Age related differences in prognosis and prognostic factors among patients with epithelial ovarian cancer

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1 MOLECULAR AND CLINICAL ONCOLOGY 9: , 2018 Age relted differences in prognosis nd prognostic fctors mong ptients with epithelil ovrin cncer KENJI YOSHIKAWA, TAKESHI FUKUDA, RYO UEMURA, HIROAKI MATSUBARA, TAKUMA WADA, MASARU KAWANISHI, REIKO TASAKA, MARI KASAI, YASUNORI HASHIGUCHI, TOMOYUKI ICHIMURA, TOMOYO YASUI nd TOSHIYUKI SUMI Deprtment of Obstetrics nd Gynecology, Osk City University Grdute School of Medicine, Osk, Osk , Jpn Received Mrch 30, 2018; Accepted July 3, 2018 DOI: /mco Abstrct. Approximtely 40% of ll ptients with ovrin cncer in Jpn re ged 65 yers. The im of the present study ws to evlute the differences in prognosis nd prognostic fctors between elderly nd younger ptients with epithelil ovrin cncer. A totl of 114 ptients with Interntionl Federtion of Gynecology nd Obstetrics (FIGO) stge I IV ovrin cncer who were initited on primry tretment t the Osk City University Hospitl (Osk, Jpn) were included in this study. Ptient chrcteristics, tretment outcome nd prognosis were compred between elderly (ged 65 yers) nd younger ptients, nd the prognostic fctors ssocited with overll survivl were evluted by univrite nd multivrite nlyses. The most common histologicl type in younger ptients ws cler cell crcinom (33.8%) vs. serous crcinom in elderly ptients (44.1%), with significnt difference in the distribution of histologicl type (P=0.006). Complete resection ws chieved in 56.2% of younger ptients compred with 32.4% of elderly ptients (P=0.03). The rtes of stndrd primry tretment were comprble (56.7% of younger vs. 50.0% of elderly ptients). Overll nd disese free survivl did not differ significntly between the two groups. Multivrite nlyses identified FIGO stge nd stndrd primry therpy s prognostic fctors in younger ptients nd performnce sttus in elderly ptients. Age ws not n independent significnt prognostic fctor mong ptients with ovrin cncer. Therefore, performnce sttus, rther thn ge, should be considered when selecting the optiml tretment for elderly ptients bsed on objective ssessment. Correspondence to: Dr Tkeshi Fukud, Deprtment of Obstetrics nd Gynecology, Osk City University Grdute School of Medicine, Ashimchi, Abeno ku, Osk, Osk , Jpn E mil: tkeshif@med.osk cu.c.jp Key words: chemotherpy, elderly, ovrin cncer, prognosis, survivl Introduction Ovrin cncer hs the highest mortlity rte mong gynecologicl tumors worldwide (1). The incidence of ovrin cncer in Jpn hs been incresing over the pst 20 yers, with n estimted ~10,400 new cses of ovrin cncer dignosed nd 4,800 ovrin cncer relted deths in 2017 (2). Epithelil ovrin cncer (EOC) is the most common histologicl type of ovrin cncer, nd the stndrd primry tretment (SPT) is primry debulking surgery (PDS), followed by six cycles of combintion chemotherpy with pclitxel nd pltinum contining drug, dministered every 3 weeks (3 5). Approximtely 40% of ll ptients with ovrin cncer in Jpn re ged 65 yers (2), nd the rpidly ging popultion suggests tht the number of elderly women requiring tretment for ovrin cncer is likely to increse. In generl, elderly ptients re likely to hve multiple comorbidities, poor performnce sttus (PS), nd require socil nd fmily support for their dily ctivities, which mens tht they my not be ble to dpt to stndrd tretments. Elderly ptients with ovrin cncer hve thus been therpeuticlly undertreted compred with younger ptients (6 8). Elderly ptients re lso more likely to be excluded from clinicl trils due to comorbidities, polyphrmcy, poor functionl sttus nd frgility; therefore, evidence for suitble tretment strtegies for elderly ptients is lcking. Previously reported prognostic fctors for ovrin cncer include Interntionl Federtion of Gynecology nd Obstetrics (FIGO) stge, histologicl subtype nd grde, volume of the residul tumor fter surgicl resection, PS nd ge (9). However, the prognostic effect of ge remins controversil (10), nd the difference in prognostic fctors between elderly nd younger ptients is not evident. The im of the present study ws to compre the survivl of elderly nd younger ptients with EOC, nd determine the differences in prognostic fctors between the two groups. Ptients nd methods Inclusion criteri. This retrospective study included consecutive ptients with epithelil ovrin, fllopin tubl or peritonel cncers, who were initited on primry tretment for ovrin cncer t our institution between Jnury 2008 nd

2 330 YOSHIKAWA et l: AGE AND PROGNOSIS OF OVARIAN CANCER December All ptients with stge I IV disese ccording to the FIGO stging clssifiction were included, wheres ll ptients with borderline tumors were excluded. Clinicopthologicl chrcteristics. Ptient dt were obtined from electronic medicl chrts t our institution nd included demogrphic, surgicl, pthologicl, therpeutic nd survivl informtion. The clinicopthologicl chrcteristics recorded included ge t dignosis, body mss index, PS, histologicl type, FIGO stge, nodl sttus, lbumin, hemoglobin nd biomrker (CA 125) levels, nd the therpeutic chrcteristics included neodjuvnt chemotherpy, surgery, intropertive blood loss, opertive time, residul tumor, SPT, recurrence sttus nd secondry debulking surgery. No residul tumor ws defined s the bsence of ny mcroscopic residul tumor t the end of PDS. SPT ws defined s completing t lest six cycles of djuvnt chemotherpy fter surgery, except for stge 1A nd 1B ptients; SPT in cses with stge 1A nd 1B disese ws defined s PDS without djuvnt chemotherpy. Adjuvnt chemotherpy minly involved six cycles of combintion chemotherpy with pclitxel nd pltinum contining drug s the bsic regimen, lthough this could vry depending on the ptient's condition. Overll survivl (OS) ws clculted s the time from the strt of primry therpy to the dte of deth, nd disese free survivl (DFS) ws clculted s the time from the strt of primry therpy to the dte of recurrence or deth. Ptients who remined live were censored on the dte of the lst follow up. Dt collection. Study dt were collected nd mnged using the Reserch Electronic Dt Cpture (REDCp) electronic tool hosted t Osk City University Grdute School of Medicine (11). REDCp is secure, web bsed ppliction designed to support dt cpture for reserch studies. Ptient groups. The registered ptients were divided into two groups: An elderly group ged 65 yers nd younger group ged <65 yers. Ptient chrcteristics, tretment outcome nd prognosis were compred between the two groups. Univrite nd multivrite nlyses were lso performed to identify nd compre prognostic fctors in the overll study popultion, nd in elderly nd younger ptients. Sttisticl nlysis. Medin vlues were compred between the two ge groups s pproprite using the Mnn Whitney U test, nd ctegoricl vribles were compred using the χ 2 test. Kpln Meier survivl nlyses were performed for OS nd DFS, nd the significnce of differences between the groups ws determined using the log rnk test. A Cox proportionl hzrds model ws used to clculte hzrd rtios for OS nd 95% confidence intervls, djusting for prognostic vribles. A P vlue of <0.05 ws considered to indicte sttisticlly significnt differences. All sttisticl nlyses were performed using EZR (Sitm Medicl Centre, Jichi Medicl University, Sitm, Jpn), which is grphicl user interfce for R (The R Foundtion for Sttisticl Computing, Vienn, Austri). More precisely, it is modified version of R commnder designed to dd sttisticl functions frequently used in biosttistics (12). Results Ptient chrcteristics. A totl of 114 ptients ged yers were included in this study, including 80 ptients in the elderly group nd 34 in the younger group. The ptient chrcteristics re summrized in Tble I. There ws significnt difference in the distribution of histologicl types between the elderly nd younger ptients (P=0.006), with cler cell crcinom being the most common histologicl type in younger ptients (33.8%), vs. serous crcinom in elderly ptients (44.1%). More dvnced cncers (stge III nd V) were observed mong elderly ptients, wheres erlier stge cncers (stge I) were observed mong younger ptients, lthough there ws no significnt difference in stge distribution between the groups. However, there ws significnt difference between the two groups in terms of residul tumor fter PDS: 56.2% of younger ptients hd no residul tumor, compred with only 32.4% of elderly ptients (P=0.03). There were no sttisticlly significnt differences between the two groups in terms of the other vribles. Survivl comprison. There ws no significnt difference in OS between the elderly nd younger groups (medin OS, 48 months vs. not reched, respectively; P=0.501, Fig. 1). The 5 yer OS in elderly ptients ws 48.3% compred with 57.6% in younger ptients. The medin DFS ws lower in elderly ptients compred with tht in younger ptients, but the difference ws not sttisticlly significnt (19.5 vs months, respectively; P=0.107, dt not shown). Uni nd multivrite nlysis. The univrite Cox proportionl hzrds model of OS for ll ptients identified PS, stge, residul tumor nd SPT s significnt prognostic fctors (P<0.0001, P<0.0001, P< nd P=0.001, respectively), while stge nd SPT were independent prognostic fctors ccording to multivrite nlysis (P= nd P<0.0001, respectively, Tble II). In younger ptients, PS, stge, residul tumor nd SPT were significnt prognostic fctors in univrite nlysis (P=0.02, P<0.0001, P< nd P=0.04, respectively), wheres stge nd SPT were independent prognostic fctors in multivrite nlysis, similr to the results for the overll study popultion (P= nd P=0.0006, respectively, Tble III). However, in elderly ptients, only PS nd SPT were found to be significnt prognostic fctors in univrite nlysis (P= nd P<0.0001, respectively), nd only PS ws n independent prognostic fctor in multivrite nlysis (P=0.02, Tble IV). Elderly ptients with PS of 0 hd 5 yer OS rte of 65.2%, which ws comprble to tht of younger ptients. By contrst, the OS in elderly ptients with PS of 1 nd 2 ws very poor, with 5 yer OS rte of 0%, which ws significntly poorer compred with tht in younger ptients (P=0.0003, Fig. 2). Discussion The im of this retrospective study ws to evlute the differences in ptient chrcteristics, survivl outcome, nd prognostic fctors between elderly nd younger ptients with FIGO stge I IV ovrin cncer who received primry tretment t single gynecologicl oncology institution in Jpn.

3 MOLECULAR AND CLINICAL ONCOLOGY 9: , Tble I. Ptient chrcteristics. Groups Chrcteristics <65 yers n=80, n (%) 65 yers n=34, n (%) P vlue Age, yers Medin (Q1, Q3) 51 (47, 58) 71 (68,73) <0.001 BMI, kg/m 2 Medin (Q1, Q3) 22.7 (19.9, 24.9) 22.2 (20.2, 24.2) 0.57 PS 0 61 (76.2) 26 (76.5) (21.2) 6 (17.6) 2 2 (2.5) 2 (5.9) Histologicl type Serous 16 (20.0) 15 (44.1) Mucinous 15 (18.8) 5 (14.7) Cler cell 27 (33.8) 2 (5.9) Endometrioid 17 (21.2) 7 (20.6) Other 5 (6.2) 5 (14.7) Stge I 31 (38.8) 5 (14.7) 0.08 II 7 (8.8) 5 (14.7) III 35 (43.8) 19 (55.9) IV 7 (8.8) 5 (14.7) Nodl sttus pn0 42 (52.5) 14 (41.2) 0.12 pn1 18 (22.5) 5 (14.7) pnx 20 (25.0) 15 (44.1) Albumin, g/dl Medin (Q1, Q3) 3.9 (3.5, 4.2) 3.9 (3.3, 4.1) 0.71 Hemoglobin, g/dl Medin (Q1, Q3) 12.0 (10.6, 13.1) 11.9 (11.0, 12.9) 0.78 CA 125, U/ml Medin (Q1, Q3) (76.5, 1,780.5) (99.5, 3,178.3) 0.27 NAC No 75 (93.8) 28 (82.4) 0.12 Yes 5 (6.2) 6 (17.6) Surgery No 1 (1.2) 1 (2.9) 1 Yes 79 (98.8) 33 (97.1) Intropertive blood loss, ml Medin (Q1, Q3) 985 (560, 2,160) 1,060 (515, 1,920) 0.63 Opertive time, min Medin (Q1, Q3) 246 (195, 299) 204 (169, 247) 0.06 Residul tumor No 45 (56.2) 11 (32.4) 0.03 Yes 35 (43.8) 23 (67.6) SPT No 34 (42.5) 17 (50.0) 0.60 Yes 46 (57.5) 17 (50.0) Recurrence sttus No 41 (51.2) 13 (38.2) 0.29 Yes 39 (48.8) 21 (61.8) SDS No 75 (93.8) 33 (97.1) 0.79 Yes 5 (6.2) 1 (2.9) SPT ws defined s completing t lest 6 cycles of djuvnt chemotherpy fter surgery in principle. Bold print indictes sttisticlly significnt P vlues. Q, qurtile; BMI, body mss index; NAC, neodjuvnt chemotherpy; SPT, stndrd primry therpy; SDS, secondry debulking surgery. Although numerous studies hve exmined the ssocition between ge nd prognosis in Europe nd the United Sttes, only few studies from Jpn hve been published to dte. Given tht dignosis, tretment, environment nd conditions differ mong countries, regionl differences should be considered when ssessing prognostic fctors. Our dt suggested tht ge, defined by cut off of 65 yers, ws not prognostic fctor for either OS or DFS. FIGO stge nd SPT were prognostic fctors in the overll ptient popultion, but the prognostic fctors differed between elderly nd younger ptients. Multivrite nlysis identified FIGO stge nd SPT s independent prognostic fctors in younger ptients, s well s for ll ptients, but only PS ws n independent prognostic fctor in elderly ptients. An ssocition between ge nd prognosis hs been reported in severl studies. Trillsch et l evluted 275 ptients with FIGO stge II IV EOC undergoing cytoreductive surgery nd pltinum bsed chemotherpy, nd found tht ge ws prognostic fctor for OS, but not for PFS (7). Sbtier et l compred 109 elderly ptients with 488 younger ptients with histologiclly invsive EOC, nd identified ge s n independent prognostic fctor for OS (8). There re severl possible

4 332 YOSHIKAWA et l: AGE AND PROGNOSIS OF OVARIAN CANCER Tble II. Univrite nd multivrite nlysis of OS for ll ptients (n=114). Univrite nlysis Multivrite nlysis Vribles HR (95% CI) P vlue HR (95% CI) P vlue Age, yers <65 vs ( ) ( ) 0.11 PS 0 vs. 1, ( ) < ( ) 0.16 Stge 1,2,3, ( ) < ( ) Residul tumor No vs. yes 4.30 ( ) < ( ) 0.18 SPT b No vs. yes 0.40 ( ) ( ) < Stge is n ordinl vrible. b SPT ws defined s completing t lest 6 cycles of djuvnt chemotherpy fter surgery in principle. Bold print indictes sttisticlly significnt P vlues. HR, hzrd rtio; 95% CI, 95% confidence intervl; PS, performnce sttus; SPT, stndrd primry therpy. Figure 1. Kpln Meier curves of overll survivl (OS) ccording to ge (0: <65 yers, 1: 65 yers). Figure 2. Kpln Meier curves of overll survivl (OS) for elderly ptients ccording to performnce sttus (PS) compred with younger ptients (0: <65 yers, 1: 65 yers with PS 0 nd 2: 65 yers with PS 1 nd 2). resons why ge ws not found to be significnt prognostic fctor in the present study. First, the results my hve been ffected by the cut off vlue for elderly ptients. Although cut off ge of 65 yers hs commonly been used, the ge criteri hve differed mong previous studies (6 8,13 17). Thus, the prognostic vlue of ge my depend on the criteri for defining ptients s elderly. Second, there ws no significnt difference in clinicopthologicl chrcteristics between the two groups, except for histologicl type, including body mss index, PS, FIGO stge, nodl sttus, lbumin, hemoglobin nd CA 125 levels. Third, there ws no mjor difference in the implementtion rte of SPT, defined s completion of t lest six cycles of djuvnt chemotherpy fter surgery, with 57.6% of younger ptients nd 50% of elderly ptients treted with SPT. By contrst, severl previous studies reported tht elderly ptients were less likely to receive stndrd tretments, such s debulking surgery nd combintion chemotherpy, due to more dvnced disese nd functionl impirments (6 8,10). However, our dt reveled similr implementtion rtes of SPT between the two groups. This fct my be bsed on the lck of significnt difference in ptient chrcteristics between the two groups or the objective functionl evlution

5 MOLECULAR AND CLINICAL ONCOLOGY 9: , Tble III. Univrite nd multivrite nlysis of OS for younger ptients (n=80). Univrite nlysis Multivrite nlysis Vribles HR (95% CI) P vlue HR (95% CI) P vlue PS 0 vs. 1, ( ) 0.02 Stge 1,2,3, ( ) < ( ) Residul tumor No vs. yes 7.31 ( ) < ( ) 0.18 SPT b No vs. yes 0.49 ( ) ( ) Stge is n ordinl vrible. b SPT ws defined s completing t lest 6 cycles of djuvnt chemotherpy fter surgery in principle. Bold print indictes sttisticlly significnt P vlues. HR, hzrd rtio; 95% CI, 95% confidence intervl; PS, performnce sttus; SPT, stndrd primry therpy. Tble IV. Univrite nd multivrite nlysis of OS for elderly ptients (n=34). Univrite nlysis Multivrite nlysis Vribles HR (95% CI) P vlue HR (95% CI) P vlue PS 0 vs. 1, ( ) ( ) 0.02 Stge 1, 2, 3, ( ) 0.17 Residul tumor No vs. yes 1.21 ( ) 0.72 SPT b No vs. yes 4.30 ( ) < ( ) 0.16 Stge is n ordinl vrible. b SPT ws defined s completing t lest 6 cycles of djuvnt chemotherpy fter surgery in principle. Bold print indictes sttisticlly significnt P vlues. HR, hzrd rtio; 95% CI, 95% confidence intervl; PS, performnce sttus; SPT, stndrd primry therpy. of the elderly ptients t our fcility, suggesting the importnce of dpting stndrd therpy to elderly ptients. The elderly comprise heterogeneous popultion. In the present study, elderly ptients with PS of 0 hd n OS comprble to tht of younger ptients, while elderly ptients with PS of 1 nd 2 hd disml OS, with 5 yer OS rte of 0% (P=0.0003). The importnce of PS in elderly ptients is consistent with previous studies (7,8). We confirmed the bckgrounds of the elderly ptients ccording to PS, nd found more dvnced tumors in those with PS of 1 nd 2 compred with elderly ptients with PS of 0, lthough the difference ws not sttisticlly significnt (P=0.09). Despite hving more dvnced tumors, only 12.5% of elderly ptients with PS 1 nd 2 completed six cycles of stndrd chemotherpy, compred with 61.5% of elderly ptients with PS 0 (P=0.04). Elderly ptients with ovrin cncer my benefit from multidisciplinry pproch, including comprehensive evlution by gynecologist, oncologist, nurse nd phrmcist. Comprehensive geritric ssessments hve been shown to be ble to predict morbidity nd mortlity in elderly cncer ptients (18). However, the high heterogeneity of elderly ptients mens tht it is not fesible to mke tretment decisions bsed on ge lone, nd more objective ssessment is required. The present study hd certin limittions. First, selection bis ws unvoidble nd inherent to the retrospective nture of this study. Second, the reltively smll number of cses, prticulrly in the elderly group, ment tht the sttisticl power my not hve been sufficient to drw definitive conclusion. Finlly, other confounding fctors my hve been overlooked. However, this study lso hd certin strengths. As ll ptients with FIGO stge I IV EOC within certin period were enrolled, the results my strongly reflect the effect of ge on prognosis in clinicl prctice compred with the selected ptient cohort. In conclusion, elderly nd younger ptients with EOC hve different prognostic fctors but similr prognoses. Elderly

6 334 YOSHIKAWA et l: AGE AND PROGNOSIS OF OVARIAN CANCER ptients were s likely to receive stndrd primry therpy s younger ptients, nd ge ws not n independent significnt prognostic fctor. A key strtegy for improving the prognosis of ptients with EOC is to ensure the dministrtion of t lest six courses of stndrd djuvnt chemotherpy fter PDS, in considertion of FIGO stge. Therefore, PS, rther thn ge, should be considered when dpting the optiml tretment to elderly ptients with ovrin cncer bsed on objective ssessment. Acknowledgements The uthors would like to thnk ll those who contributed to this study, prticulrly the sttisticins nd collegues of Osk City University Grdute School of Medicine. We pprecite their help with dt mngement nd sttisticl support. We would lso like to thnk Susn Furness, PhD, from Ednz Group ( for editing drft of this mnuscript. Funding No funding ws received. Avilbility of dt nd mterils The dtsets used nd/or nlyzed during the current study re vilble from the corresponding uthor on resonble request. Authors' contributions KY nd TF contributed to the conception, design nd conduction of the study nd nlysis nd interprettion of the dt. TS contributed to the conception of the study nd interprettion of the dt. RU, HM, TW, MK, RT, MK, YH, TI nd TY contributed to dt collection nd the conduction of the study. All the uthors hve red nd pproved the finl version of this mnuscript. Ethics pprovl nd consent to prticipte This study ws performed ccording to the principles set out in the Declrtion of Helsinki 1964 nd ll subsequent revisions, nd ws pproved by the Institutionl Review Bord of Osk City University Grdute School of Medicine (IRB pprovl no. 3779). Ptient consent for publiction Not pplicble. Competing interests All uthors declre tht they hve no competing interests to disclose. 2. Cncer informtion service. 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