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Malignant pleural mesothelioma _MPM_

VIEWS: 2 PAGES: 70

  • pg 1
									  ASCO 2012
Aggiornamento
 Mesotelioma

           Federica Grosso
           fgrosso@ospedale.al.it
 “mesothelioma” : 19 abstracts

Cathegory                                    Session type
(sub-cathegory)
                            Poster discussion General poster Abstract book


Lung cancer                        3               11             3
(mesothelioma)
Tumor biology                                       1
(molecular diagnostic and
imaging)
Cancer                                              1
prevention/epidemiology
(cancer genetics)
Cancer prevention/epidemiology


          Cancer genetics
Clinical characteristics of patients with malignant
pleural mesothelioma (MPM) harboring somatic BAP1
mutations.
Marjorie Glass Zauderer, et al; Memorial Sloan-Kettering Cancer
Center, New York, NY
J Clin Oncol 30, 2012 (suppl; abstr 1541)

 BRCA1    associated  protein-1   (ubiquitin carboxy-terminal
 hydrolase) is a deubiquitinating enzyme that in humans is
 encoded by the BAP1 gene.

 plays a key role in chromatin by mediating deubiquitination of
 histone H2A and HCFC1

 Defects in BAP1 are a cause of tumor predisposition syndrome
 (TPDS) characterized by predisposition to develop a variety of
 tumors, including benign melanocytic tumors as well as several
 malignant tumors, including uveal melanoma, cutaneous
 melanoma, malignant mesothelioma on exposure to asbestos,
 lung adenocarcinoma and meningioma
      Somatic   inactivating
      mutations in BAP1 in
      23% of 53 MPMs




Nat Genet. 2011 Jun 5;43(7):668-72
        Germline mutations in
        the gene encoding
        BAP1 in two families
        with a high incidence
        of mesothelioma, and
        somatic alterations
        affecting BAP1 in
        familial mesotheliomas




Nat Genet. 2011 Aug 28;43(10):1022-5
                        121
                        20%




% of current/former smokers but no other clinical feature was
significantly different among those with and without BAP1
mutations
No correlations with NF2 mutation and p16 deletion in 53 pts
analyzed
Further efforts to evaluate the features of germline mutations and
therapeutical implications
    tumor biology


molecular diagnostic and imaging
Novel malignant-mesothelioma-associated antigens
(Gene-X and THBS-2) in the diagnosis of malignant
pleural mesothelioma (MPM).
Fumihiro Tanaka, et al; Japan
J Clin Oncol 30, 2012 (suppl; abstr 10585)


                                Gene-X
                                and
                                thrombospondin-2
                                (THBS2/antiangiogenetic)
                                are novel
                                mesothelioma-related
                                antigens
                                recognized      by    tumor
                                infiltrating B cells.



                        Cancer Sci. 2009 Jul;100(7):1326-34
Novel malignant-mesothelioma-associated antigens
(Gene-X and THBS-2) in the diagnosis of malignant
pleural mesothelioma (MPM).
Fumihiro Tanaka, et al; Japan
J Clin Oncol 30, 2012 (suppl; abstr 10585)


 120 pleural biopsy suspicious for MPM: 97 MPM and 27 NM




 The antibody-titers against Gene-X and THBS-2 in the sera were
 measured by ELISA method.
The serum antibody-titer against THBS-2 was significantly higher
in MPM patients than in NM (P<0.01), but there was no
difference in the serum antibody-titer against Gene-X




The serum antibody-titer against THBS-2 can be a useful non-
invasive marker in the diagnosis of MPM.
  Lung Cancer
poster duscussion

    mesothelioma
Comparison of prognostic impact between metabolic
and radiologic response after induction chemotherapy
for resectable malignant pleural mesothelioma: A
multicenter study.
Yasuhiro Tsutani, et al; Japan
J Clin Oncol 30, 2012 (suppl; abstr 7031)

 Induction  CT    EPP    for   resectable   malignant   pleural
 mesothelioma (MPM) is controversial.

 To select optimal candidates for EPP, based on metabolic
 response on FDG-PET vs radiologic response on HRCT after
 induction chemotherapy in pts with resectable MPM who
 underwent EPP in the setting of multicenter study

 HRCT and FDG-PET before and after induction platinum-based
 chemotherapy

 50 patients with clinical T1-3 N0-2 M0 MPM who underwent EPP
 ± postoperative hemithoracic radiation.

 ↓> 30% in SUVmax=metabolic responder.
Radiologic response using modified RECIST      or   metabolic
response and surgical results were analyzed




14 metabolic responders (28%) vs 36 non-responders (72%).
mOS = 20.5 month (15.0-26.0 CI95%).




                                 mOS for met-resp=
                                 not reached
                                 OS@3yrs 60.0% vs
                                 OS@3yrs 26.5% for
                                 non-resp
No correlation between OS and radiologic response

mOS for 20 radiologic responders = 25.7 month (14.5-37) and
OS@3yrs 35.8% vs OS@3yrs 35.1% for 30 non-responder (p =
0.216).

decreased SUVmax (%) (p = .010) was a significantly
independent factor for OS as well as epithelioid subtype
(p = 0.044).

Metabolic response on FDG-PET has higher predictive value of
prognosis than radiologic response on HRCT after induction
chemotherapy for patients with resectable MPM.
Patients with metabolic responder and/or epithelioid subtype can
be good candidates for EPP after induction chemotherapy.
Randomized phase II trial of pemetrexed/cisplatin with
or without CBP501 in patients with advanced malignant
pleural mesothelioma (MPM).
Lee M. Krug, et al; USA-Mexico-Russia
J Clin Oncol 30, 2012 (suppl; abstr 7029)
Randomized phase II trial of pemetrexed/cisplatin with
or without CBP501 in patients with advanced malignant
pleural mesothelioma (MPM).
Lee M. Krug, et al; USA-Mexico-Russia
J Clin Oncol 30, 2012 (suppl; abstr 7029)

 CBP501, a synthetic duodecapeptide, enhances the cytotoxicity
 of DDP in cell lines and xenografts, including NCI-H226 human
 mesothelioma

 CBP501 increases DDP influx into tumor cells through an
 interaction with calmodulin, and inhibits cell cycle progression by
 abrogating DNA repair at the G2 checkpoint

 Phase I trials CBP501+DDP alone or with Pem: acceptable safety
 profiles and suggested activity

 most common toxicity is infusion-related urticaria, managed with
 diphenhydramine
2:1 to Arm A: Pem/DDP + CBP501 25 mg/m2 IV (42 pts
planned), or Arm B: p Pem/DDP alone at standard doses (21 pts
planned).

63 pts: characteristics similar in the 2 arms; median age 65,
82% male, 71% epithelioid histology, 8% PS2.

Grade 3/4 treatment-related toxicities were uncommon, no
different than expected from standard chemotherapy, and
comparable in the two arms.

70% of patients treated with CBP501 had infusion reactions, all
grade 1-2.
Amatuximab, a chimeric monoclonal antibody to
mesothelin, in combination with pemetrexed and
cisplatin in patients with unresectable pleural
mesothelioma: Results of a multicenter phase II clinical
trial.
Raffit Hassan, et al; USA-Germania
J Clin Oncol 30, 2012 (suppl; abstr 7030)

 Amatuximab (MORAb-009) is a chimeric monoclonal antibody to
 mesothelin, a cell surface glycoprotein highly expressed in many
 cancers including malignant mesothelioma (MM)

 phase II study of amatuximab +Pem/DDP in unresectable
 epithelial or biphasic pleural MM, no prior chemotherapy and KPS
 > 70%

 Amatuximab 5 mg/kg days 1 and 8 +P 500 mg/m2 and C 75
 mg/m2 (PC) given on day 1, of each 21 day cycle for 6 cycles.

  Pts. with OR/SD received amatuximab monotherapy until
 disease progression.
Primary endpoint = PFS at 6 months; Secondary endpoints =
OS, RR and safety

2/2009-10/2010: 89 pts at 26 sites.

median age 67 (46-80) yrs; 78% M, 70% KPS >90%, 89%
epithelial, 11% biphasic and 88% stage III/IV disease.

Median No of PC + amatuximab cycles = 5 (1-6); 56 (63%)
pts. received single agent amatuximab.
hypersensitivity reactions 12.4%; Grade 3/4=4.5%
13 pts. receiving maintenance amatuximab

Amatuximab + PC was well-tolerated in this study with 90% of
pts. having DC by independent radiological review.

Although PFS is not significantly different from historical results
of PC alone, the median OS is 14.5 months

Biomarker for activity and efficacy
 Lung Cancer
general poster

   mesothelioma
 IFCT-GFPC-0701 MAPS trial, a multicenter randomized
 phase III trial of pemetrexed-cisplatin with or without
 bevacizumab in patients with malignant pleural
 mesothelioma (MPM).
 Gerard Zalcman, et al; France
 J Clin Oncol 30, 2012 (suppl; abstr TPS7112)


   Author          Regimen      Phase       Status     N pts     RR/DCR         PFS       OS


Kindler et al.    Cis/Gem/Bev                           53     24.5% / 75.5%   6.9 mo   15.6 mo
                                 II R      Completed
JCO 2012          Cis/Gem/Pla                           55     21.8% / 81.8%   6.0 mo   14.7 mo


Dowell et al.     Cis/Pem   +
                                   II      Completed    43      43% / 81%      6.9 mo   14.8 mo
IASLC 2009        Beva


Ceresoli et al.   Carbo/Pem +
                                   II      Completed    77      40% / 88%      7.9 mo   14.3 mo
IMIG 2010         Beva


 Zalcman et                                                       57.4%
 al.              Cis/Pem/Bev   II R-III    Phase II
                                                        47        45.7%         NR        NR
                  Cis/Pem/Pla      R       completed
 ASCO 2010                                                     (DCR at 6 mo)
IFCT-GFPC-0701 MAPS trial, a multicenter randomized
phase III trial of pemetrexed-cisplatin with or without
bevacizumab in patients with malignant pleural
mesothelioma (MPM).
Gerard Zalcman, et al; France
J Clin Oncol 30, 2012 (suppl; abstr TPS7112)

 Gem+CDDP, +/- bevacizumab, gave an appealing 15.6 months
 median OS in the bevacizumab arm.

 French Intergroup aimed to test Pem+CDDP +/- bevacizumab
 (PCB), in a randomized phase III trial.

 unresectable histologically proved MPM, no prior chemo, PS 0-2,
 no thrombosis, nor bleeding.

 Primary endpoint: OS; Secondary endpoin: PFS

 Pem 500 mg/m2, CDDP 75 mg/m2 (PC),at D1, and vitamin B12
 +B9 substitution, with (arm B) or without bevacizumab (arm A),
 15 mg/kg Q21D, for 6 cycles.
Arm   B   nonprogressive     patients   received     bevacizumab
maintenance therapy until progression or toxicity.

445 patients to be recruited during a period 48 months, with at
least 24 months fup, and 385 events (deaths), will be needed to
assure a power of 80% and detect at least a 4.3 months of
median survival increase.

Accrual status: 2.2008-1.2012, 257 patients from 85 French
centers had been enrolled. The end of accrual can be expected
for September 2013.

Ancillary  studies:    molecular    biomarker  analyses   on
thoracoscopic tissue specimens (TS, ERCC1, MSH2, TUBB3, NF2,
p16, RASSF1A methylation,15 microRNAs ) and blood samples
(micro-RNAS, VEGF, osteopontin, SRMP)at diagnosis

prospective study comparing PET-CT to standard CT with central
blinded analysis for evaluation of response, and accuracy of
modified RECIST criteria for mesothelioma.
Phase II study of bortezomib with cisplatin as first-line
treatment of malignant pleural mesothelioma (MPM):
EORTC 08052.
Mary O'Brien, et al; EORTC
J Clin Oncol 30, 2012 (suppl; abstr 7081)


 DDP = most active drug in MPM (Berghmans T, Lung Cancer.
 38(2), 111-21 2002)

 Bortezomib = some activity in single agent phase II

 phase II study of Cisplatin and bortezomib (CB) in the first line
 treatment of MPM.

 histological proven MPM, with performance status (PS) 0/1, were
 eligible. The doses were cisplatin 75mg/m2 /3 wks and
 bortezomib 1.3mg/m2 day 1, 4, 8, 11 every 3 wks.
2007-2010 82 patients; mFUP 32.3 months

median age 55 years (range: 22-77yrs), M/F: 55/27 , PS 0/1:
9/73, Stage T1: 10%; T2: 42%, T3: 25%; T4: 23% and N0:
57%; N1: 4%; N2: 33%; N3: 6%.

median number of cycles = 4; 38% received 6 cycles.

Toxicity: Grade 3/4 neutropenia 10%, thrombocytopenia 11%,
anaemia 1%.
Grade 3-4 hyponatraemia 46 - hypokalaemia       17%. Grade 2
tinnitus = 16%, grade 3 fatigue = 12%
2 toxic deaths at 32 and 74 days due to acute pneumonitis and
cardiac arrest.
            Bortezomib + Cisplatin: a phase II study
                   PRIMARY ENDPOINT: PFSR-18 >50%




                                                    77.8%




OS 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%)
alive at 1 year.

On the basis of the PFRS-18, the null hypothesis could not be
rejected, although CB gave predictable toxicity and was as active
as other reported regimens in MPM.
Phase II trial of BNC105P as second-line chemotherapy
for advanced malignant pleural mesothelioma (MPM):
Australasian Lung Cancer Trials Group and NHMRC
Clinical Trials Centre Collaboration.
Anna K. Nowak, et al; Australia
J Clin Oncol 30, 2012 (suppl; abstr 7079^)

 BNC105P is a tubulin polymerization inhibitor that acts as a
 Vascular Disrupting Agent (VDA), has direct cytotoxic effects,
 and had preclinical and phase I activity in MPM.

 Aim: activity and safety of BNC105P as second-line therapy after
 pemetrexed and a platin in MPM.

 Inclusion: progressive MPM, prior pemetrexed and platinum,
 measurable disease by modified RECIST, ECOG 0-1, adequate
 organ and cardiovascular function.

 Exclusions:   recent    thromboembolic,      cardiovascular   or
 cerebrovascular disease, or therapeutic anticoagulation.
BNC105P 16 mg/m2 IV Day 1 + 8 q21d until progression or
toxicity.

Primary endpoint= centrally reviewed RR


                                30 pts:
                                90% M
                                median age 65 (41-83)
                                PS ECOG 1 77%
                                Histology: Epit 67%, biph
                                10%; sarc 7%, other 17%
                                at least 1 dose of study drug;
                                median no 2 cys
No significant haematologic, biochemical, peripheral neurotoxic
or cardiac adverse events (AEs) including hypertension were
observed. Grade 3 or 4 AEs occurred in 10 pts (33%). There
were 2 deaths on study: 1 due to stroke, the other due to
pneumonia and respiratory failure.

BNC105P was safe and tolerable but its single agent response
rate failed to meet the pre-specified primary endpoint of
interest.
NGR-hTNF as second-line treatment in malignant
pleural mesothelioma (MPM).
Gloria Rossoni, et al; Molmed
J Clin Oncol 30, 2012 (suppl; abstr 7076)

NGR-hTNF exploits the asparagine-glycine-arginine (NGR)
peptide for selectively targeting tumor necrosis factor (TNF) to
cancer endothelial cells.

Tumor hypervascularity is an independent predictor of poor
overall survival (OS) in MPM patients (pts).

long-term results of a phase II trial that assessed NGR-hTNF in
MPM pts with performance status (PS) ≤ 2 and radiologic
progressive disease (PD) after a pemetrexed-based regimen.

NGR-hTNF was given at 0.8 g/m2 every 3 weeks (q3w) in 43
pts and weekly (q1w) in 14 pts.

Primary endpoint = PFS; Secondary endpoint: DC rate and OS +
Impact on outcome NLR at baseline
mFUP 32.5 mm (95% CI 27.5-
37.5).

n=57: median age 57 years; M/F
35/22; PS 0/1-2 31/26; EORTC

Common grade 1/2 AEs transient
chills (75%); No higher toxicity
was reported using the q1w
schedule.

mPFS = 2.8 mm (2.2-3.3). DC =
46% (32-59; 26/57 pts);

OS rates at 1 and 2 years were
47% and 16%, respectively.

mOS>in pts with DC vs early PD
(16.2 and 8.3 months; p=.02).

6-month PFS: 11% and 36% for
q3w and q1w, respectively.
By Cox analyses, a PS of 0
(p=.01) and a low baseline NLR
(p=.004) were the only variables
associated with improved OS.

Median OS in pts stratified by NLR
≤ 2, 3 to 4, and ≥ 5 were 15.7,
10.5,     and     4.2      months,
respectively (p=.0002 for trend).

A double-blind phase III trial is
currently testing best investigator
choice ± NGR-hTNF q1w in
pemetrexed-pretreated MPM pts
(NCT01098266).
SWOG 0722: A phase II study of mTOR inhibitor
everolimus (RAD001) in malignant pleural
mesothelioma (MPM).
Linda L Garland, et al; USA
J Clin Oncol 30, 2012 (suppl; abstr 7083)

 MPM preclinical studies demonstrate activation of AKT pathway
 proteins, including mTOR, and provide the rationale to test
 everolimus, an mTOR inhibitor

 Unresectable MPM patients after 1-2 systemic regimens
 (including a platinum-based regimen), with PS 0-1, measurable
 disease and adequate organ function were treated with daily oral
 everolimus 10 mg.

 PFS at 4 months, response rate, overall survival (OS), and
 frequency/severity of toxicities.

 61 pts between 12/2008 and 9/2011; 57 evaluable pts for the
 primary endpoint of 4-month PFS.
57 evaluable pts: RR 0% by standard RECIST and DCR of 14/35
(40%); data by mod RECIST are not yet available.

Estimated 4-mm PFS 36% (23-48%); median PFS of 3 (2-4)
mm.

Median OS is estimated at 6 months (4-8; 4 deaths).
Frequent grade 1-3 toxicities were fatigue (55.4%),
hypertriglyceridemia (41.1%),   anemia    (39.3%),   nausea
(33.9%), oral mucositis (32.1%), anorexia (32.1%), diarrhea
(26.8%), and hyperglycemia (26.8%). One pt each had grade 4
and grade 5 dyspnea.

The trial did not achieve the primary endpoint            of   an
improvement of PFS at 4 months from 30% to 50%.

Inhibition of mTOR using single agent everolimus is not active in
unselected MPM patients.

Other strategies for targeting the activated AKT pathway in MPM
remain of interest.
Phase II trial of anti-transforming growth factor-beta
(TGFß) monoclonal antibody GC1008 in relapsed
malignant pleural mesothelioma (MPM).
James Stevenson, et al; USA
J Clin Oncol 30, 2012 (suppl; abstr 7077)


TGFβ is a pleiotropic cytokine overexpressed by MPM with a key
role in promoting growth and progression of MPM

Anti-TGF-beta monoclonal antibody GC1008 binds to the protein
transforming growth factor-beta (TGFß) and may block the
growth of cancer cells that make it. (kidney cancer, melanoma,
and pulmonary fibrosis)

phase II trial of GC1008 in progressive MPM pts.

Inclusion: progressive MPM; PS 0-1 with 1-2 prior systemic
therapies (at least 1 pemetrexed-based)

GC1008 3mg/kg IV over 90 minutes every 21 days.
Primary endpoint PFS rate at 3 mm; Secondary objectives:
safety with GC1008, RR by modified RECIST, TTP and OS

13 pts (10 PS 0; 3 PS 1) with MPM (median age 69; 2F, 11M; 11
epithelial, 1 sarcomatoid, 1 biphasic)

toxicities G1/2 fatigue (3 pts), nausea (1 pt) and xerosis (1 pt).
Possibly related to GC1008 rapid disease progression in 1 pt
after 2 cycles, and G2 skin keratoacanthoma in 1 pt after 5
cycles.

3 pts met the primary objective of 3 month PFS at 4.1, 4.2 and
9 months each; SD 3 pts (23%).

Median TTP is 1.4 months (95% CI 1.2-∞); median OS is 13
months (95% CI 6-∞).

Increased serum mesothelin levels have closely tracked disease
progression.
Serum from 6/13 pts showed new antibodies against MPM tumor
lysates as measured by immunoblotting. Two of 3 pts with SD
had anti-tumor antibody responses.

Mean baseline plasma level of TGFβ was 2447 pg/ml but did not
correlate with TTP.

GC1008 was well tolerated in pretreated MPM patients. SD
occurred in 3 pts, all with prior disease progression. Evidence for
humoral anti-tumor immunity was seen in nearly half of
enrollees and in 2 of 3 pts with SD.

OS compares favorably        to   prior   single-agent   studies   in
pretreated MPM.

…
Malignant pleural mesothelioma (MPM) in elderly
patients:multicenter survey.
Federica Grosso, et al; Italy
J Clin Oncol 30, 2012 (suppl; abstr 7082)

 To evaluate OS of elderly MPM patients (4 centers in North Italy)
 To evaluate factors affecting OS
 Retrospective analysis of the clinical records of MPM pts
 aged≥70 observed from January 2005 to November 2011.
 Collected variables: standard + Charlson Comorbidity Index
 (CCI),treatment modalities.
 CCI is a method for classifying comorbid conditions which might
 alter the risk of mortality. It considers 22 conditions with a score
 of 1,2,3 or 6 depending on the associated risk of dying.
 1 each: myocardial infarct, congestive heart failure, peripheral vascular disease, dementia,
 cerebrovascular disease, chronic lung disease, connective tissue disease, ulcer, chronic liver
 disease.
 2 each: hemiplegia, moderate or severe kidney disease, diabetes, diabetes with
 complications, tumor, leukemia, lymphoma.
 3 each: moderate or severe liver disease.
 6 each: malignant tumor, metastasis, AIDS.
 The scores are summed up and the total score predicts mortality
 (Charlson ME, et al. J Chronic Dis. 1987;40(5):373-83)
Demographics (N=210)
Variable                                                   N. of pts             % of pts
Age                                                              Median 75 (range 70-92)
≥ 75 yrs                                                      111                  53%
≥ 80 yrs                                                      46                   22%
Gender
M                                                              132                              63%
F                                                              78                               37%
Asbestos exposure
Occupational                                                    82                              39%
Environmental                                                   90                              43%
Uncertain                                                       16                              8%
Not documented                                                  22                              10%
PS ECOG
0                                                              130                                62
1                                                              67                                 32
2                                                               9                                 4
Unknown                                                         4                                 2
Diagnosis
Histological                                                   198                                94
Cytological only                                                5                                 2
Clinical-radiological only                                      7                                 4
Histology
Epithelial                                                     140                                67
Mixed                                                          27                                 13
Sarcomatoid                                                    27                                 13
Unspecified/unknowna                                           16                                 7
a) 5 pts histological diagnosis and unspecified subtype; 4 cytology only; 7 clinical/radiological diagnosis only.
CCI

CI score   N. of pts          % of pts
0             128      CI =0 (n=128), 61%
1              7       CI ≥ 1 (n=79), 38%
2             11
3              2
4             31       CI ≥ 4 (n=59), 28%
5             18
6              3
7              1
8              0
9              5
10             1
Unknown        3
First line chemotherapy

Treatment                       N. of pts   %
All                                169      80
Multimodality treatment (MMT)       16       7
Chemotherapy (CT)                  153      73
Pemetrexed (PMT)based              150      71
PMT single agent                    21      10
PMT+carboplatin                    103      49
PMT+carboplatin+bevacizumab         16       7
PMT+cisplatin                       10       5
Other                               19       9
First line chemotherapy:
Response Rate
               CR

                     PR
         PD



                    SD




        RESPONSE RATE
      OR (CR+PR)         = 24%
      SD                 = 35%
      DCR (OR+SD)        = 59%
Overall Survival
           157 dead and 53 alive at the time
           of the analysis.

           Median OS   = 11.0 months
           Range       = 0.20 - 68.77
HR in the multivariate model

Variable                  HR (CI 95%)        P value
Charlson                 1.15 (1.07;1.23)    <0.001
Histology (E vs non E)   0.56 ( 0.40;0.79)   <0.001
Pemetrexed (Y vs N)      0.39 (0.27;0.57)    <0.001
Age                      1.07 (1.03;1.11)    <0.001
         OS by PMT treatment




          PMT                     PMT+DDP/CBDCA




                                  PMT single agent
NO PMT
                         NO PMT
                OS by CCI




CCI=0




                            CCI=1-3
        CCI≥1                         CCI=0
                        CCI≥4
OS by Age           OS by histology




                                 Epithelioid


           Age<75


  Age≥75

                     Non Epithelioid
Conclusion
In this retrospective survey on a population of 210 elderly
MPM pts, absence of comorbidity (CCI=0) was a strong
prognostic factor for survival.

PMT-based chemotherapy was feasible. With the clear
limitation of a retrospective analysis, PMT based
chemotherapy was associated with a survival advantage in
the multivariate analysis.

Epithelioid histology and age <75 years were related to a
better survival, as expected.

Prospective dedicated trials in elderly MPM pts selected
according to comorbidity scales are warranted.
Outcomes of sarcomatoid malignant pleural
mesothelioma, a distinct clinical entity.
Elisabetta Gattoni, et al; Italy
J Clin Oncol 30, 2012 (suppl; abstr 7084)


 To assess the clinical outcome of SARCOMATOID MALIGNANT
 PLEURAL MESOTHELIOMA (SMPM) treated at our oncological
 department, located in a highly asbestos polluted geographic
 area.

 672 patients (1993 and 2010)

 53 (8%) SMPM patients (17 females, 36 males)
Predominant symptom                     N pts (%)
    thoracic pain                       34 (64)
    dyspnea                             16 (31)
    fatigue and weight loss             2 (4)
    palpable mass                       1 (1)


Predominant radiological finding
      diffuse pleural thickening        23 (43)
      pleural effusion                  14 (26)
      pleural thickening and effusion   10 (19)
      localized mass                    4 (8)
      unknown                           2 (4)
Treatment
1st line chemotherapy


                                 Pts n 48 (%)
     Platinum + pemetrexed       29 (61)
     pemetrexed                  8   (17)
     cisplatin and raltitrexed   3   (6)
     cisplatin and               3   (6)
     gemcitabine
     gemcitabine                 2   (4)
     doxorubicin based           3   (6)
     combination
Treatment
1st line chemotherapy

CT median number of cycles = 4                             SD
                                                           PD
                                                           NE


Overall response rate



11 SD (21%) - 31 PD (58%)
6 (11%) not evaluable for response.

Median progression free survival = 3.3 months (95%CI 2.6 - 4.1)
Median OS was 7.6 months
SMPM accounts for 8% of patients in our series, in line with the
literature

To our knowledge this is the largest series of SMPM analyzed for
clinical features and treatment outcomes

The commonest symptom at presentation was chest pain and
the commonest radiological sign diffuse pleural thickening

standard CT has a negligible activity (SD 21% - NO responses)

OS slightly better than that reported for this histological
subtype. Early diagnosis?

SMPM patients should ideally be treated with investigational
agents within phase I-II studies.

There is an highly unmet clinical need in this setting and new
drugs with novel mode of action are eagerly awaited.

…..
Circulating tumor cell (CTC) as a significant clinical
marker in epithelioid-type malignant pleural
mesothelioma (MPM).
Kazue Yoneda, et al; Japan
J Clin Oncol 30, 2012 (suppl; abstr 7080)

 Circulating tumor cell (CTC) is a surrogate of distant metastasis,
 and our preliminary study suggested that CTC detected by an
 EpCAM-based        immuno-magnetic         separation     system
 (“CellSearch”) was a useful clinical marker in the diagnosis of
 malignant pleural mesothelioma (MPM)

 Pleural biopsy for suspicion of MPM.

 CTCs in 7.5mL of peripheral blood were quantitatively evaluated
 with the CellSearch system

 136 eligible patients: 104 MPM and 32 NM

 CTC was positive (CTC≥1) in 33% (37/104) of MPM pts, and in
 9% (3/32) of NM pts (p=0.011).
CTC-count > in MPM (range, 0-9) than in NM (range, 0-1;
p=0.007).

Among MPM pts, CTC-positivity and CTC-count increase with
tumor progression (p=0.026 and p=0.008, respectively).




CTC predict poor prognosis: mOS 8.0 mm for CTC+ vs 20.3
months for CTC- pts; (p=0.012) in pts with epithelioid-type
MPM.

CTC independent prognostic factor (HR=2.38; P=0.006) in
multivariate analysis.

CTC diagnostic marker in discrimination between MPM and NM.
CTC-positivity significant and independent prognostic factor of
poor prognosis in epithelioid MPM.
Elevated PDGFRB gene copy number gain as prognostic
in resected malignant pleural mesothelioma.
Anne S Tsao, et al; MDACC Houston
J Clin Oncol 30, 2012 (suppl; abstr 7078)




 88 tumor blocks from resected MPM with full clinical information

 IHC biomarkers for PDGFRα,β and p-PDGFRβ, and fluorescence
 in situ hybridization for analysis of PDGFRB gene CNG +
 correlation to clinical outcome
high cytoplasmic
PDGFRα occurring
in patients with
no prior known
asbestos exposure
(p=0.029)
while PDGFRB gene CNG in > 40% of tumor cells had a higher
cytoplasmic PDGFRβ (p=0.04).

PDGFRB gene CNG status did not associate with patient
demographics or tumor characteristics.

PDGFRB CNG > 40% of tumor cells had an improved relapse-
free survival (RFS) [HR 0.25 (95% CI 0.09, 0.72), p=0.0096].
Pts with PDGFRB CNG > 40% chemotherapy appeared to
improve RFS (p=0.017).

In the multi-covariate analyses for    RFS,   there   was   no
association with any IHC biomarker.

In the overall survival (OS) analysis, having PDGFRB gene CNG
> 40% of tumor cells correlated with an improved OS [HR 0.32
(95% CI 0.11, 0.89), p=0.029] and the addition of peri-
operative chemotherapy led to a trend towards improved OS
(p=0.089).
The Lung Cancer Symptom Scale (LCSS) as a prognostic
indicator of overall survival in malignant pleural
mesothelioma (MPM) patients: Post hoc analysis of a
phase III study.
Ping Wang, et al; Eli Lilly
J Clin Oncol 30, 2012 (suppl; abstr 7075)

 Post-hoc analysis Vogelzang 2003

 To determine the patients likely to benefit from therapy,
 clinicians seek factors associated with outcomes.

 Prognostic effect of baseline patient-reported symptoms on
 overall survival (OS) in the presence of demographic/clinical
 factors among MPM patients.

 Intent-to-treat patients (N=448) included in the analysis.
LCSS consists of 6 symptom items (anorexia, cough, dyspnea,
fatigue, pain, hemoptysis) and 3 general items (interference with
activity level, symptoms distress, global quality of life), each
ranging from 0 (no symptoms) to 100 (worst).

Pts LCSS baseline

Average symptom burden index (ASBI) was the mean of 6
symptom items.

Patients were classified into subgroups based on ASBI: low
symptom burden (LSB; ASBI<25) and high symptom burden
(HSB; ASBI ≥25).

Univariate Cox models were used to determine the prognostic
effect of 7 demographic/clinical factors, 9 LCSS items, and ASBI
on OS. Multivariate Cox model was used to determine the
prognostic    effect  of   ASBI     in    the  presence    of  7
demographic/clinical factors.

Kaplan-Meier curves of OS were generated for patients with LSB
and HSB and compared using both univariate and multivariate
Cox models.
In    the   univariate   analysis,
significant prognostic effects on
OS were observed for baseline
KPS 90-100 vs. 70-80, (hazard
ratio [HR]=0.45, p<0.0001) and
baseline stage (I/II/III vs. IV,
HR=0.63, p<0.0001).

significant  prognostic    effects
were observed for 5 LCSS
symptom       items    (anorexia,
cough, dyspnea, fatigue, and
pain), 3 LCSS general items
(interference with activity level,
symptom distress, and quality of
life; HRs=1.08-1.20 for every 10
points worsening, all p<0.02), as
well     as    ASBI    (HR=1.32,
p<0.0001).
                            In the multivariate Cox model,
                            ASBI     remained    a   significant
                            prognostic factor of OS (HR=1.22,
                            p<0.0001), along with baseline
                            KPS and stage.
                            Patients with LSB (N=265) had
                            significantly better OS than those
                            with HSB (N=181) (12.9 vs. 6.9
                            months,     HR=0.46, unadjusted
                            p<0.0001; HR=0.59, p<0.0001
                            adjusted        for     the        7
                            demographic/clinical variables).




The results suggest that baseline patient-reported symptoms as
measured by LCSS provide distinct prognostic information in the
presence of demographic and clinical measures in MPM.
fgrosso@ospedale.al.it

								
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