Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma.

0.89 MB·English

by  Federico, Rea

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RESEARCH ARTICLE Open Access
Phase II trial of neoadjuvant pemetrexed plus
cisplatin followed by surgery and radiation in the
treatment of pleural mesothelioma
Rea Federico1*, Favaretto Adolfo2, Marulli Giuseppe1, Spaggiari Lorenzo3, DePas Tommaso Martino4,
Ceribelli Anna5, Paccagnella Adriano6, Crivellari Gino6, Russo Francesca7, Ceccarelli Matteo7, Kazeem Gbenga8,
Marchi Paolo7* and Facciolo Francesco9
Abstract
Background: Malignant pleural mesothelioma is an aggressive tumor that has a poor prognosis and is resistant to
unimodal approaches.Multimodal treatment has provided encouraging results.
Methods: Phase II,open-label study of thecombination ofchemotherapy (pemetrexed 500mg/m2+cisplatin
75 mg/m2IV every 21 days ×3 cycles), followed by surgery (en-bloc extrapleural pneumonectomy, 3–8weeks after
chemotherapy) and hemithoracic radiation (total radiation beam 54 Gy, received 4–8weeks post-surgery). The
primary endpoint was event-free survival, defined as the time from enrollment to time of firstobservationof
disease progression,death due to any cause, or early treatment discontinuation.
Results: Fifty-four treatment-naïve patientswith T1-3N0-2 malignantpleural mesothelioma were enrolled,52
(96.3%) completed chemotherapy, 45 (83.3%) underwent surgery, 22 (40.7%) completed the wholetreatment
including 90-day post-radiation follow-up. The median event-free survival was 6.9 months (95%CI: 5.0-10.5), median
overall survival was 15.5 months (95%CI 11.0-NA) whilemedian time-to-tumor response was 4.8 months (95%CI:
2.5-8.0). Eighteen (33.3%) and 13 (24.1%)patientswere still event-free after 1and 2 years, respectively.The most
common treatment-emergent adverse events were nausea (63.0%), anemia (51.9%) and hypertension(42.6%).
Following two cardiopulmonary radiation-related deaths the protocol was amended (21 [38.9%] patients were
already enrolled inthestudy): the total radiation beam was reduced from 54 Gy to 50.4 Gy and a more accurate
selection of patients was recommended.
Conclusions: The combination ofpemetrexed plus cisplatinfollowed by surgery and hemithoracic radiation is
feasible and has a manageable toxicity profilein carefully selected patients. It may be worthy offurther
investigation.
Trial registration: Clinicaltrial.com registrationID #NCT00087698.
Keywords: Pemetrexed, Pleural mesothelioma,Chemotherapy, Surgery, Radiation
*Correspondence:[email protected];[email protected]
1AziendaOspedaliera-UniversitàdiPadova,U.O.ChirurgiaToracica,Via
Giustiniani2,35121Padova,Italy
7EliLillyItalia,ViaGramsci731/733,50019SestoFiorentino,(FI),Italy
Fulllistofauthorinformationisavailableattheendofthearticle
©2013Federicoetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
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Background and assess efficacy and safety of the combined modality
Malignant pleural mesothelioma (MPM) is an aggressive approach (induction chemotherapy followed by EPP and
tumor originating from the superficial serosal cells of hemithoracic radiation) in patients with MPM with clin-
pleural cavities that has long been considered rare. In- icalstage I,II,orIII(T1-3 N0-2).
deed, its incidence has considerably increased over the
past two decades in industrialized countries on account Methods
of the widespread use of asbestos, the main carcinogen The present clinical trial (clinicaltrial.com ID #NCT00
involved in its pathogenesis. The incidence of malignant 087698) aimed to assess the efficacy of the trimodality ap-
mesothelioma is currently reported to range from 7 to proach(chemotherapy,surgeryandradiation)forthetreat-
40 cases per million people, but it is believed that it will ment of stage I-III MPM. A CONSORT (consolidated
increaseinthenext 10to15years[1]. standard in reporting trials)-like diagram, including study
MPM rapidly spreads to adjacent structures of the design and patients disposition is presented in Figure 1.
thoracic cavity. This explains why the majority of The study was approved by local ethics committees
patients present with locally advanced or metastatic dis- (Comitato Etico degli Istituti Fisioterapici Ospitalieri
ease:48%areinstageIIIand40%areinstage IV[2,3]. (IRCCS) di Roma, Rome, Italy; Comitato Etico Istituto
The prognosis of MPM is poor. The median overall Europeo di Oncologia, Milan, Italy; Comitato Etico Per La
survival (OS) from diagnosis is 12 months, ranging from Sperimentazione Azienda Ospedaliera of Padua, Padua,
8 months in stage IV patients to 40 months in stage I Italy;ComitatoEticoULSS12Veneziana,Venice,Italy)and
patients[4]. was conducted in accordance with the Declaration of Hel-
At present, an optimal therapy for MPM has not been sinki on ethical principles for medical research involving
established. In the recent Mesothelioma and Radical humansubjects.
Surgery (MARS) study, in which patients with patho-
logically confirmed mesothelioma were randomized to Objectivesofthestudy
extrapleural pneumonectomy (EPP) or no EPP within The primary efficacy objective of this study was to assess
the context of trimodal therapy, the surgery option was the EFS, defined as the time from enrollment to the first
reported to offer no benefit and possibly harms patients observationofdiseaseprogression, deathduetoanycause,
[5]. Previous studies showed that MPM is refractory to a orearlytreatmentdiscontinuation.EFSwascensoredatthe
series of single modality regimens based on chemother- dateofthelastfollow-upvisitforpatientswhodidnotdis-
apy, surgery, or radiotherapy [6]. An attempt to curative continueearly,whowerestillaliveandhadnotprogressed.
surgery, consisting of EPP, is feasible in no more than Secondary efficacy objectives were to assess: 1- and 2-
5% of subjects [2]. Single-agent chemotherapy provides year EFS rates; progression-free survival (PFS), defined
poor response rates (<20%) and no improvement in me- as the time from study enrollment to the first date of
dian survival [4]. The only advancement with a single disease progression or death as a result of any cause
modality is the identification of cisplatin as the best (PFS was censored at the date of the last follow-up visit
anticancer agent for MPM in a meta-analysis of studies for patients who were still alive and who have not pro-
published between 1965 and 2001. The combination of gressed); OS, defined as the time from study enrollment
cisplatin and pemetrexed has shown to improve the ob- totimeofdeathfrom any cause (OS wascensored atthe
jective response rate and to prolong median overall sur- date of last follow-up for patients who were still alive);
vival of patients with MPM versus cisplatin alone (41% and time to tumor response (TTR), defined as the time
vs 16.7%, 12.1 vs 9.3 months) within the context of a from study enrollment to the first observation of an ob-
prospective, randomized, phase III clinical trial [7,8]. jectivetumor response.
Radiotherapy with curative intent is usually not recom-
mended, as target volumes exceed normal tissue toler- Eligibilitycriteria
ance limits [9]. Even though the modern Intensity Patients who were at least 18 years old, had signed
Modulated Radiation Therapy (IMRT) technique seems informed consent and met all criteria listed in Table 1
to provide additional treatment options, it still requires were enrolled inthestudy.
furtherinvestigation [4,7].
In view of the resistance of MPM to single modality Treatmentplan
approaches, multimodal therapeutic strategies have been Chemotherapy
proposed. Studies assessing trimodal treatment (induc- Pemetrexed (500 mg/m2 intravenous [IV] infusion) fol-
tion chemotherapy, followed by EPP and post-operative lowed bycisplatin(75mg/m2IVinfusion) were adminis-
radiotherapy) haveprovidedencouraging results[10,11]. tered topatientsonDay 1of a21-day cycle for atotal of
The present trial, whose primary endpoint is event- three cycles. Supportive therapyoffolic acid, vitamin B
12
free survival (EFS), was designed to test the feasibility, anddexamethasone(4mgbidper os)weregiven.
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Figure1Studydesignandpatientsdispositionadoptedinthisstudy.Studydesignhighlightsthetrimodalitytherapyadopted:patients
dispositionisprovidedforpatientsenrolledbeforetheprotocolamendment(PA)aswellasforthoseenrolledafterPAandoverall.Trimodality
therapywasconsideredcompletedforthosepatientswhoreceived≥28dosesofradiotherapy(RT)whilethestudywasconsideredcompleted
forthosesubjectscompletingRTandthe90-daypost-radiationfollow-up.pts=patients;MPM=malignantpleuralmesothelioma;
HTR=hemithoracicradiation;EPP=extrapleuralpneumonectomy;BA=beforeamendment;AA=postamendment.
Surgery oncologist and thoracic surgeon had discussed it. A total
EPP was performed 3 to 8 weeks after the last dose of 54 Gy radiation beam (30 × 1.8 Gy fractions) was
of chemotherapy in eligible patients to achieve the administered to patients. Once patients received a total
complete resection of the gross residual tumor. EPP radiationof40Gyanon-enhancedCTscanwasperformed
involved en-bloc resection of the pleura, lung, dia- for safety evaluation. Due to two cardiopulmonary-related
phragm, and ipsilateral half of the pericardium. Patients deathsthatoccurredearlierinthestudy,thestudyprotocol
were eligible for surgery unlessobjective evidence of dis- wasamendedreducingthetotalradiationbeamto50.4Gy
ease progression was present or deterioration of func- (28×1.8Gyfractions).Additionalcardiopulmonaryandre-
tionalstatusoccurred. spiratoryfunctiontestswerealsoperformed(Table2).
Radiation
Radiation was given to patients starting from 4 to Statistics
8 weeks after EPP (an extension to 12 weeks was pos- Determinationofsamplesize
sible as per study protocol). The clinical target volume Based on the assumption of a 1-year EFS rate of about
(CTV) was contoured on each patient after a radiation 30%, 53 patients were planned to be enrolled in the
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Table1Eligibilitycriteriaofthisstudy
Eligibility ClinicalstageI,IIorIII(M0;N0-2;T1-3)pleuralmesothelioma
Criteria
Performancestatus0to1ontheECOGaperformancestatusschedule
Noprevioussurgicalresectionofmesothelioma
Nopreviousradiationtherapy
Estimatedlifeexpectancyofatleast12weeks
Adequatecardiacfunction
Mustbejudgedsuitabletothetherapybymedicaloncologistandthoracicsurgeon.
Pulmonaryfunctiontests:FEV1b>0.8,DLCOc>35%ofpredictedpostoperativeFEV1(ppoFEV1)
ABGdPredictedpostoperativepCO2<50.
Adequatebonemarrowreserve:
(cid:129)absoluteneutrophil(segmentedandbands)count(ANC)≥1.5×109/L,
(cid:129)Platelets≥100×109/L,andhemoglobin≥9g/dL.
Hepatic:bilirubin≤1.5timestheupperlimitofnormal
(×ULN),alkalinephosphatase(AP),aspartatetransaminase(AST)andalaninetransaminase(ALT)≤3.0×ULN.
Femalepatientsofchild-bearingpotentialmusttestnegativeforpregnancyatthetimeofenrollmentbasedonaserumpregnancy
test.Maleandfemalepatientsmustagreetouseareliablemethodofbirthcontrolduringandfor3monthsfollowingthelastdose
ofstudydrug.
Geographicalconditionmustnothamperthecompliancewiththestudyprotocolandfollow-upschedule.
aEasternCooperativeOncologyGroup;bForcedExpiratoryVolume;cDiffusingCapacityoftheLungforCarbonmonoxide;dArterialBloodGas.
study to obtain a 95% confidence interval (CI) width of time-to-event rates) were calculated and 95% CIs around
about ±12%aroundthe1-yearEFSrate. theestimateswereprovided.
Efficacyanalysis Safetyanalysis
Efficacy analyses were performed on the full analysis set Safety analyses were performed on the safety population,
(FAS),definedasallpatientswithhistologicalorcytological defined as all patients who received at least one dose of
diagnosisofMPM;nopriororconcurrentsystemicchemo- pemetrexed/cisplatin. Safety analyses included analyses
therapy,immunotherapy,or biological therapy; presenceof of vital signs, laboratory and non-laboratory variables at
measurable or evaluable disease (for clinical response); and each visit, and the changes from baseline. Shift tables
treated with at least one dose of pemetrexed/cisplatin. For showing laboratory test values classified as below nor-
all time-to-event variables, Kaplan-Meier curves were gen- mal, normal, and above normal, based on reference
erated, quartiles and point probabilities (1- and 2-year ranges,from baseline toeachvisit,were alsoproduced.
Table2Summaryofvariationinselectioncriteriaforcardiopulmonaryandrespiratorytestsbyprotocolamendment
Selection Beforeprotocolamendment Afterprotocolamendment
criteria
FEV1 >2L,or>35%ofpredictedpostoperative(ppoFEV1);if<2L,the >0.8
ppoFEV1mustbeatleast35%basedonthefollowingformula
usingthequantitativeV/Qscan:Predictedpost-resection
FEV1=FEV1x%perfusiontouninvolvedlungfromquantitative
lungV/Qscanreport.
DLCO >35%ofppoFEV1
ABG pCO <50 predictedpostoperativepCO2<50
2
Adequate Thepatient'scardiacfunctionandpresenceorabsenceofcoronary Thepatient'scardiacfunctionandpresenceorabsenceof
cardiac arterydiseaseorvalvularheartdiseaseshouldbeassessedbyoneof coronaryarterydiseaseorvalvularheartdiseaseshouldbe
function thefollowingtests: assessedbythefollowingtests:
(cid:129)Radionuclidestresstest:preferred (cid:129)Echocardiogram(mandatory): VentricularEjectionFraction345%
(cid:129)Exercisestresstesttomaximalexerciselevel (cid:129)Electrocardiogram(mandatory)
(cid:129)Stressechocardiogram (cid:129)Radionuclidestresstest(optional)
(cid:129)Exercisestresstesttomaximalexerciselevel(optional)
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Results cisplatin (4.4%) were delayed, one (0.6%) was reduced,
The study was conducted at four centers in Italy from andtwo (1.3%)weredelayed andreduced.
June 2005 to February 2010. A total of 56 patients were
screenedfor thestudy and54were enrolled. Surgery
Of the 54 patients enrolled, 9 patients dropped out of
Patientcharacteristics the study before surgery (6 due to lack of efficacy, 2 due
The patients were mostly men (n=47, 87%) and had a to death and one patient was found to have invasion of
medianageof63.0years(range:39–75years)(Table 3). the esophagus) while 45 (83.3%) underwent surgery. Of
Twelve patients (22.2%) were in clinical stage I (T1, these, 9 patients were in clinical stage I, 8 were in clin-
N0, M0), 9 (16.7%) were in clinical stage II (T2, N0, M0) ical stage II and 34 were in clinical stage III. Among the
and 33 (61.1%) were in clinical stage III (T1-3, N1-2, patients who underwent surgery, 41 (91.1%) received
M0). Twenty-one patients (38.9%) were enrolled before EPP,while4(8.9%) did not. En-bloc EPP wasperformed
the protocol amendment, implemented after two cardio- in 36 patients (80.0%), non-“en- bloc” EPP in 5 patients
pulmonary failure-related deaths, reducing the dose of (11.1%). Resection of the pericardium was performed in
radiotherapy from 54 Gy in 30 fractions to 50.4 Gy in 28 38 patients (84.4%), resection of the diaphragm in 40
fractions. (88.9%) patients. A diaphragmatic prosthesis was inserted
during 34 procedures (75.6%), a pericardial prosthesis in
Treatment 33patients(73.3%).Atotalof2patients(4.4%)diedwithin
Chemotherapy 30daysofsurgery.
Of the 54 patients enrolled, 52 (96.3%) patients com-
pleted pre-operative chemotherapy; one patient received Radiotherapy
only 2 cycles because of lack of efficacy and another Of the 45 patients who underwent surgery, 32 received
received only one cycle because he experienced an acute radiotherapy (59.3% of total enrolled patients) while 13
myocardial infarction. (24.1%) did not (see Figure 1 for details). The median
The median relative dose intensity of pemetrexed was number of fractions received was 28 (range 12–30) and
100% (range 33%-113%), that of cisplatin was 100.3% the median total dose received was 50.4 Gy (range: 21.6
(range 33%-144%). Out of 159 cycles, 8 cycles of peme- to54.0Gy).
trexed (5.0%) were delayed, one (0.6%) was reduced, and Twenty-two patients (40.7%) completed the trimodal-
one (0.6%) was reduced and delayed, whereas 7 cycles of ity treatment and the 90-day post radiation follow-up
(Figure 1). Out of the remaining 32 patients, 16 were
Table3Characteristicsofpatientsenrolledbeforeand removed from the study earlier because of inefficacy
afterthestudyprotocolamendment (29.6%), mainly after chemotherapy or after surgery; 11
BeforePAa AfterPA All (20.4%) died, two (3.7%) violated the protocol, one
NGender,n(%) 21 33 54 experienced an unacceptable adverse event, one decided
to withdraw, and one was removed from the study by
Male 17(81.0) 30(90.9) 47(87.0)
the investigator. Out of the 11 deaths, five were consid-
Female 4(19.0) 3(9.1) 7(13.0)
ered to be unrelated to the study (diagnosis: broncho-
Age(yrs)Median 61.0 64.0 63.0
pneumonia, septic shock, suspected heart attack,
(range) (39–71) (44–75) (39–75)
underlying disease, suicide), two were due to study drug
Race,n(%)
toxicity (cardiopulmonary failures), four were procedure
Caucasian 21(100.0) 33(100.0) 54(100.0) related(1empyema,1cardiacarrest,and2sepsis).
ClinicalStaging,n(%)
I(T1,N0,M0) 1(4.8) 11(33.3) 12(22.2) Efficacy
The median EFS was 6.9 months (95%CI: 5.0- 10.5)
II(T2,N0,M0) 2(9.5) 7(21.2) 9(16.7)
(Figure 2A). A total of 18 (33.3%; 95%CI: 21.1- 47.5)
III(T3,N1- 17(81.0) 16(48.5) 33(61.1)
2M0) and 13 (24.1%, 95%CI: 13.7- 36.0) patients were still
event-free after 1 and 2 years, respectively. The median
Histology,n(%)
PFSwas8.6months(95%CI:6.3,14.4months)(Figure2B);
Epithelial 18(85.7) 30(90.9) 48(88.9)
the one-year PFS rate was 40.7% (95%CI: 27.7-53.4); the
Biphasic 2(9.5) 1(3.0) 3(5.6)
2-year PFS rate was 31.5% (95%CI: 19.7-43.9). The median
Desmoplastic 1(4.8) 2(6.1) 3(5.6) OS was 15.5 months (95%CI: 11.0-NA) (Figure 2C). The
aProtocolAmendment 1-yearOSratewas59.2%(95%CI:44.9-70.9).MedianTTR
Dataarepresentedstratifiedbytimeofenrollmentinthisstudywithrespect
was 4.8 months (95%CI: 2.5-8.0) (Figure 2D). Overall, 31
totheprotocolamendmentandareexpressedasnumberofpatients
(percentage)exceptforage,expressedasmean(SD). patients had progression of disease. Of these, 10 patients
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Figure2Efficacyvariablesofthisstudy.Kaplan-Meierplotsforefficacyvariablesanalyzedforthisstudyarepresented:MedianEFS(panelA),
MedianPFS(panelB),MedianOS(panelC)andmedianTTR(panelD).Resultsareexpressedinmonths.EFS=event-freesurvival;PFS=
progression-freesurvival;OS=overallsurvival;TTR=timetotumorresponse.
hadprogressionofdiseaseduringthestudy(siteofprogres- Twenty-six patients (48.1%) required a blood transfu-
sion:6local,4distant),while21hadprogressionofdisease sion. Thirty-six (66.7%) patients experienced at least one
during the follow-up period (site of progression: 5 local, grade 3/4 toxicity and two patients died because of car-
1 contralateral intrathoracic, 15 distant). Following two diopulmonary failure. Forty-two patients (77.8%) experi-
cardiopulmonary-related deaths, the study protocol was enced at least one AE related to chemotherapy, which in
amendedbyreducingthetotalradiationdoseadministered 5 patients (9.3%) were serious. The corresponding rates
to patients (see Methods section) and including additional for radiotherapy were 48.1% and 13%, respectively. The
cardiopulmonary and respiratory function tests (Table 2), number of episodes of grade 3/4 toxicities related to
which led to a more careful selection of patients being treatment were: lymphopenia (n=3), neutropenia (n=3),
carriedout. dyspnea (n=3, all serious), anemia (n=2, 1 serious), heart
failure (n=2, both serious), respiratory failure (n=2, both
serious), acute cor pulmonale, myocardial infarction,
Safety pericardial effusion, emphysema, acute respiratory dis-
No important changes in vital signs, body weight, and tress syndrome, pneumonia, bronchial fistula, subcuta-
Eastern Cooperative Oncology Group (ECOG) perform- neous emphysema(n=1each,allserious),dysphagia(n=1),
ancestatus wererecorded. mucosalinflammation(n=1),hyponatremia(n=1),andscar
Nearly all patients experienced at least one adverse pain (n=1). No important qualitative differences were
event (AE) (n=53, 98.1%). The most common treatment- recordedaftertheimplementationofprotocolamendment.
emergent AEs were nausea (63.0%), anemia (51.9%) and
hypertension (42.6%). The total number of deaths Discussion
recorded was 32 patients (59.3%). Of these, 11 patients Malignant pleural mesothelioma is an aggressive tumor
died during the study (causes of death were: 1 broncop- refractory to single regimens based on chemotherapy,
neumonia, 1 septic shock, 1 empyema, 1 suspect heart surgery, or radiation [5]. Although IMRT technique
attack, 1 cardiac failure, 1 respiratory failure, 1 cardiac seems toprovidean additional treatment option (still re-
arrest, 2 sepsis, 1 suicide and 1 death for unknown quiring further investigations) clinical studies provided
causes) while 21 died during the follow-up period encouraging results on combined modality approach
(causes of death were: 19 progression of disease [10 dis- treatments [10,11]. The present study was designed to
tant vs9local],1sepsis,1unknown). test the feasibility and assess the efficacy and safety of
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the combination of pemetrexed and cisplatin followed Table4Summaryresultsforefficacyvariables
byEPPandhemithoracicradiation. BeforePAa AfterPA Overall
For the primary endpoint of EFS assessed for the EFSb
study, the median EFS was 6.9 months (95% CI: 5.0 to
Median 6.3(3.3-10.5) 8.1(4.1-19.7) 6.9(5.0-10.5)
10.5), while the 1- and 2-year EFS rates were, respect-
1-yearRate 23.8(8.2-47.2) 39.4(22.9-57.9) 33.3(21.1-47.5)
ively,33.3%(95%CI:21.1-47.5)and24.1%(95%CI:13.7-
36.0).Consideringthatthesamplesizedeterminationwas 2-yearRate 14.3(3.6-32.1) 30.3(15.9-46.1) 24.1(13.7-36.0)
based on the assumption that the expected 1-year EFS PFSc
rate of about 30% (with a 95% CI of about ±12%), the Median 6.6(5.0-11.0) 11.9(6.9-26.9) 8.6(6.3-14.4)
1-year EFS rate observed in the present study aligned
1-yearRate 28.6(11.7-48.2) 48.5(30.8-64.1) 40.7(27.7-53.4)
with the initial assumption. Therefore, these results in-
2-yearRate 19.1(5.9-37.7) 39.4(23.1-55.4) 31.5(19.7-43.9)
dicate that the adopted multimodality approach is
OSd
feasible.
Although the 1-year EFS rate observed based on all Median 12.6(6.9-21.1) NA 15.5(11.0-NA)
the enrolled patients in the present study aligns with TTRe
what is expected, it is possible that the subgroup of Median 2.8(1.4-5.1) 7.6(4.1-8.9) 4.8(2.5-8.0)
patients who completed all the three treatments have aProtocolAmendment;bEvent-freeSurvival;cProgression-freeSurvival;d
higher survival benefits. Indeed, a total of 22 (40.7%) of OverallSurvival;eTimetoTumorResponse.
Overallresultsarepresentedaswellasresultsstratifiedbytimeofenrollment
the 54 patients completed all the study treatments in-
inthestudywithrespecttotheprotocolamendment.Resultsareexpressedin
cluding the 90-day post-radiation follow-up. However, months(95%CI)formedianvariablesandaspercentage(95%CI)for1-and
given the change in patients’ selection criteria following 2-yearrates.
the protocol amendment (as described in the Methods
section), it is important to consider mainly results based (Table 4) but this hypothesis needs to be confirmed in a
on all enrolled patients rather than the subgroup of further study. With regard to the safety profile, the
patientsinthepresent study. adopted combination of pemetrexed plus cisplatin fol-
Generally, results obtained for efficacy endpoints other lowed by EPP and hemithoracic radiation did not result
than EFS, were lower than those reported by Van Schil inabnormalvalueseitherforcardiacorpulmonaryfunc-
etal.[12]intheEORTCstudy,aclinicaltrialwithsimilar tion tests at baseline and after surgery. These results,
study design but different primaryobjective. Themedian takentogetherwithnoclinicallyrelevantchangesinvital
PFS and 1-year PFS rate were 8.6 months (95% CI: signs, no substantial changes in the blood chemistry
6.3- 14.4) and 40.7% (95% CI: 27.7-53.4), respectively, from baseline and generally acceptable decreases in cer-
compared to 13.9 months (95% CI: 10.9-17.2) and 54.4% tain hematologic values (hemoglobin, red blood cells
(95% CI: 40.7-66.2), respectively, obtained in the EORTC [RBCs] count, white blood cells [WBCs] count, platelets
trial [12]. The median OS was 15.5 months (95% CI: and neutrophils), indicate a manageable toxicity profile
11.0-NA) compared to 18.4 months (95% CI: 15.6-32.9) followingthe reduced radiation dose.
in the EORTC [12]. The same outcome in the MARS Unlike the MARS trial [5] that was designed to assess
trial was of 14.4 months (95%CI: 5.3-18.7) for patients the clinical outcomes of patients who were randomly
randomizedtoEPPandof19.5months(95%CI:13.4-not assigned to EPP or no EPP in the context of trimodal
reached) for patients randomized to no EPP. [5]. Fur- therapy, the present non-randomized study, that was
thermore, the efficacy outcomes of the present study disegned to to test the feasibility and assess the efficacy
were less favorable as compared with those obtained in and safety of the combination of pemetrexed and cis-
theSAKKandUSAphaseIItrials[9,10]. platin followed by EPP and hemithoracic radiation,
However, we have to consider that following two recruited also patients of worst outcome (i.e. desmoplas-
cardio-pulmonary related deaths the study protocol was tic MPM histotype – see also Table 3). However, the low
amended and the total radiation dose was reduced from number of patients belonging to this subpopulation may
54 Gy to 50.4 Gy. It is noteworthy that the outcomes of not have had an impact on the final results. Moreover,
efficacy endpoints, including the primary endpoint of the MARS trial allowed three different regimens of
EFS, did not worsen but instead seem to benefit from chemotherapy at physician discretion [5] while the
the changes introduced by the protocol amendment. present trial considered a pemetrexed-based regimen as
Even though no claim of statistical significance can be theonlychemotherapyoption.
made against the variation of efficacy variables when Basedonmediansurvival(14.4months(95%CI:5.3-18.7)
measuredbeforeoraftertheamendments,thesefindings for patients randomized to EPP and of 19.5 months (95%
seem to suggest that the reduced post-surgery radiation CI: 13.4-not reached) for patients randomized to no EPP)
dose may lead to increased OS, EFS, PFS and TTR andmortality(18%)outcomesrecordedintheMARStrial,
Federicoetal.BMCCancer2013,13:22 Page8of8
http://www.biomedcentral.com/1471-2407/13/22
Treasure et al. [5], concluded that EPP within trimodality Corporation),RogelioE.GarcíaB.(PRIMOScientificCorporation),DrDavide
therapy offers no benefit and possibly harms patients. As Boyand,DrJoannaLeadbetterforcriticalreview.
suggested by Weder et al. [13] this conclusion is not sup-
Authordetails
ported by data and possibly might move clinical research 1AziendaOspedaliera-UniversitàdiPadova,U.O.ChirurgiaToracica,Via
formesotheliomainthewrongdirection[13].Providedthat Giustiniani2,35121Padova,Italy.2IstitutoOncologicoVeneto,U.O.
OncologiaMedica2,ViaGattamelata64,35128Padova,Italy.3Istituto
superiorityofpleurectomyvsEPPhasnotbeenprovedyet,
EuropeodiOncologia,Div.ChirurgiaToracica,ViaRipamonti435,20141
we would like to strongly remark that the present study Milan,Italy.4IstitutoEuropeodiOncologia,Div.OncologiaMedica,Via
was not designed to compare different surgical strategies, Ripamonti435,20141Milan,Italy.5IstitutoNazionaleTumori“ReginaElena”,
Div.OncologiaMedica,ViaChianesi53,00144Rome,Italy.6Ospedale
thereforenoconclusionnorspeculationaboutpleurectomy dell’Angelo,Div.OncologiaMedica,ViaPaccagnella11,30174Mestre,(VE),
vs EPP can be done. On the other hand, the low rate of Italy.7EliLillyItalia,ViaGramsci731/733,50019SestoFiorentino,(FI),Italy.8Eli
completion (40.7%) recorded in this study, highlight the LillyUK,ErlWoodManor,Windhlesham,SurreyGU206PHUnitedKingdom
(formeremployee).9IstitutoNazionaleTumori“ReginaElena”,Div.Chirurgia
needforacarefulpatientselectionandeventually,foratai-
Toracica,ViaChianesi53,00144Rome,Italy.
loredsurgicalandmedicalapproach.
The present study has limitations that were mainly Received:3April2012Accepted:4January2013
Published:16January2013
introduced by the protocol amendment even though not
predictable in advance. Because improvement of efficacy References
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Abbreviations
pemetrexedincombinationwithcisplatinversuscisplatinalonein
AE:AdverseEvent;CI:ConfidenceInterval;CONSORT:ConsolidatedStandard
patientswithmalignantpleuralmesothelioma.JClinOncol2003,
ofReportingTrials;CTV:ClinicalTargetVolume;ECOG:EasternCooperative 21:2636–2644.
OncologyGroup;EFS:EventFreeSurvival;EORTC:EuropeanOrganizationfor
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ResearchandTreatmentofCancer;EPP:ExtrapleuralPneumonectomy; mesothelioma.IntJRadiatOncolBiolPhys2009,75:326–337.
IMRT:IntensityModulatedRadiationTherapy;MARS:Mesotheliomaand
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RadicalSurgery;MPM:MalignantPleuralMesothelioma;NA:NotAssessable;
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Competinginterests
Research,etal:Multicentertrialofneo-adjuvantchemotherapyfollowed
Theauthorsdeclarethefollowingconflictofinterest:FR,AF,GM,LS,TMDP,
byextrapleuralpneumonectomyinmalignantpleuralmesothelioma.
AC,AP,GCandFFdeclarenoconflictofinterest.FR,MCandPMarefull AnnOncol2007,18:1196–1202.
timeemployeesofEliLillyItaly.GKwasacontractoremployeeofEliLillyUK.
12. VanSchilPE,BaasP,GaafarR,etal:Trimodalitytherapyformalignant
ThisstudywasfullysponsoredbyEliLillyItaly,SestoFiorentino,Florence,
pleuralmesothelioma:resultsfromanEORTCphaseIImulticentretrial.
Italy. EurRespirJ2010,36:1362–1369.
13. WederW,StahelRA,BaasP,etal:TheMARSfeasibilitytrial:conclusions
Authors’contributions notsupportedbydata.LancetOncol2011,12(12):1093–1094.
FFistheprincipalinvestigator,hassupervisedthestudyandhascontributed
tostudydesign,interpretationofdataandhassubstantiallyrevisedthe
doi:10.1186/1471-2407-13-22
manuscript.FR,GM,AF,LS,TMDP,AC,AP,GCandFRhavecontributedto
Citethisarticleas:Federicoetal.:PhaseIItrialofneoadjuvant
acquisitionofdata,datainterpretationandcontentreview.MChas
pemetrexedpluscisplatinfollowedbysurgeryandradiationinthe
contributedtoacquisitionofdata,dataanalysis,datainterpretationand treatmentofpleuralmesothelioma.BMCCancer201313:22.
contentreview.GKhascontributedtodataanalysis,datainterpretationand
contentreview.PMhascontributedtodataanalysis,datainterpretation,
manuscriptwritingandcontentrevision.Allauthorsreadandapprovedthe
finalmanuscript.
Acknowledgements
TheauthorsacknowledgeDrJenniferHartwigformedicalwritingsupportin
draftingthismanuscript;DrSreekanthDevalraju(PRIMOScientific