Malignant Mesothelioma – Current Approaches to a Difficult Problem

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Malignant Mesothelioma – Current
Approaches to a Difficult Problem
Raja M Flores, MD
Thoracic Surgery
Memorial Sloan-Kettering Cancer Center
1
Malignant Pleural Mesothelioma
Clinical Presentation
•
•
•
•
•
Insidious and nonspecific
Dyspnea and chest pain
Pleural effusion
Cough
Bilateral involvement ~ 5%
2
Natural Progression
• Blunting costophrenic angle
• Pleura thickens encasing lung
• Pleural rind fixes the lung , diaphragmatic and
intercostal muscles – “Frozen Chest”
• Dyspnea out of proportion to radiologic
findings
• Shunting, hypoxia, Infection, sepsis, death
• Adjacent Structures- Dysphagia, SVC
syndrome, etc.
3
Survival by Presentation
P=0.020
P=0.020
Flores et al JTO, 2007 2(10): 957-65
4
Diagnosis
• Thoracentesis (cytology) (26%)
• Closed pleural biopsy (21%)
• Open pleural biopsy / VATS (98%)
Boutin and Rey, Cancer, 1994
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6
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Versus Adenocarcinoma
Histology
PAS stain
Mucicarmine
Meso
Neg
Neg
Adeno
Pos
Pos
Immunostaining
CEA
LeuM-1
Vimentin
Cytokeratin
Calretinin
Neg
Neg
Pos
Pos
Pos
Pos(75%)
Pos
Neg
Neg
Neg
8
adenocarcinoma
mesothelioma
9
Malignant Pleural
Mesothelioma is NOT a
frozen section diagnosis
10
Problems with Natural History
• Diagnostic problems - newer techniques of
immunohistochemistry and electron
microscopy
• Imprecise staging - Most studies prior to 1985
(No CT scan)
• Lack of a well defined, universally applicable,
staging system
11
T status
• T1- T1a- tumor limited to ipsilateral pleura,
no involvement of visceral pleura
T1b- involvement of visceral pleura
• T2- Involvement of diaphragmatic muscle ,
invasion of lung parenchyma
• T3- Locally advanced but potentially
resectable tumor (i.e. pericardium)
• T4- Locally advanced but potentially
unresectable tumor
Rusch, Chest 1995
12
N status
• N0- no regional lymph node involvement
• N1- Metastasis in the ipsilateral
bronchopulmonary or hilar lymph nodes
• N2- Metastasis in the mediastinal lymph nodes
• N3- contralateral mediastinal or
supraclavicular lymph nodes
Rusch, Chest 1995
13
AJCC Staging System
• Stage I
– Ia
– Ib
• Stage II
• Stage III
• Stage IV
T1aN0M0
T1bN0M0
T2N0M0
Any T3M0
Any N1M0
Any N2M0
Any T4
Any N3
Rusch, Chest 1995
Any M1
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Surgical Options
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•
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Observation
Talc Pleurodesis
Palliative pleurectomy
Pleurectomy/Decortication
Extrapleural Pneumonectomy
30
Supportive care only
Law
Hulks
Ruffie
Lewis
# patients
64
68
176
14
median survival (mo.)
18
7.0
6.8
9.6
31
To treat or not to treat ?
Nihilistic view stems from:
1. Misconception about surgical mortality with
extrapleural pneumonectomy
2. Poor overall survival based upon old
retrospective studies on heterogeneous patient
populations
3. Lack of experience with this uncommon
malignancy
32
Surgical History
• 1976 – Butchart, Thorax, 31% mortality with EPP
• Dismal survival in surgically treated patients. Median
survival of 6 months
– Poor patient selection
– Technique
– Diagnosis and Staging (no immunohistochemistry
or EM)
– Imaging ( No CT scan)
33
Mortality of Extrapleural Pneumonectomy
# of patients
Balmer
Butchart
Faber
Rusch
Sugarbaker
Flores
1974
1976
1994
1999
1999
2007
17
29
40
115
183
208
Op. Mortality
23%
31%
8%
5%
4%
5%
34
Results in 115 EPP and 59 P/D
Stage I
Stage II
Stage III
Stage IV
Median survival (mo.)
30
19
10
8
• Poor prognostic factors
– Advanced T status
– Advanced N status
– Nonepithelial histology
Rusch, Ann Thorac Surg, 1999
35
Results in 183 EPP (prognostic variables)
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•
•
•
•
Epithelial Histology
N2 Status
“Resection margins”
68% 2-year , 46% 5-year survival
31 patients with epithelial histology, negative
N2 nodes, and “Negative Margins” 51 month
median survival
Sugarbaker, Flores , et al, JTCVS 1999
36
Surgical and Multimodality Rx:
Initial experience
• 1939-1981
• 170 patients with pleural mesothelioma
– Epithelioid - 102
– Sarcomatoid – 47
– Benign - 21
• Surgery- Pleurectomy
• Additional therapy
– Adjuvant chemotherapy (cyclophosphamide,
adriamycin)
– Radiation (external beam, I125 seeds)
• Survival
– epithelioid – MS – 21, Sarcomatoid – MS – 12
McCormack et al. JTCVS 84:834-842, 1982
37
Brachytherapy and External Beam
Radiotherapy
• 1976- 1988
• Total 105 patients
• Surgery - Pleurectomy
– 54 patients – implants and external beam (192Ir,
32P)
– 41 patients – external beam
• Survival
– Radioactive implants : MS- 9.9 months
– No radioactive implants: MS- 22.5 months
• Local failure
Myhalchek et al Endocurie Hypertherm Oncol 1989;5:245 abstr
38
Intrapleural Cisplatin
• 1989 – 1992
• 36 patients enrolled
• 28 had pleurectomy and IP (Cisplatin
100mg/m2 and mitomycin8mg/m2)
• 23 patients had IP and systemic chemotherapy
• Extrapleurals were excluded
Rusch et al. J Clin Oncol 1994, 12:1156-1163
39
• MS – 17 months
• Complications
– 1 postoperative death (UGI bleed, then MSOF)
– 2 grade 4 renal failure
– 1 postoperative hemorrhage requiring a
pneumonectomy
– 1 myocardial infarction
40
• Feasible
• Potential for serious toxicity
• Local control remains the main problem (80%)
41
Phase I Trial
• Sugarbaker – 44/61 patients found to be
resectable. Pleurectomy/Decortication and 1
hour cisplatin lavage. Dose escalation study
(50-250).
• Operative Mortality – 11%
• Overall Median survival – 13 months
• Epithelioid – 19 months
Richards,2006 JCO;24:1561-1567
42
Local control
•
•
•
•
•
•
Brachytherapy
Photodynamic therapy
Postoperative Intrapleural chemotherapy
Intraoperative hyperthermic chemotherapy
Immunotherapy
Gene therapy
• Surgery is the Foundation
43
Pattern of Recurrence
• Baldini et al. Ann Thorac Surg 1997
– 46 patients extrapleural pneumonectomy, CAP
chemotherapy, external beam radiotherapy (3000
Gy)
– Most common site of recurrence was locally,16
patients (35%) total. 67% of all recurrences
• Problem – Local recurrence after surgical
resection.
44
Local Control
• Rusch et al. A phase II trial of surgical resection
(EPP) and high dose radiation for malignant
pleural mesothelioma.
JTCVS 2001:122:788-95
• 54 Gy to hemithorax
• 54 patients underwent EPP and adjuvant
radiation.
45
Local control
• Locoregional only – 2
• Distant only – 30
• Locoregional and distant – 5
• Adequate local control (~ 10%) achieved with
EPP and high dose adjuvant radiotherapy
(5400)
46
Induction chemotherapy followed by EPP and
high dose radiotherapy
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•
•
•
•
•
2002-2003
19 patients with stage III-IV disease
Gemcitabine and cisplatin 4 cycles
Repeat radiologic imaging
Extrapleural pneumonectomy
High dose external beam radiation (5400 rads)
Flores et al. J Thorac Oncol 2006:289-295
47
48
Pemetrexed (ALIMTA)
• Multi-targeted antifolate
• Vogelzang et al, JCO
• Phase III study comparing Premetrexed/Cisplatin
versus cisplatin alone.
• 448 patients randomized
• Primary endpoint: survival
• 80% power to detect a hazard ration of .67 based
upon alpha= 0.05, 2 sided logrank test
49
Pemetrexed (ALIMTA)
• Overall survival improved 12.1 versus 9.3
months
• Overall response rate 41% versus 17%
• Improved pulmonary function tests
• Improvement in dyspnea and pain
50
Current Multimodality Approach
“Locally advanced”
(T3 or N2)
Induction Chemotherapy
Extrapleural Pneumonectomy
Hemithoracic Radiation
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60
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Flores RM, J Ped Surg 2006: 1738-42
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Surgical pitfalls and considerations
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•
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•
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Not mesothelioma
Subclavian vessels
Vena cavae
Aorta and intercostal branches
Esophagus
Intrapericardial left, beware of main PA
Recurrent laryngeal
Cardiac tamponade
Cardiac herniation
Not repairing diaphragm, keep diaphragm low
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DSC_0766
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DSC_0763
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DSC_0760
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DSC_0773
73
DSC_0774
74
DSC_0778
75
DSC_0785
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DSC_0818
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DSC_0795
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EPP versus P/D in MPM
•
•
•
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•
From 1990-2006, 663 consecutive patients
Memorial Sloan-Kettering – n=448
National Cancer Institute
– n=96
Karmanos Cancer Institute – n=119
Median Follow up – 17 months
Flores et al JTCVS, 2008 135: 620-6
79
EPP (n=385) P/D (n=278) p-value
Age (mean)
60
63
<0.001
Male Gender
316 (82%)
220 (79%)
0.267
Epithelioid Histology 269 (69%)
178 (64%)
0.090
Early Stage (I + II)
96 (25%)
98 (35%)
<0.001
80
Results
• Mortality
– EPP 7% (n=27/385)
– P/D 4% (n=13/278)
81
Proportion Surviving
0.25
0.50
0.75
1.00
Survival by Histology
0.00
p<0.001
0
20
40
60
Months
Epithelioid n=447 MS−16
Non−epithelioid n=216 MS−9
82
0.25
0.50
0.75
1.00
Survival by AJCC Stage
0.00
P<0.001
0
20
40
60
Months
stage I n=52 MS−38
stage III n=411 MS−11
stage II n=142 MS−19
stage IV n=58 MS−7
83
0.25
0.50
0.75
1.00
Survival by Procedure
0.00
P<0.001
0
20
40
60
Months
P/D n=278 MS−16 months
EPP n=385 MS−12 months
84
0.25
0.50
0.75
1.00
Stage I
0.00
p=0.20
0
20
40
60
Months
85
0.25
0.50
0.75
1.00
Stage II
0.00
p=0.45
0
20
40
60
Months
86
0.25
0.50
0.75
1.00
Stage III
0.00
p=0.47
0
20
40
60
Months
87
0.25
0.50
0.75
1.00
Stage IV
0.00
p=0.08
0
20
40
60
Months
88
Multivariate Model
Hazard
Ratio
Confidence
Interval
p value
EPP
1.2
(1.0, 1.4)
p=0.04
Non-epithelioid
1.5
(1.3, 1.8)
p<0.001
Stage III/IV
1.9
(1.6, 2.3)
p<0.001
89
Conclusions
• Diagnosis requires special stains / EM
• Surgical mortality for EPP acceptable
• EPP and P/D similar survival – type of surgery
dictated by intra-operative findings
• If an R1 resection is not possible with P/D then
an EPP is the procedure of choice
• If an R2 resection is inevitable at surgical
exploration then an EPP should not be
performed
• Decision about procedure type should consider
multimodality therapy and protocol options
90
Patterns of Recurrence
Local Recurrences
Ipsilateral chest
Pericardium
Distant Recurrences
Contralateral lung/pleura
Peritoneum
Peritoneum + chest
Abdominal viscera
Bone
Brain
Cutaneous (distant)
Other
EPP (n=219)
n (%)
73 (33%)
68 (31%)
5 (2%)
146 (66%)
49 (22%)
57 (26%)
17 (8%)
12 (5%)
7 (3%)
1
1
2
P/D (n=133)
n (%)
86 (65%)
84 (63%)
2 (2%)
47 (35%)
14 (11%)
24 (18%)
1
4 (3%)
1
1
2 (2%)
91
92
Patient Characteristics
Median Age 63 (range 26-93)
Men/Women
Laterality
Right/Left
History of asbestos
Histology
Epithelioid
Non-epithelioid
AJCC Stage
I + II
III + IV
Adjuvant Therapy
Chemotherapy
Radiotherapy
Both
n (%)
536 (81%) / 127 (19%)
390 (59%) / 273 (41%)
380 (57%)
447 (67%)
216 (33%)
194 (29%)
469 (71%)
186 (28%)
152 (23%)
89 (14%)
93
• The optimal procedure for surgical
resection is controversial
• Studies fail to demonstrate significant
differences in survival due to small
numbers of patients
• A multi-institutional study was
performed to increase statistical power
94
Role of EPP
• 1985-1988
• Lung cancer study group: multi-institutional trial
• 83 patients
– Potentially completely resectable disease by CT
– FEV1 > 1
– Medically suitable
• EPP -20, P/D - 26, limited or no resection - 37
Rusch et al JTCVS 1991;102:1-9
95
Systemic control
• Chemotherapy
– Carboplatin / taxol (ineffective)
– Cyclophosphamide, adriamycin, cisplatin (CAP)
(ineffective)
• Byrne et al, JCO, 1999
– Gemcitabine and cisplatin
– 21 patients
– 4 cycles
– 47% response rate
96
Role of EPP
• Recurrence free survival best for EPP
• Overall Survival (p>0.05)
– EPP: MS - 14 mos.
– P/D: MS - 10 mos.
– No surgery: MS - 7 mos.
• EPP better at local control but still not great, and
systemic disease is seen in more cases
Rusch et al JTCVS 1991;102:1-9
97

Malignant Mesothelioma – Current Approaches to a Difficult Problem

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