1. Mesothelioma studies within our region – 2016 update Nick Maskell

3. Meso MDT - review
Mesothelioma MDT – all cases referred between 1/1/ /12/15
Definitive diagnosis in 171 of 210 cases (81%)
Mesothelioma diagnosed in 153/210 (73%)
Further investigation advise suggested in 35 non diagnostic cases
86/210 cases (41%) invited to participate in research study
43/86 (50%) agree and were recruited
Overall process was <2 weeks in 75% of cases
Also prevented the need for PM in over 95% of cases referred to Avon coroner

4. Cytology Clusters of abnormal epithelial cells in pleural fluid
? Adenocarcinoma or
mesothelioma
Can we rely on cytology alone?

5. Histology
A combination of at least two positive mesothelial (Calretinin, Cytokeratin 5/6, Wilms Tumour 1, D-240) and at least two negative adenocarcinoma immunohistochemical markers (TTF1, CEA, Ber-EP4) should be used in the differential diagnosis of MPM. (Markers listed in likely order of value). Grade D.
Do not rely on cytology alone to make a diagnosis of MPM unless biopsy is not possible or not required to determine treatment due to patient wishes or poor performance status. Grade D.

6. Target study
Randomised controlled trial to compare the diagnostic yield of Positron Emission Tomography Computed Tomography (PET-CT) TARGETed pleural biopsy versus CT-guided pleural biopsy in suspected pleural malignancy 

7. Target
76 participants
7 UK sites planned, 3 sites currently recruiting
Suspected pleural malignancy with negative initial biopsy
Randomised 1:1 PET vs CT
Primary outcome is pleural malignancy identified on second biopsy
Secondary outcomes include time to diagnosis, no of investigations, healthcare costs

8. TARGET Study – NIHR multicentre RCT

9. Chemotherapy

10. Lancet 2015

11. MAPS trial 448 patients to treatment (223 to PCB and 225 to PC).
Given 15 mg/kg bevacizumab (VEGF inhibitor) in 21 day cycles for up to six cycles, until progression or toxic effects
OS was significantly longer with PCB (median 18·8 months [95% CI 15·9–22·6]) than with PC (16·1 months [14·0–17·9]; hazard ratio 0·77 [0·62–0·95]; p=0·0167)..
Interpretation
Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease.

12. Chemotherapy
Patients with MPM with good performance status should be offered the option of first-line therapy with cisplatin and pemetrexed and bevacizumab. (Grade A)

13. a
Radiotherapy

14. Immediate Radiotherapy
203 patients with MPM and large bore pleural procedure in the past 35 days
Baseline history, examination and QOL questionnaires
RANDOMISATION (1:1)
Minimising by: Histology (epithelioid or other), IPC or other, Surgical procedure or other
Immediate Radiotherapy
21Gy in 3#s within 42 days of the chest wall procedure
Deferred Radiotherapy
No radiotherapy initially. If the patient develops a PTM, 21Gy in 3#s
FOLLOW UP
Clinic visits at 1,3, 6, 9, 12 months
Phone consultations every month (unless seen in clinic)
Semi-structured interviews at 6 months (Bristol & Oxford only)
Clive et al., Lancet Oncology 2016.

15. Recruitment 203 patients recruited from 22 UK centres
December August 2014

16. Baseline patient characteristics
Immediate RT (n = 102)
Deferred RT (n = 101)
Male
91/102 (89.2%)
90/101 (89.1%)
Age (years) mean(std)
70.5 (8.3)
71.6 (7.8)
Time from diagnosis to randomisation (days) median (2.5th – 97.5th centile)
21 (4 – 261)
20 (4 – 304)
WHO Performance Score
29 (28.4%)
34 (33.7%) 1
61 (59.8%)
53 (52.5%) 2
9 (8.8%)
11 (10.9%) 3
3 (2.9%)
3 (3.0%)
Histological subtype
Epithelioid only
71 (69.6%)
71 (70.3%)
Sarcomatoid
8 (7.8%)
8 (7.9%)
Biphasic (mixed)
19 (18.6%)
18 (17.8%)
Desmoplastic
4 (3.9%)
Other
4 (4.0%)
Basis for diagnosis
Pleural fluid cytology
Pleural biopsy
102 (100%)
98 (97.0%)
Baseline oral morphine equivalent dose (mg) median (2.5th – 97.5th centile)
0 (0 – 50)
0 (0 – 84.5)
Baseline QOL,
median (2.5th-97.5th centile)
QLQ-C30 global health status
66.7 (16.7 – 100)
QLQ-C30 physical functioning
80 ( )
76.7 (20 – 100)
QLQ-C30 pain
16.7 ( 0 – 83.3)
16.7 ( 0 – 100)
Overall chest pain VAS Score median (2.5th – 97.5th centile)
 5.0 ( )
 4.0 ( )

17. Randomised procedures
Type of intervention randomised
Immediate RT
(n=102)
Deferred RT
(n=101)
Large bore chest drain insertion
4 (4.0%)
Local anaesthetic thoracoscopy
38 (37.3%)
35 (34.7%)
Thoracotomy
3 (2.9%)
6 (5.9%)
VATS procedure
45 (44.1%)
45 (44.6%)
Indwelling pleural catheter insertion
15 (14.7%)
11 (10.9%)
Other
1 (1.0%)
Clive et al Lancet Oncology 2016

18. Primary Outcome Immediate RT n (%) Deferred RT Treatment effect
Immediate RT
n (%)
Deferred RT
Treatment effect
% (95% CI)
p-value
Primary ITT analysis
Number of patients developing a PTM
9/102 (8.8)
16/101 (15.8)
7% (95%CI: -2, 16)
0.141
Number of patients developing a chest wall nodule anywhere on the ipsilateral hemithorax
13/102 (12.8)
3.1% (95% CI: -6.5, 12.7)
0.554
Per-protocol analysis
5/84 (6)
16/99 (16)
10.2% (95% CI: 1.4, 19.1)
0.037
Clive et al Lancet Oncology 2016

19. Pre-defined subgroup analyses
Number of patients
(n=203)
Number of patients developing a PTM, n (%)
Immediate RT
Deferred RT
Treatment effect
% (95% CI)
p-value
Randomised procedure type
Local anaesthetic thoracoscopy 73
4 (10.5)
4 (11.4)
0.9% (95% CI: -13.5, 15.3)
1.000
Thoracic surgery 99
4 (8.3)
9 (17.7)
9.3% (95% CI: -3.7, 22.4)
0.236
Indwelling pleural catheter 26
1(6.7)
3 (27.3)
20.6% (95% CI: -8.6, 49.8)
0.279
Tumour subtype
Epithelioid only
143
6 (8.5)
15 (20.8)
12.4% (95%CI: 1.0, 23.8)
0.057
Other 60
3 (9.7)
1 (3.5)
-6.2% (95%CI: -18.6, 6.1)
0.613
Patients followed up for ≥6 months
156
8 (10.0)
13 (17.1)
7.1% (95% CI: -3.6, 17.8)
0.243
Chemotherapy after trial entry
Yes
120
7 (13)
8 (13)
0% (95% CI: -11.9, 11.9) No 83
2 (4)
8 (22)
17.3% (95% CI: 2.8, 31.8)
0.021

20. Symptoms and quality of life
No difference between treatment arms in terms of:
Morphine equivalent doses
Chest pain VAS scores
EQ5D quality of life
QLQ-C30 Global health status
QLQ-C30 Physical functioning
QLQ-C30 Pain
Immediate RT
Deferred RT
p-value 
Number of patients developing a painful PTM
2/102 (2%)
6/101 (6%)
0.170
Proportion of nodules which were painful
2/9 (22%)
6/16 (38%)
0.661
7/8 of the painful PTMs diagnosed after 6 months
7/8 had received chemotherapy
5/8 had undergone thoracic surgery; 2/8 had LAT; 1/8 IPC
Clive et al Lancet Oncology 2016

21. Summary The largest RCT of prophylactic radiotherapy in mesothelioma
Primary endpoint using ITT analysis shows no statistically significant difference in rate of PTM between arms;
Treatment effect= 7% (95%CI: -2, 16); p=0.141.
Significant difference identified in secondary, per-protocol analysis;
Treatment effect= 10.2% (95%CI: 1.4, 9.3); p=0.037.

22. Radiotherapy
Do not offer prophylactic radiotherapy to chest wall procedure tracts routinely. Grade A

23. Zoledronic Acid in the management of Mesothelioma
(A feasibility study)
RfPB funded, 50 patients recruited over a year in 3 centres. Three arms – randomised ZA vs placebo alongside chemo, and third arm of patients who decline chemo who get just ZA.
Opening imminently.

24. DOI:10.1371/journal.pone.0118569 March 17, 2015
No statistically significant results in small trial (n=24). In MPM patients ?some CT response

25. ZA NIHR RfPB funded 50 participants, recruited from 3 centres
Randomised 1:1 to ZA + chemo vs placebo + chemo
Third arm of just ZA for patients who decline chemo
1 outcome is feasibility
Survival, response rates and PROMs also collected
Opening this month

26. Treating mesothelioma with Intra-pleuraL bacterial immunoTherapy
A feasibility study using the ‘trial within a cohort’ methodology to assess the role of intra-pleural OK-432 in mesothelioma

27. Bacterial immunotherapy
Intra-pleural staph superantigen extended survival in a series of 14 patients with MPE 2 to lung cancer
Intra-pleural lactobacillus casei extended survival in an RCT of 95 patients with MPE 2 to lung cancer

28. TILT Funded by NIHR Doctoral Research Fellowship
45 participants from 2 centres
Patients with mesothelioma who have finished chemo or declined chemo
OK-432 (attenuated Strep pyogenes) delivered via IPC
1 outcome is feasibility
Also collecting data on clinical outcomes, cellular & cytokine responses in pleural fluid

29. Aduro Biotech & CRS-207
CRS-207 is a live attenuated listeria vaccine to mesothelin
Phase 1 trial in 16 patients with mesothelioma looked promising