascular and Thoracic Annals 2006;14:206-9 Pre-HpD 17 pts

25 Prognostic Value of 18 F-FDG PET/CT in Patients with Malignant Pleural Mesothelioma ST Lee, M Ghanem, RA Herbertson, SU Belangieri, AJ Byrne, K Tabone, P Mitchell, SR Knight, M Feigen, AM Scott Molecular Imaging and Biology 2009;14: patients

26 Establishing locoregional control of malignant pleural mesothelioma using high dose radiotherapy and 18 F-FDG PET/CT scan correlation. M Feigen, ST Lee, C Lawford, K Churcher, E Zupan, AM Scott, C Hamilton Journal of Medical Imaging and Radiation Oncology 2011;55: mths post-rt 14 mths post-rt

27 TARGET VOLUME Allen et al. Boston 2008 Gupta et al. MSKCC 2009 Locoregional failure sites. MDRT HDRT O in-field below field Allen et al. IJROBP 2007;68:1366

28 IMRT FOR MESOTHELIOMA Rationale Locoregional progression within and beyond the hemithorax is the major problem as surgery and chemotherapy alone are ineffective The potential for radiation toxicity to organs at risk is high The risk of radiation pneumonitis is low if high doses are confined to one lung (contralateral mean lung dose < 7.5 Gy, V 5 < 60% and V 20 < 10%)

29 AIMS Is mesothelioma radiosensitive? Using recent advances in radiotherapy, to assess - treatment toxicity - symptom palliation - locoregional disease control

30 TOOLS Advanced radiotherapy technologies - 3DCRT > IMRT > IGRT > VMAT 18 FDG-PET/CT scans Total Glycolytic Volume Mesothelin assays CTCAE toxicity grading

31 METHODS Dose of Gy over 6 weeks to a tolerable target contained within a single hemithorax Selection criteria: Mesothelioma on biopsy Any previous mesothelioma therapy Normal blood tests Approval from Austin MDM

32 Patient 27 T3N2M0 Stage III M 72 R E Pleurodesis 2/2009 CP x 6 3-6/2009 IMRT 2/ Gy Jan

33 Intensity- Modulated Radiotherapy

34 AUSTIN RADIOTHERAPY PROGRAM PATIENT REFERRALS REGION TOTAL TREATED UNTREATED VICTORIA N.S.W QLD WEST. AUST STH. AUST TASMANIA A.C.T Gold Coast NTHN. TERRIT NEW ZEALAND TOTAL

35 PATIENT DEMOGRAPHICS (1) July 2003 August DCRT 16 pts IMRT 42 pts TOTAL 58 pts Age (yrs) Median Range Gender Male Female Side Right Left Histology Epithelioid Biphasic Sarcomatoid Stage I II III IV T1N0M0 T2N0M0 Any T3M0/N1M0/N2M0 Any T4/N3/M

36 PATIENT DEMOGRAPHICS (2) 3DCRT 16 pts IMRT 42 pts TOTAL 58 pts Surgery Extrapleural Pneumonectomy Pleurectomy/Decortication - Extended - Partial Pleurectomy Pleurodesis Biopsy Chemotherapy Yes No Trimodality Yes Interval from diagnosis to RT: (months) Median Range

37 DOSE-VOLUME HISTOGRAMS Pre-RT Mesothelin 25.3 TGV mths post-rt Mesothelin 13.8 TGV mths post-rt Mesothelin 6.5 TGV 1619 Died 12 mths post-rt of pulmonary embolus without mesothelioma progression No acute or late radiation toxicity

38 Pt 15 T4N0M0 M 60 L Desmoplastic No prior surgery or chemotherapy 3DCRT May Gy Pre-RT RT Volume 5 mths post-rt 12 mths post-rt TGV reduction 99% at 3 mths 60 Gy 50 Gy 40 Gy Mild transient radiation pneumonitis grade 2 In-field local recurrence adjacent to spinal cord in low-dose region below 50 Gy Out of field relapse in contralateral lung unresponsive to chemotherapy

39 Pt 8 T2N0M0 M 69 R E PD PDT No chemo 3DCRT 1/ Gy 3DCRT 10/ Gy Alive NED 8 yrs after diagnosis, 3 yrs after salvage radiotherapy Out of field relapse at 5 yrs

40 RADIATION TOXICITY CTCAE Version 4.0 No grade 3, 4 or 5 acute or late toxicities Respiratory pneumonitis grade 2 in 10 cases All deaths from disease progression or intercurrent disease

41 Significant reductions in mesothelin assays (6/30 pts) Total Glycolytic Volume assessments showed median TGV reduction 57% after RT (13 evaluable patients) 87 followup PET/CT scans in of 27 cases 16 cases unevaluable (13 radiation pneumonitis in 13, 2 outside scans, 1 talc pleurodesis after RT

42 TOTAL GLYCOLYTIC VOLUME WATERFALL PLOT 100 CHANGE FROM BASELINE (%) * * PATIENTS (N=27)

43 PALLIATION Pain on presentation significant improvement in 11 of 11 cases 4 cases of T4 disease reirradiation in 3 Subcutaneous nodules regression in 10 of 10 cases Mesothelin assays

44 MESOTHELIN ASSAYS Mesothelin assay in mmol/l Time post-radiotherapy (Years)

45 MESOTHELIN ASSAYS Mesothelin assay in mmol/l Time post-radiotherapy (Years)

46 PATTERNS OF FAILURE 3D-CRT IMRT TOTAL Local only Local + Distant Distant Nil Unevaluable Total % locoregional control 1 salvaged

47 HEMITHORACIC IMRT IN MESOTHELIOMA PATIENTS WITH BOTH LUNGS INTACT AUSTIN NEW YORK MILAN AVIANO Patient No Median Dose (Gy) Toxicity (% grade 3/4/5 pneumonitis) 0/0/0 14/3/3 13/0/0 7/0/0 Local Failure 14% 4 54% 76% - 1. Rosenzweig et al. Int J Rad Onc Biol Phys For 36 patients post-2008 who had RT 2. Fodor et al. Strahlenther Onkol 2011 to the complete hemithorax. Those 3. Minatel et al. J Thor Oncol 2012 treated before 2008 had a local failure rate of 88%.

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49 AUSTIN MESOTHELIOMA PROGRAM High-dose Radiotherapy ACTUAL SURVIVIVAL (Yrs) Musk et al. Predicting survival in malignant mesothelioma. Eur Resp J 2011;38: Survival = exp (-t 0/97 exp((-1.04)( (a/10) (a/10) 3 ln (a/10)+0.41f-0.40p-0.15l-0.16r s+0.22e 0.17b+0.51d1980s+0.61d1990s+0.76d2000s))) KEY: Age at diagnosis (a in years) Site (peritoneal; l or r pleura) 60.0 Time after diagnosis (t in months) Histology (epithelioid; biphasic; sarcomatoid ) Sex (1= f; 0= male) Decade of diagnosis 1 (if true) or 0 (if untrue) ESTIMATED SURVIVAL (Yrs) Musk 2011

50 ACKNOWLEGEMENT Comcare Australian Innovation Fund for two year grant to explore the effects of high dose hemithoracic radiotherapy for localised pleural mesothelioma using advances in technology, covering data manager and radiation oncology medical physicist support.