Quaternary cytoreductive surgery in ovarian cancer: does surgical effort still matter?

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by  Fotopoulou, C

FULL PAPER
British Journal of Cancer (2013) 108, 32–38 | doi: 10.1038/bjc.2012.544
Keywords: ovarian cancer relapse; quaternary cytoreduction; overall survival; morbidity; tumour dissemination
Quaternary cytoreductive surgery in ovarian
cancer: does surgical effort still matter?
C Fotopoulou*,1,4, K Savvatis2,4, P Kosian1, I E Braicu1, G Papanikolaou1, K Pietzner1, S-C Schmidt3 and
J Sehouli1
1Department of Gynecology, Charite´ University Medical Center Berlin, 13353 Berlin, Germany; 2Department of Cardiology and
Pneumology,Charite´,CampusBenjaminFranklin,UniversityHospital,Berlin,Germanyand3DepartmentforGeneral,Visceraland
Transplantation Surgery, Charite´ University Medical Center Berlin, Berlin,Germany
Background:Toevaluatesurgicaloutcomeandsurvivalbenefitafter quaternarycytoreduction(QC)inepithelialovariancancer
(EOC)relapse.
Methods:WesystematicallyevaluatedallconsecutivepatientsundergoingQCinourinstitutionovera12-yearperiod(October
2000–January 2012).All relevant surgicaland clinical outcomeparameters weresystematically assessed.
Results: Forty-nine EOC patients (median age: 57; range: 28–76) underwent QC; in a median of 16 months (range:2–142) after
previouschemotherapy.ThemajorityofthepatientshadaninitialFIGOstageIII(67.3%),peritonealcarcinomatosis(77.6%)andno
ascites(67.3%).AtQC,patientspresentedfollowing tumourpattern:lowerabdomen85.7%;middleabdomen79.6%andupper
abdomen42.9%.Mediandurationofsurgerywas292min(range:atotalmacroscopictumourclearancecouldbeachieved.Rates
ofmajoroperativemorbidityand30-daymortalitywere28.6%and2%,respectively.Meanfollow-upfromQCwas18.41months
(95%confidenceinterval(CI):12.64–24.18)andmeanoverallsurvival(OS)23.05months(95%CI:15.5–30.6).MeanOSforpatients
without vs any tumour residuals was 43 months (95% CI: 26.4–59.5) vs 13.4 months (95% CI: 7.42–19.4); P¼0.001. Mean OS for
patientswhoreceivedpostoperativechemotherapy(n¼18;36.7%)vsthosewhodidnotwas40.5months(95%CI:27.4–53.6)vs
12.03months(95% CI:5.9–18.18);Po0.001. Multivariate analysisindentified multifocal tumour disseminationto beof predictive
significance for incomplete tumour resection, higher operative morbidity and lower survival, while systemic chemotherapy
subsequenttoQChadaprotectivesignificantimpactonOS.Noprognosticimpacthadascites,platinumresistance,highgrading
andadvancedage.
Conclusion:EveninthishighlyadvancedsettingofthethirdEOCrelapse,maximaltherapeuticeffortcombiningoptimalsurgery
andchemotherapy appearto significantly prolongsurvival inaselected patients‘group’.
Theknowledgearoundepithelialovariancancer(EOC),ararebut Even though many questions remained to be answered in the
most often fatal ending disease, has been constantly increasing future, such as the optimal timing of primary debulking, the
overthelastdecades.Noveltheoriesanddiscoveriesaboutitstrue therapeutic benefit of targeted agents and most importantly
origin and its special histopathological features have shed light putative mechanisms of early detection or even prevention of the
into the actual nature and behaviour of EOC, aiming to set the disease, the value of optimal tumour resection defined by the
basis for an optimal therapeutic management of the affected amountofpostoperativeresidualdiseasehaswellbeenestablished
patients (Singer et al, 2002; Shih and Kurman, 2004; Shih and innumerousprospectiveandretrospectiveanalysesfortheprimary
Kurman,2005;KurmanandShih,2008;Vangetal,2009;Kurman situationofthedisease(Bristow,2000;Chietal,2004;duBoisetal,
and Shih, 2010). 2005;Kurmanetal,2008;Zivanovicetal,2008;duBoisetal,2009;
*Correspondence:DrCFotopoulou;E-mail:[email protected]
4Sharedfirstauthorship.
Received25September2012;revised6November2012;accepted10November2012
&2013CancerResearchUK.Allrightsreserved0007–0920/13
32 www.bjcancer.com|DOI:10.1038/bjc.2012.544
Quaternary surgeryinovarian cancer BRITISH JOURNALOF CANCER
Fanfani et al, 2010). Complete tumour resection outranks tumour dissemination in imaging modalities and without symp-
prognostically other unfavourable factors such as peritoneal toms, which made an operative intervention inevitable, were not
carcinomatosis or even advanced FIGO stage (Aletti et al, 2009; operated but received a systemic treatment.
Harter et al, 2009; Wimberger et al, 2010). In every patient, the detailed tumour pattern was intraopera-
Variousauthorshaveattemptedtodefinetheroleofsurgeryin tively assessed by an independent trained person as based on the
the relapsed setting of the disease. Numerous analyses mainly of surgicalproceduresperformedandbyasystematicinterviewofthe
retrospective design could show a benefit of patients who surgicalteam.Postoperativelyallhistologicalfindingsandcollected
underwent complete secondary or even tertiary cytoreduction data were entered into a validated documentation system
(Leitaoetal,2004;Pfistereretal,2005;Chietal,2006;Harteretal, (intraoperative mapping of ovarian cancer (IMO)), especially
2006; Karam et al, 2007; Gultekin et al, 2008; Schorge et al, 2010; developed for ovarian neoplasms with special focus on the
Shih et al, 2010a; Fotopoulou et al, 2011a; Hızlı et al, 2012). Two description of the tumour pattern, maximal tumour burden,
multicenter, prospective randomised trials, one of the AGO postoperative tumour residuals and the amount of preoperative
German group (DESKTOP III) and one of the American GOG ascites.Allfurtherrelevantpatients’dataincludinghistory,follow-
(GOG 213) are ongoing randomising EOC patients to secondary up andsurvivaldatawereabstractedfromtheindividual patients’
cytoreduction and subsequent second-line chemotherapy or records.
second-line chemotherapy alone. The results of these trials will
Intraoperative mapping of ovarian cancer. Intraoperative map-
reliably define the final role of high-quality surgery in the first
ping ofovarian cancerrepresents adetailed andobjective surgical
relapse of the ovarian cancer disease and change the global
andhistopathologicaldocumentationsystemvalidatedtoobtainan
standard of treatment.
objective description of the ovarian tumour spread within the
Dataaboutquaternarycytoreductivesurgeryare,however,very
abdominalcavity,bothinprimaryandrecurrentsituationsandto
scarce. To our knowledge only one single monocentric analysis
define more precisely the histopathological features of the
exists so far including 15 patients who underwent quaternary
malignancy (Sehouli et al, 2003; Sehouli et al, 2009; Fotopoulou
surgery treated in the Memorial Sloan–Kettering Cancer Center
et al, 2011b; Braicu et al, 2012). Three ‘IMO levels’ divide the
(Shihetal,2010).Thisstudywasconductedtoevaluatetheimpact
abdomen into three spaces: lower (level 1), middle (level 2) and
of quaternary cytoreduction (QC) on overall survival (OS) of
upper(level3)abdomen(Table2).Nine‘IMOfields’,threeateach
patients with recurrent EOC. We analysed the surgical outcome
level,provideasubclassificationoftheperitonealcavityaimingata
including operative morbidity and mortality, identified indepen-
moreprecisedocumentationofthetumourdisseminationpattern.
dent predictors of complete tumour resection and described the
The patients’ informed consent was always given before surgery
intraoperative tumour dissemination patterns followed in the
and sample collection and documentation.
third-OC relapse as defined by a validated intraoperative
documentation tool for ovarian cancer mapping. Follow-up. Patients were regularly evaluated at the end of the
treatment for evidence of a new disease recurrence. Clinical
examinations,transvaginalandtransabdominalultrasound,CA125
(if the preoperative value was elevated) assays were performed
MATERIALS AND METHODS
every 3 months. A CT/MRI scan was ordered if the above
examinationsrevealedanypathology.IsolatedCA125increasewas
Asystematicevaluationwasperformedtoassesstheintraoperative not regarded as a recurrence.
tumour dissemination pattern, the surgical procedures performed
aswellastheoperativemorbidityandmortalityforallconsecutive Statistics. Statisticalanalysiswasperformed usingSPSSstatistical
women, undergoing quaternary surgical cytoreduction in the software,version16.0(SPSSInc.,233S.WackerDrive,Chicago,IL,
Department of Gynaecology at the Charite´, Campus Virchow USA).TheFisher’sexacttestandKendall’stau-bwereusedforthe
Clinic between October 2000 and January 2012. Quaternary univariate analysis, where appropriate. Crude and adjusted odds
surgery was defined as the fourth surgical cytoreductive attempt ratioswithcorresponding95%confidenceintervals(95%CIs)were
due to the third or higher histologically proven ovarian cancer obtained using logistic regression analysis. Estimates of survival
relapse (i.e., primary, secondary, tertiary and QC). Staging at werecalculatedusingtheKaplan–Meiermethodandlog-ranktests
primary operation was defined in accordance with the FIGO were used for univariate statistical comparisons. The relative
criteria for epithelial ovarian carcinoma (International Federation importance of variables as independent predictors of OS was
ofGynaecologyandObstetrics:Changingindefinitionsofclinical analysedwiththemultivariateCoxproportionalhazardregression.
staging for carcinoma of the cervix and ovary, 1987). Adjusted hazard ratios (HRs) and 95% CIs for prognostic factors
All operations were performed through midline laparotomy by wereestimated.Allsignificancesreportedweretwo-tailedatalevel
oneoffourgynaecologiconcologicsurgeonsincooperationwithin of 0.05. The follow-up time was calculated starting on the day of
a multidisciplinary surgical team to achieve radicality through a surgery.
multivisceral approach. Primary aim was maximal tumour
reduction in an elective setting for symptomatic but resectable
recurrence and/or to achieve palliation in situations like bowel RESULTS
obstruction,bleedingorpainintheminorityofthecases.However,
eveninthepalliativeemergencysetting,allpatientswereoperated A total of 49 patients who underwent quaternary surgery in our
also in terms of en-bloc resections, and removal of large parts of institution were identified. The total number of operations
thetumourtogetherwiththeobstructedsmallorlargebowel.Main conducted at the same time due to primary malignant lesions of
reasonforthatwasthatinthisquaternarysettingasimplesurgery, theovary/peritoneumorfallopiantubeofanystagewas1029and
suchasmerelyileostomyorcolostomywasnotfeasibleduetothe 743forovariancancerrelapseofanyline.Ineight(16.3%)patients
massive adhesions, which in combination with the peritoneal quaternarysurgerywasperformedafterthefourthrelapse,whereas
carcinosis or even peritonitis made any simple dissection in four (8.2%) patients quaternary surgery was even performed
impossible. For that reason, surgical effort was in these patients after the fifth relapse. In all, 70% of the patients underwent QC
equal if not higher compared with the elective surgeries and we between 3 and 10 years after primary diagnosis of the malignant
performed all dissections in terms of an extraperitoneal, en-bloc disease withamedian of16months (range: 2–142)after previous
preparation. Patients who presented with ascites and/or diffuse chemotherapy. Forty-four (89.8%) patients had a first-line
www.bjcancer.com|DOI:10.1038/bjc.2012.544 33
BRITISHJOURNAL OF CANCER Quaternary surgery inovarian cancer
Table1.Patients,tumour-relatedandsurgicalcharacteristicsofthe49 Table1.(Continued)
patientswhounderwentQCduetoEOCrelapse
Operativemorbidityandmortality
Variables Patients,n(%)
Anymajoroperativecomplication 14(28.6%)
N 49
Medianageatsurgery(years) 57(28–76) Majorcomplications
FIGOstageatprimarydiagnosis Anastomoticinsufficiency 3(6.1%)
Postoperativefistulaformation 1(2%)
I 6(12.2%) Thromboembolicevent 1(2%)
II 6(12.2%) Infection/sepsis 9(18.4%)
III 33(67.3%) Postoperativehaemorhage 4(8.2%)
IV 1(2.04%)
Symptomaticthrombosis/embolism
Histology
Shortbowelsyndrome 1(2%)
Serous-papillary 33(67.3%) Bowelobstruction 1(2%)
Mucinous 1(2%) Pneumonia/Pleuraeffusion 6(12.2%)
Endometriod 12(24.5%) Multiorganfailure 2(4.1%)
Clearcell 3(6.1%) 30-daysmortality 1(2%)
Intraoperativeascites
Abbreviations:EOC¼epithelialovariancancer;FIGO¼InternationalFederationofGyne-
cologyandObstetrics;LND¼lymphnodedissection;QC¼quaternarycytoreduction.
None 33(67.3%)
o500ml 12(24.5%)
X500ml 2(4.1%)
Grading platinum-based chemotherapy (i.e., paclitaxel plus carboplatin or
carboplatin plus cyclophosphamide). Thirty-one patients (63.3%)
G1 3(6.1%) wereinitiallyplatinumsensitive.Only13patients(26.5%)received
G2 11(22.4%) platinum asthird- orfourth-line chemotherapy beforequaternary
G3 29(59.2%) surgery. The vastmajority of thepatients (67.3%) hada FIGO III
MedianCA125(U/ml) tumourstage.Although490%ofthepatientshadnooro500ml
ascites, 38 patients (77.6%) presented a peritoneal carcinomatosis
Preoperative 736(28–2843) at quaternary surgery. Relevant patients- and tumour-related
After3cyclesofchemotherapy 220(19–365) characteristicsarepresentedinTable1.Only4(8%)patientswere
Afterchemotherapycompletion 84(21–156) operatedinanacuteemergencysettingduetobowelobstructionor
perforation, the other 45 patients (92%) were operated in an
Postoperativetumorresiduals
elective setting due to symptomatic but potentially resectable
None 16(32.6%) disease.
p0.5cm 15(30.6%) Median duration of surgery was 292min (range: 62–670min).
0.5–1cm 9(18.3%) In 32.6% of the patients a total macroscopic tumour clearance
41cm 9(18.3%) couldbeobtained(Table1).Morethan80%ofthepatientshada
tumour involvement of the middle and lower abdomen. Detailed
Yearsafterprimarydiagnosis
tumourdisseminationpatternsarepresentedinTable2.Following
2–3years 3(6.1%) anatomic structures were affected with tumour: large bowel 34
3–5years 20(40.8%) (69.4%),smallintestine30(61.2%),mesentery24(49%),pelvicside
5–10year 14(28.5%) wall 22 (44.9%), abdominal wall 21 (42.9%), pouch of douglas/
410years 12(24.5) vaginal cuff 15 (30.6%), diaphragm 11 (22.4%), omentum 10
(20.4%),liver/livercapsule8(16.3%),greatercurvatureofstomach
Lymphnodesaffected
5 (10.2%) and spleen 5 (10.2%).
N0 4(8.2%) In the vast majority of the patients a multivisceral surgical
N1 14(28.6%) approach was required to achieve optimal tumour resection. All
Nx 31(63.3%) surgical procedures performed are presented in Table 1. Median
numberofperformedintestinalresectionswas1(range:0–4)with
Operativeprocedure
mediannumbersofintestinalanastomosesof1(range:0–4).Inup
Peritonectomy 21(42.9%) to10%ofthepatientsbulkylymphnodeshadtoberemoved;with
PelvicLND 2(4.1%) mediannumberofremovedpelvicandparaaorticlymphnodesof
ParaaorticLND 5(10.2%) 3 (range: 1–11) and 5 (range: 1–23), respectively. Rates of major
Peritonectomy 21(43%) operative morbidity and 30-day mortality were 28.6% and 2%,
Partialliverresection 3(6.1%) respectively. Details are presented in Table 1.
Livercapsuleresection 1(2%) Withinameanfollow-uptimeof18.41months(95%CI:12.64–
Smallbowelresection 25(51%) 24.18), 38 patients (77.6%) have died. No autopsy was performed
Largebowelresection 21(42.9%) in any of the cases, but clinically all patients died due to tumour
Partialgastrectomy 1(2%) progression or tumour-related complications.
Ileostomy 10(20.4%) Mean PFS for the entire patient population was 22.5 months
Colostomy 6(12.2%)
(95% CI: 13.6–32.2). In a patients population where 32.6% of the
Cholecystectomy 2(4.1%)
patients underwent total macroscopic clearance, mean OS was
Splenectomy 2(4.1%)
23.05months(95%CI:15.5–30.6)andmedianOSwas10months
Diaphragmaticresection 1(2.0%)
(95% CI: 0.1–22 months).
34 www.bjcancer.com|DOI:10.1038/bjc.2012.544
Quaternary surgeryinovarian cancer BRITISH JOURNALOF CANCER
Table2.Intraoperativetumourdisseminationpatternandfieldsof Survival functions
highertumourloadandtumourresidualsaccordingtointraoperative
10
mappingofovariancancer
A B C 0.8 Total
Median (range) macroscopic
Level 3 Nabudmobmeirn oafl ftiuemldosr involved 4 (1–9) clearance
Number of abdominal fields with 1 (1–6)
highest tumor load
Level 2 Number of abdominal fields with 1 (0–9) al 0.6
tumor residuals v
Level 1 T-luomweorr apbadttoemrnen (level 1) 4n2 ( %(8)5.7%) survi
-middle abdomen (level 2) 39 (79.6%) m
IMO: intraoperative mapping of ovarian cancer-upper abdomen (level 3) 21 (42.9%) Cu 0.4
P=0.001
0.2
Any tumor
When stratifying the patients according to their postoperative
residuals
tumour residuals, then patients who underwent a total macro-
0.0
scopic tumour clearance had with a mean OS of43 months (95%
CI: 26.4–59.5) a highly significantly better outcome (P¼0.001)
0 20 40 60 80
thanthosepatientswithanytumourresidualswhopresentedmean
OS rates of 13.4 months (95% CI: 7.42–19.4). Survival curves are Postoperatives follow-up
presented in Figure 1. Interestingly, there was no significant
difference in OS between patients operated due to the third or Survival functions
more than the third relapse (P¼0.42).
10
Thirty-one patients (63.3%) did not receive any subsequent
systemicchemotherapyafterquaternarysurgery.Thereasonswere
as follows: 1 (2%) patient died, 23 (47%) patients refused any Postoperative
systemictreatmentand7(14.2%)patientsweretooweaktoreceive 0.8 chemotherapy
any chemotherapy. Mean OS was for those patients who received
postoperative adjuvant treatment significantly higher compared
withpatientswhodidnotreceiveanychemotherapy(40.5months; al 0.6
95% CI: 27.4–53.6 vs 12.03 months; 95% CI: 5.9–18.18, viv
respectively; Po0.001). Survival curves are presented also in ur
s
Figure1.Thereasonsfornotreceivingapostoperativechemother- m
apy were not assessed. Cu 0.4 P<0.001
Univariateanalysisidentifiedonlyincompletetumourresection
(P¼0.001), multifocal tumour dissemination (P¼0.001; i.e., 44
IMO fields involved with tumour) and no chemotherapy after 0.2
quaternary surgery (Po0.001) as having a negative significant
impactonOS.NosignificantimpactonOSappearedtohave:age No postoperative
465 years (P¼0.32), ascites (P¼0.45), extrapelvic tumour chemotherapy
0.0
involvement (P¼0.24), grading (P¼0.16), FIGO IIIc/IV vs lower
(P¼0.8) and initial platinum response (P¼0.67).
0 20 40 60 80
However, in multivariate analysis, tumour residuals failed to
Postoperatives follow-up
retain any prognostic significance for OS and only multifocal
tumour dissemination, defined as 44 IMO fields affected with Figure1.Survivalcurvesofovariancancerpatientsafterquaternary
tumour, was identified to negatively affect OS. Systemic debulkingsurgeryaccordingto(A)postoperativetumourresidualsand
chemotherapy subsequent to quaternary surgery was shown to (B)theapplicationofpostoperativesystemicchemotherapy.
have a significant protective impact on OS (Table 3).
In univariate analysis no factors could be identified to
significantlyaffectPFS:advancedage465years(P¼0.10),ascites residuals, extrapelvic tumour involvement, platinum sensitivity
4500ml (P¼0.60), tumour residuals (P¼0.25), 44 IMO fields and advanced age 465 years failed to reveal any independent
oftumourinvolvement(P¼0.34),extrapelvictumourinvolvement significant impact. Detailed multivariate analysis data are pre-
(P¼0.664),initialadvancedFIGOstageIIIcorIV(P¼0.83),high sented in Table 3.
grading (P¼0.17) and platinum responder after first-line che- When evaluating separately only the four patients who were
motherapy (0.78). operated in anonelective setting due to bowel obstruction (n¼3)
Multivariate analysis identified only limited tumour pattern, or intestinal perforation (n¼1); then median OS was only
defined as 4 or less IMO fields being involved with tumour, 5months(range:0.1–11months).Theonepatientwithperforation
to be protective against surgical morbidity (HR¼0.082; 95% CI: died on the twentieth postoperative day and all other patients
0.011–0.61; P¼0.015). Also multifocal tumour dissemination, developed at least one major complication such as abscess
defined as44tumouraffected IMOfields, wasidentified tohave formationorimpairedwoundhealing.Noneofthepatientscould
an independent significant risk of incomplete tumour resection beoperatedcompletelytumourfree,butintwoofthefourpatients
(HR¼11.5; 95% CI: 1.17–112.4; P¼0.036). Other factors postoperative residual disease was o1cm. One of these four
such as high grading, ascites 4500ml, postoperative tumour patients managed to receive a postoperative systemic treatment.
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BRITISHJOURNAL OF CANCER Quaternary surgery inovarian cancer
Table3.MultivariateanalysisforOS,postoperativetumourresidualsandoperativemorbidityafterquaternaryinEOCrelapse
Variable HR 95%CI P-value
OSa
Postoperativechemotherapy(yesvsno)b 0.29 0.13–0.65 0.003
Multifocaltumourdissemination(44vsp4numberoftumouraffectedIMOfields) 3.14 1.43–6.9 0.004
Postoperativetumourresidualsc
Multifocaltumourdissemination(44vsp4numberoftumouraffectedIMOfields) 11.5 1.17–112.4 0.036
Operativemorbidityd
Limitedtumourdissemination(p4vs44numberoftumouraffectedIMOfields)b 0.082 0.011–0.61 0.015
Abbreviations:CI¼confidenceinterval;EOC¼epithelialovariancancer;HR¼hazardratio;IMO¼intraoperativemappingofovariancancer;OS¼overallsurvival.
aNotsignificant:grading;G3vsG1/G2(P¼0.09);ascites:o500mlvsX500ml(P¼0.41);tumourresiduals:nonevsany(P¼0.65);extrapelvictumourinvolvement:yesvsno(P¼0.79)andage:
o65vs465years(P¼0.49).
bProtective.
cNotsignificant;grading:G3vsG1/G2(P¼0.37);platinumsensitivity:yesvsno(P¼0.46)andextrapelvictumourinvolvement:yesvsno(P¼0.55).
dNotsignificant;grading:G3vsG1/G2(P¼0.58);extrapelvictumourinvolvement:yesvsno(P¼0.108),platinumsensitivity:yesvsno(P¼0.16)andage:o65vs465years(P¼0.99).
couldbeobtained.Incontextwithourdatatheyalsoreportedthat
DISCUSSION
all other well-established predictive factors for primary ovarian
cancerandfirstrelapsesuchastimetorecurrenceandresponseto
The present systematic evaluation represents the largest analysis platinum failed to retain any prognostic value on survival. This
of cytoreductive surgical effort beyond the tertiary cytoreduction paradigm shift that appears to occur in terms of loss of value of
sofar.Wecouldshowthateveninthishighlypalliativesituationof conventionalprognosticandpredictivefactorsisnotnew.Inallsix
the fourth or higher EOC relapse postoperative residual tumour so far existing studies evaluating tertiary cytoreduction in EOC,
andmultimodalityoftreatmentintermsofpostoperativesystemic there is clear evidence that otherwise established common clinical
chemotherapy were associated with a significant prolongation of factors were not able to adequately predict surgical outcome after
survival. These findings are congruent to the well-established tertiary surgery (Leitao et al, 2004; Karam et al, 2007; Gultekin
experiences already reported for the primary, secondary or even et al, 2008; Shih et al, 2010a; Fotopoulou et al, 2011a; Hızlı et al,
tertiarycytoreductionagainstEOC;wheremaximalsurgicaleffort, 2012). This is probably attributed to the high patients’ selection
reflected in minimal postoperative residual disease, was translated thatinevitablyoccursintheseadvancedsettings.Incontrasttothe
inasignificant survivalbenefit (Gadducci et al,2000;Leitao et al, initial onset of EOC where all patients undergo surgery, even of
2004; Pfisterer et al, 2005; Chi et al, 2006; Harter et al, 2006; variablequalityandeffort,candidatesforsecondaryandevenmore
Benedetti et al, 2007; Karam et al, 2007; Gultekin et al, 2008; for tertiary surgery are mostly being carefully selected, so that
Schorgeetal,2010;Shihetal,2010a;Fotopoulouetal,2011a;Hızlı selection bias interfere with any prognostic analyses. A major
et al, 2012). Despite the extensive tumour dissemination with drawback of most evaluations of relapse surgeries is the retro-
almost half of the patients carrying tumour load in the upper spective and not systematic character of data assessment,
abdomen and more than two-thirds of the patients presenting resulting in complete lack of transparency of the indications
peritoneal carcinomatosis, we could achieve an optimal tumour forsurgeryandofthecriteriausedtoselecttheoptimalcandidates.
reduction in 460% of the patients. This underlines the value of An ongoing open prospective randomised trial of the German
high-quality surgery performed in specialised centres with AGO group, the DESKTOP III, aims to prospectively validate
adequate infrastructure and experience (Aletti et al, 2009). The for the first time the AGO score for identification of the
fact that tumour residual disease failed to retain any prognostic ‘optimal’ candidates for secondary cytoreduction, who would
significance forsurvivalinmultivariate analysismaybeattributed benefit from a surgical approach. A further prospectively
to the small number of patients, where multifactorial multivariate randomised trial of the GOG group (GOG 213) bring the entire
analysis has to be interpreted with caution. concept even a step forward by additionally testing the value
Interestingly, other factors with well-established prognostic of bevacizumab in the secondary setting: patients are stratified
value such as ascites, peritoneal carcinomatosis, platinum resis- to whether or not they are surgical candidates. If patients are
tance, high grading and extrapelvic tumour involvement failed to deemedtobesurgicalcandidatestheyarerandomisedtosurgeryor
retain any prognostic significance for this quaternary setting. no surgery followed by randomisation to chemotherapy.
Moreover, we found that survival was not significantly different If patients are randomised to no surgery they are subsequently
between patients operated due to the third or higher number for randomised to carboplatin and paclitaxel or carboplatin/paclitaxel
relapses. The factor ‘platinum resistance’, which nowadays and bevacizumab.
constitutes an almost restrictive factor against secondary cytor- Wereportofmajoroperativemorbidityratessimilartothe20%
eduction, does not appear to have any role in the quaternary reported by Shih et al (2010b). When we evaluate this under the
setting.Thismaybeexplainedbythehighselectionprocessofthe perspective of heavy pretreatment, including multiple prior
surgical candidates. cytotoxic therapies and multiple surgeries, it cannot be regarded as
Two years ago Shih et al (2010b) published the first unexpectedly high. A relevant point of attention is, however, that
monocentric experience with quaternary surgery for EOC relapse both centres represent highly specialised, reference centres for
includingthelimitednumberof15patients.Theirfindingsshowed ovariancancersurgery,emphasisingoncemorethetightassociation
remarkable equivalence to ours: thenumber of sites of recurrence ofsurgicalexcellenceandlowoperativemorbidity(Alettietal,2009).
and optimal tumour debulking were associated with a prolonged A further highly important finding of this analysis is the
survival, especially when a total macroscopic tumour clearance significantimpactofpostoperativesystemicchemotherapyonOS.
36 www.bjcancer.com|DOI:10.1038/bjc.2012.544
Quaternary surgeryinovarian cancer BRITISH JOURNALOF CANCER
Even though this may constitute a selection bias as those patients T,KayeS,KitchenerH,KristensenG,MannelR,MeierW,MillerB,Neijt
who were fit enough to tolerate chemotherapy following radical JP,OzaA,OzolsR,ParmarM,PecorelliS,PfistererJ,PovedaA,
surgery may anyway have a more favourable survival compared ProvencherD,Pujade-LauraineE,RandallM,RochonJ,RustinG,SagaeS,
with those patients who were too weak to tolerate any systemic StehmanF,StuartG,TrimbleE,VaseyP,VergoteI,VerheijenR,Wagner
U.GynecologicCancerIntergroup;AGO-OVAR;ANZGOG;EORTC;
treatment, our findings underline the importance of combinative
GEICO;GINECO;GOG;JGOG;MRC/NCRI;NCIC-CTG;NCI-US;
systemic and surgical treatment in the fight against EOC even in
NSGO;RTOG;SGCTG;IGCS;Organizationalteamofthetwoprior
this advanced setting. These results are similar to those recently
InternationalOCCC(2005)2004Consensusstatementsonthe
reported by the authors of the largest multicenter, international
managementofovariancancer:finaldocumentofthe3rdInternational
analysis of tertiary surgery evaluating 4400 EOC patients GynecologicCancerIntergroupOvarianCancerConsensusConference
(Fotopoulouetal,2012),wherethepatientscohortthatunderwent (GCIGOCCC2004).AnnOncol16(Suppl8):viii7–viii12.
postoperative systemic chemotherapy had a highly significant duBoisA,ReussA,Pujade-LauraineE,HarterP,Ray-CoquardI,PfistererJ
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