Annex section - Guidelines for malignant pleural mesothelioma from the experts of the ERS/ESTS taskforce (Scherpereel et al)
Table 1. Grading Recommendations from the American College of Chest Physicians (ACCP) (Guyatt et al, Chest 2006; 129(1): 17481)
Grade of Recommendation /
Description
Benefit vs Risk and Burdens
1A/ strong recommendation,
High-quality evidence
Benefits clearly outweigh risk
and burdens, or vice versa
1B/ strong recommendation,
moderate quality evidence
Benefits clearly outweigh risk
and burdens, or vice versa
1C/ strong recommendation,
low-quality or very low quality
evidence
Benefits clearly outweigh risk
and burdens, or vice versa
2A/ weak recommendation, high
quality evidence
Benefits closely balanced with
risks and burden
2B/ weak recommendation,
moderate-quality evidence
Benefits closely balanced with
risks and burden
Methodological Quality of
Supporting Evidence
Randomized controlled trials
(RCTs) without important
limitations or overwhelming
evidence from observational
studies
RCTs with important limitations
(inconsistent results,
methodological flaws, indirect,
or imprecise) or exceptionally
strong evidence from
observational studies
Observational studies or case
series
RCTs without important
limitations or overwhelming
evidence from observational
studies
RCTs with important limitations
(inconsistent results,
methodological flaws,
indirect, or imprecise) or
Implications
Strong recommendation, can
apply to most patients in
most circumstances without
reservation
Strong recommendation, can
apply to most patients in
most circumstances without
reservation
Strong recommendation but
may change when higher
quality evidence becomes
available
Weak recommendation, best
action may differ depending
on circumstances or patients’
or societal values
Weak recommendation, best
action may differ depending
on circumstances or patients’
or societal values
2
2C/ weak recommendation, low
quality
or very low-quality evidence
Uncertainty in the estimates of
benefits, risks, and burden;
benefits, risk, and burden
may be closely balanced
exceptionally strong evidence
from observational studies
Observational studies or case
series
Table 2: Summary of TNM classification in malignant pleural mesothelioma [28]
T1
Ipsilateral parietal pleura
T1a
No visceral pleura
T1b
Visceral pleura
T2
Ipsilateral lung, diaphragm, confluent involvement of visceral pleura
T3
Endothoracic fascia, mediastinal fat, focal chest wall, non-transmural
pericardium
T4
Contralateral pleura, peritoneum, rib, extensive chest wall or mediastinal
invasion, myocardium, brachial plexus, spine, transmural pericardium,
malignant pericardial effusion
N0
No regional lymph node metatstasis
N1
Ipsilateral bronchopulmonary, hilar
N2
Subcarinal, ipsilateral mediastinal, internal mammary
N3
Contralateral mediastinal, internal mammary, hilar, ipsi/contralateral
supraclavicular, scalene
M0
No extrathoracic metastasis
M1
Extrathoracic metastasis
Very weak recommendations;
other alternatives may be
equally reasonable
3
Table 3: Phase II and III studies assessing the efficacy of chemotherapy in malignant pleural mesothelioma.
Treatment
n pts
evaluable
Histology
(Epithelioïd/other)
RR
(%)
Median survival
(months)
QOL
Phase III randomised trials
CDDP/Pemetrexed (5)
CDDP
226
222
154/72
152/70
41
17
12,1
9,3
no
CDDP/Raltitrexed (6)
CDDP
126
124
94/32
75/49
24
14
11,4
8,8
Yes
Active symptom control (31)
ASC plus MVP ou VNR
136
273
99/37
198/75
NA
7,6
8,5
Yes
Phase II randomised trials
CDDP/MMC (32)
CDDP/Doxo
35
35
24/11
24/11
26
14
7,7
8,8
No
Doxo/CPA/Imidazole carboxamide (33)
Doxo/CPA
36
40
16/20
21/19
11
13
7,0
5,8
No
Doxo (11)
CPA
15
16
9/23
0
0
-
no
Non randomised studies
Cisplatin-based chemotherapy : monotherapy
CDDP (34)
14
-
36
-
CDDP (35)
21
-
14
12,0
No
No
CDDP (36)
35
-
14
7,5
No
CDDP (37)
24
13/10
13
5
No
4
L-NDDP (liposome entrapped cisplatin)
(38)
33
23/10
(42%
biopsy
-)
11,2
no
Cisplatin-based chemotherapy : combinations
CDDP/VP16 (39)
25
-
24
-
No
CDDP/VP16 (40)
26
13/14
12
-
No
CDDP/VBL (41)
20
13/7
25
-
No
CDDP/MMC/VBL (42)
39
-
21
6,0
Symptoms
CDDP/5Fluorouracil/Leucovorin/MMC
/Etoposide (43)
45
33/12
38
16,0
Symptoms
CDDP/MMC/INF2a (44)
43
24/19
23
11,5
No
CDDP/MMC/INF2b (45)
19
19/0
11
15,0
No
CDDP/MMC/INF (46)
23
16/4
0
12,0
CDDP/INF2b/Tamoxifène (47)
39
25/11
19
8,7
Symptoms
No
CDDP/INF
(48)
30
17/13
27
15,0
No
CDDP/INF2a (49)
12
11/2
42
16,5
CDDP/INF2a (50)
26
14/12
40
12,0
Symptoms
No
CDDP/5 Azacytidine (51)
36
22/14
14
6,4
No
CDDP/Gemcitabine (52)
21
13/8
48
9,5
Symptoms
CDDP/Gemcitabine (53)
30
26/6
13.3
9,6
Yes
CDDP/Gemcitabine (54)
53
42/11
32
11,2
CDDP/Gemcitabine (55)
35
22/13
26
13,0
Yes
No
CDDP/Gemcitabine (56)
26
26/0
23
19.5
Symptoms
CDDP/Gemcitabine (57)
50
25/25
12
10,0
No
5
CDDP/Gemcitabine/Vinorelbine (58)
12
7/5
58
11
No
CDDP/Irinotecan (59)
15
10/5
40.0
6,5
No
CDDP/Irinotecan/MMC (12)
43
32/11
37
10.8
Yes
CDDP/Doxo/MMC (60)
23
18/6
22
10,5
Symptoms
CDDP/Doxo/MMC/Bleo/Hyal (61)
27
22/5
44
15,0
CDDP/Doxo/CPA (62)
23
14/9
30
13,9
Symptoms
No
CDDP/Doxo (63)
19
-
42
12,0
No
CDDP/Doxo (64)
24
5/21
25
10,0
Symptoms
CDDP/Doxo/INF2b (65)
35
19/16
29
9,3
No
CDDP/Epirubicine (66)
63
43/20
19
13,3
No
CDDP/Gemcitabine followed by
Mitoxantrone/Méthotrexate/MMC (67)
54
44/10
30
13
No
CDDP/Vinorelbine (68)
54
40/14
30
16,8
No
Carboplatin-based chemotherapy
Carboplatin (69)
17
-
12
-
Carboplatin (70)
9
-
22
-
Symptoms
No
Carboplatin (71)
31
-
16
8,0
No
Carboplatin (72)
40
-
7
7,1
No
Carboplatin/Gemcitabine (73)
50
34/17
26
15,2
Carboplatin/Gemcitabine (74)
21
20/1
33
25.5
Symptoms
Symptoms
Carboplatin/Gemcitabine/Doxo
liposomal (75)
173
116/45
32
13
No
Carboplatin/INF2a (76)
15
11/4
7
6,1
No
Carboplatin/Ifo/Etoposide/WBHT (77)
27
16/9
19
17,7
no
6
Carboplatin/Pemetrexed (78)
102
80/22
19
12.7
no
Carboplatin/Pemetrexed (79)
76
57/19
25
14
no
Oxaliplatin-based chemotherapy
Oxaliplatin/Raltitrexed (80)
70
46/24
20
7,4
Oxaliplatin/Raltitrexed (81)
11
10/1
45
-
Symptoms
No
Oxaliplatin/Gemcitabine (82)
25
16/9
40
13,0
No
Oxaliplatin/Vinorelbine (83)
26
13/12
23
8,8
yes
Anthracyclin-based chemotherapy (without cisplatin)
Doxo/INF2a (84)
25
-
16
11,0
No
Doxo/Ifo (85)
24
15/9
32
7,0
No
Doxo/Ifo (86)
17
-
13
7,9
No
Liposomal Doxo (Caelyx) (87)
Liposomal Doxo (Doxil) (88)
31
17/14
6
13,0
No
24
14/10
0
8,5
No
Liposomal Doxo (Doxil) (89)
15
-
7
-
No
Detorubicin (90)
35/21
31/4
42.9
(on 21
evaluab
le)
23,0
No
Epirubicin (91)
51
17/35
15
9,2
No
Epirubicin/Ifo (92)
17
-
6
6,0
No
Epirubicin/IL-2 (93)
21
12/9
5
10,0
No
Epirubicin (94)
21
-
5
7,5
No
Epirubicin/Gemcitabine (95)
26
-
14
13,3
No
Epirubicin/Gemcitabine High dose (96)
23
15/8
13
9,3
Yes
7
Low dose
45
31/14
7
5,7
Liposomal Daunorubicin (97)
14
9/5
0
6,1
No
Pirarubicine (98)
35
21/14
9
10,5
No
Mitoxantrone (99)
29
-
7
-
No
Mitoxantrone (100)
40
25/16
3
4,5
No
Menogaril (101)
22
-
5
-
No
Antimetabolite-based chemotherapy
Mitoxantrone/Methotrexate/MMC (102)
22
14/3
32
13,5
Methotrexate/IFN/IFN1b (103)
26
17/9
27
17,0
Symptoms
No
Methotrexate (104)
62
42/20
37
11,0
No
Edatrexate (105)
Edatrexate/Leucovorin
20
38
13/7
23/15
25
16
9,6
6,6
No
Trimetrexate (106)
51
38/13
12
5,0-8,9
No
Pemetrexed (107) sans AF/B12
avec AF/B12
43
21
45/19
10
16
8,0
13,0
Yes
Pemetrexed/Gemcitabine (108)
108
69/39
20
8/10
Pralatrexate (109)
16
11/5
0
7
No
No
5 Azacytidine (110)
41
30/11
17
6,7
No
5 Azacytidine (111)
15
-
0
4,7
No
5 Fluorouracil (9)
20
7/13
5
5,0
No
Raltitrexed (112)
24
21/3
21
7,0
No
Capecitabine (113)
26
15/11
4
4,9
No
Gemcitabine (114)
17
9/8
0
4,7
No
Gemcitabine (115)
27
18/9
7
8,0
No
8
CB 3717 (116)
18
-
6
-
No
Alkylating agents based chemotherapy
Ifo (117)
26
18/8
4
10,0
No
Ifo (118) group A (2,3 g/m²)
group B (1,2 g/m²)
13
16
28/1
38
6
8,0
9,0
No
Ifo (119)
39
10/29
3
6,9
No
Ifo (120)
26
20/6
8
6,5
No
Ifo (121)
38/21
21/17
6
7,0
No
Ifo/INF2a (122)
39
-
21
10,0
No
CPA (123)
13
3/10
23
6,0
Symptoms
Temozolomide (124)
27
17/10
4
8,2
Amsacrine (125)
20
-
5
6,2
Yes
No
Vinca-alcaloïdes based chemotherapy
Vinorelbine (126)
29
17/12
24
10,6
Vindesine (127)
21
14/7
0
-
Yes
No
Vindesine (128)
20
-
6
-
No
Vinblastine (129)
20
-
0
3,0
No
Vincristine (130)
23
19/4
0
7,0
No
Vinflunine (131)
65
55/10
14
10.8
No
Topoisomerase inhibitors based chemotherapy
Etoposide (intravenous) (132)
Etoposide (oral)
47
41
8/39
18/23
4
7
6,7
8,5
No
Etoposide (133)
22
11/8
5
17,0
No
Topotécan (134)
22
15/7
0
7,6
No
9
Irinotécan (135)
28
17/11
0
9,3
No
Taxane-based chemotherapy
Docetaxel/Irinotecan (136)
15
8/7
0
8,5
No
Paclitaxel (137)
33
23/8
9
5,0
No
Paclitaxel (138)
23
14/10
0
9,0
No
Docetaxel (139)
31
-
10
12,2
No
Docetaxel (140)
19
-
5
4,0
No
Immunomodulating agents based chemotherapy
IL-2 IP (141)
22
19/3
55
18,0
No
IL-2 IP + SC (142)
31
22/9
23
15,0
No
IL-2 IV + SC (143)
29
20/9
7
12,0
No
rINF2b IM (144)
13
-
8
15,5
No
INF2a SC (145)
25
-
12
-
No
INF IP (146)
89
71/18
19
-
No
INF IM (147)
15
-
0
9,1
No
INF + Macrophages IP (148)
17
16/3
12
29,2
No
Mycobacterium vaccae (149)
16
10/6
38
10,5
No
Thalidomide (19)
40
36/4
0
7,7
No
Gefitinib (21)
43
-
4
6,8
No
Imatinib mesylate (22)
25
20/5
0
13,3
No
Erlotinib (25)
63
28/35
0
10
No
21
-
No
Various
MMC (150)
19
11/8
10
Diaziquone (151)
20
-
0
5,9
No
Acivicine (152)
23
5/18
0
7,0
No
Ranpirnase (153)
81
50/55
5
6,0
No
Second line
Doxo (9)
11
3/8
9
4,5
No
ZD0473 (8)
43
-
0
6,7
Yes
Oxaliplatine/Raltitrexed (10)
14
8/6
0
3,2
No
Doxorubicin (11)
Cyclophosphamide
6
5
-
0
-
No
Pemetrexed (13)
Pemetrexed/Carboplatin
28
11
22/6
11/0
21
18
9.8
8.6
No
Pemetrexed (18) versus
Best Supportive Care
123
120
90/33
86/34
18.7%
1.7%
8.4
9.7
Yes
CDDP/Irinotecan/MMC (12)
10
8/2
20
7.3
Yes
Erlotininb/Bevacizumab (154)
24
16/8
0
5.8
No
Belinostat (155)
13
7/6
0
5
No
Vinorelbine (156)
63
39/24
16
9.6
No
CDDP= cisplatin; VBL= vinblastine; INF= interferon; IL-2= interleukin 2; MMC= mitomycin C; Doxo= doxorubicin; Ifo= ifosfamide;
CPA= cyclophosphamide; Bleo= bleomycin; Hyal= hyaluronidase; RR= response rate; QOL = quality of life
References list for the Table 3 on chemotherapy in MPM
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Table 4: EORTC guidelines for therapeutic response assessment with PET (29)
Complete metabolic response complete resolution of uptake within the tumour volume
so that it was indistinguishable from surrounding normal
tissue
reduction of F18-FDG (SUV) tumoural uptake of at least
Partial metabolic response
15-25% after one cycle of chemotherapy and of more than
25% after more than one cycle
24
Stable metabolic disease
Progressive metabolic disease
increase in SUV of less than 25% or a decrease of less
than 15% and no visible extent of tumour uptake (<20% in
the longest dimension)
increase in SUV greater than 25% or a visible increase in
the extent of tumour uptake (> 20% in the longest
dimension) or the appearance of a new metastatic lesion
Table 5: Most common symptoms in malignant pleural mesothelioma
(Nowak AK et al, J Clin Oncol 2004;22(15):3172-80)
Symptom
Dyspnoea
Number of patients
Percentage
with symptom (n=80)
77
96%
Pain
73
91%
Cough
33
41%
Weight loss
33
41%
Anorexia
20
25%
Sweating
14
18%
Nausea
11
14%
Fatigue
10
13%
Dysphagia
9
11%
Constipation
6
8%
Ascites
6
8%
Vomiting
4
5%
Painful metastasis 4
5%