Advertisement

Impact of surgery and chemotherapy timing on outcomes in older versus younger epithelial ovarian cancer patients: A nationwide Danish cohort study

Open AccessPublished:August 18, 2022DOI:https://doi.org/10.1016/j.jgo.2022.08.008

      Abstract

      Introduction

      To explore differences in surgical complexity, chemotherapy administration, and treatment delays between younger and older Danish patients with epithelial ovarian cancer (EOC).

      Materials and Methods

      We included a nationwide cohort diagnosed with EOC from 2013 to 2018. We described surgical complexity and outcomes, the extent of chemotherapy and treatment delays stratified by age (<70 and ≥ 70 years), and surgical modality (primary, interval, or no debulking surgery).

      Results

      In total, we included 2946 patients. For patients with advanced-stage disease, 52% of the older patients versus 25% of the younger patients did not undergo primary debulking surgery (PDS) or interval debulking surgery (IDS). For patients undergoing PDS or IDS, older patients underwent less extensive surgery and more often had residual disease after surgery >0 cm compared to younger patients. Furthermore, older patients were less often treated with chemotherapy. Older patients had PDS later than younger. We did not find any differences between age groups concerning treatment delays. Two-year cancer-specific survival differed significantly between age groups regardless of curatively intended treatment.

      Discussion

      This study demonstrates that older patients are treated less actively concerning surgical and oncological treatment than younger patients, leading to worse cancer-specific survival. Older patients do not experience more treatment delays than younger ones.

      Keywords

      1. Introduction

      Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy for which long-term survival is conditioned by surgery often combined with chemotherapy [
      • Ferlay J.
      • Ervik M.
      • Lam F.
      • Colombet M.
      • Mery L.
      • Piñeros M.
      • et al.
      Global Cancer Observatory: Cancer Today.
      ,
      • Sorensen S.M.
      • Schnack T.H.
      • Hogdall C.
      Impact of residual disease on overall survival in women with Federation of Gynecology and Obstetrics stage IIIB-IIIC vs stage IV epithelial ovarian cancer after primary surgery.
      ]. The balance between performing this comprehensive treatment combination and the EOC patient population, with a considerable number of older women, poses a continuous challenge in a clinical setting [
      • Ekmann-Gade A.W.
      • Høgdall C.K.
      • Seibæk L.
      • Noer M.C.
      • Fagö-Olsen C.L.
      • Schnack T.H.
      Incidence, treatment, and survival trends in older versus younger women with epithelial ovarian cancer from 2005 to 2018: A nationwide Danish study.
      ]. Older patients with EOC repeatedly demonstrate poor survival compared to younger [
      • Cabasag C.J.
      • Butler J.
      • Arnold M.
      • Rutherford M.
      • Bardot A.
      • Ferlay J.
      • et al.
      Exploring variations in ovarian cancer survival by age and stage (ICBP SurvMark-2): A population-based study.
      ]. However, although age may be an independent prognostic factor associated with decreased survival, age itself cannot explain the survival gap, and the underlying mechanisms remain unclear.
      Older patients may experience treatment delays, less aggressive surgery, and fewer chemotherapy cycles than their younger counterparts. Treatment biases in patterns of care may thus contribute to diverse prognostic outcomes. Although it has been established that older patients benefit equally from standard therapy regimens as younger, they are still less likely to undergo treatment [
      • Dumas L.
      • Bowen R.
      • Butler J.
      • Banerjee S.
      Under-treatment of older patients with newly diagnosed epithelial ovarian cancer remains an issue.
      ]. Thus, while inherent patient factors contribute to decreased survival, there is likely an effect related to differences in the patterns of care too.
      Almost half of EOC cases occur in patients ≥70 years, which is projected to increase [
      • Ekmann-Gade A.W.
      • Høgdall C.K.
      • Seibæk L.
      • Noer M.C.
      • Fagö-Olsen C.L.
      • Schnack T.H.
      Incidence, treatment, and survival trends in older versus younger women with epithelial ovarian cancer from 2005 to 2018: A nationwide Danish study.
      ]. As older patients seem to desire full treatment and disease cure as strongly as the young and do not regard their age as a barrier, challenges in clinical management should be scientifically prioritized [
      • Nordin A.J.
      • Chinn D.J.
      • Moloney I.
      • Naik R.
      • de Barros Lopes A.
      • Monaghan J.M.
      Do elderly cancer patients care about cure? Attitudes to radical gynecologic oncology surgery in the elderly.
      ,
      • Dumas L.
      • Lidington E.
      • Appadu L.
      • Jupp P.
      • Husson O.
      • Banerjee S.
      Exploring older women’s attitudes to and experience of treatment for advanced ovarian cancer: A qualitative phenomenological study.
      ].
      In Denmark, a national cancer patient pathway (NCPP), national treatment guidelines, mandatory multidisciplinary team conferences, and centralization of treatment have been implemented to optimize the time frame and uniform the diagnosis and treatment of EOC. Specific time frames describing steps leading to the diagnosis and treatment are carefully defined in the NCPP and enforced by the Danish Health Authorities [
      • Danish Health Authority [Sundhedsstyrelsen]
      Cancer patient pathway for ovarian cancer - for professionals [Pakkeforløb for kræft i æggestokkene - for fagfolk].
      ]. The NCPP ensures that patients are diagnosed and treated according to national guidelines without unnecessary waiting time, regardless of social factors. Adherence to guidelines is assured by registration in the Danish Gynecological Cancer Database (DGCD) and yearly reported clinical indicators [
      • Sorensen S.M.
      • Bjorn S.F.
      • Jochumsen K.M.
      • Jensen P.T.
      • Thranov I.R.
      • Hare-Bruun H.
      • et al.
      Danish gynecological cancer database.
      ]. While the NCPP has been shown effective regarding diagnostic delays [
      • Jensen H.
      • Tørring M.L.
      • Olesen F.
      • Overgaard J.
      • Fenger-Grøn M.
      • Vedsted P.
      Diagnostic intervals before and after implementation of cancer patient pathways - a GP survey and registry based comparison of three cohorts of cancer patients.
      ], very little is known about the benefits of the further treatment pathway for patients with EOC and whether differences exist between subgroups.
      To identify the gaps in the treatment of older patients, detailed and comprehensive assessments of baseline characteristics and treatment outcomes are required. We aimed to evaluate differences between older and younger patients regarding surgical complexity, chemotherapy management, and treatment delays with real-world data from Denmark.

      2. Materials and Methods

      2.1 Study Population and Data Sources

      We conducted a nationwide cohort study with data from the DGCD. We included all patients in Denmark aged 18 or older diagnosed with EOC (including primary cancer in the ovaries, fallopian tubes, or peritoneum) between January 1, 2013, and August 31, 2018. Patients with borderline or non-epithelial tumors were excluded.
      Patients were identified in the DGCD. The DGCD is a nationwide multidisciplinary database containing comprehensive information about all gynecological cancers with around 97% coverage rates and almost 100% follow-up [
      • Sorensen S.M.
      • Bjorn S.F.
      • Jochumsen K.M.
      • Jensen P.T.
      • Thranov I.R.
      • Hare-Bruun H.
      • et al.
      Danish gynecological cancer database.
      ]. In Denmark, cancer treatment is fully covered by public healthcare services, and all gynecological and pathological departments involved in the diagnostics and treatment of gynecological cancers are required to report to the DGCD by law. Data is registered prospectively and continuously in online data forms by gynecologists, pathologists, and nurses involved in the treatment. Shortage lists are created specifically for each hospital and repeatedly updated to provide maximal coverage. The DGCD is regularly linked to the Danish National Patient Registry (NPR) and the Danish Register of Causes of death. The NPR is a population-based administrative registry providing longitudinal recordings of diagnoses, treatments, and examinations with nationwide coverage from Danish hospitals since 1978 [
      • Schmidt M.
      • Schmidt S.A.J.
      • Sandegaard J.L.
      • Ehrenstein V.
      • Pedersen L.
      • Sorensen H.T.
      The Danish National Patient Registry: a review of content, data quality, and research potential.
      ]. In the current study, the NPR supplies data on the date of chemotherapy treatments allowing us to define the following chemotherapy outcomes; adjuvant chemotherapy treatment (yes/no), number of chemotherapy cycles, time-to-treatment (TTT), and time-to-chemotherapy (TTC). The patient was regarded as having had chemotherapy treatment if they had received one or more cycles in the first-line setting. The number of chemotherapy cycles describes the first-line treatment; however, it does not include maintenance therapy such as Bevacizumab and poly (ADP-ribose) polymerase inhibitors. The Danish Register of Causes of Death provides data from mandatory death certificates, including the date and ICD-10 coded cause of death [].
      We stratified the study population into two cohorts according to age at diagnosis: a younger cohort of patients aged <70 years and an older cohort of patients aged ≥70 years. Treatment modalities were divided into three groups based on the surgical treatment: primary debulking surgery (PDS), interval debulking surgery (IDS), and no debulking surgery (NDS), including palliative surgery, and chemotherapy only, or absence of any surgical or oncological treatment.
      To describe the extent of the surgery (PDS or IDS), we have used a laparotomy classification system (LAP) that was initially developed in Denmark to optimize interdisciplinary perioperative collaboration [
      • Bjørn S.F.
      • Schnack T.H.
      • Lajer H.
      • Christensen I.J.
      • Lundvall L.
      • Thomsen L.N.
      • et al.
      Classification of ovarian cancer surgery facilitates treatment decisions in a gynecological multidisciplinary team.
      ]. It comprises three categories of surgical intervention:
      LAP1: Bilateral salpingectomy, total hysterectomy, omentectomy, possibly appendectomy, and possibly pelvic lymphadenectomy.
      LAP2: LAP1 + at least one of the following: extensive pelvic peritonectomy, bowel resection with an ostomy, small intestine anastomosis, splenectomy, cholecystectomy, or aortic lymphadenectomy.
      LAP3: LAP2 + at least one of the following: extensive peritonectomy in the upper abdomen, diaphragm resection, liver resection, bowel resection with anastomosis.
      The standardized NCPP for EOC comprises a “package solution” with specified time intervals for each step from referral to diagnostic workup followed by evaluation by a multidisciplinary team and, finally, the start of treatment [
      • Danish Health Authority [Sundhedsstyrelsen]
      Cancer patient pathway for ovarian cancer - for professionals [Pakkeforløb for kræft i æggestokkene - for fagfolk].
      ,
      • Probst H.B.
      • Hussain Z.B.
      • Andersen O.
      Cancer patient pathways in Denmark as a joint effort between bureaucrats, health professionals and politicians--a national Danish project.
      ]. When analyzing time intervals and treatment delays in the current study, patients treated with PDS were separated from those treated with NACT-IDS in accordance with the NCPP pathway. We defined TTT as the time from the first visit to a tertiary center to the start of treatment (PDS or NACT) (Fig. 1). The NCPP specifies that a time interval of 24 days is permitted for patients referred to PDS, while a maximum of 25 days is allowed for patients referred to NACT [
      • Danish Health Authority [Sundhedsstyrelsen]
      Cancer patient pathway for ovarian cancer - for professionals [Pakkeforløb for kræft i æggestokkene - for fagfolk].
      ]. Hence, delay in TTT was classified as >24 or 25 days for PDS or NACT-IDS, respectively.
      Fig. 1
      Fig. 1Timing of epithelial ovarian cancer treatment
      Additionally, we defined TTC as the period from debulking surgery (PDS/IDS) to the start of adjuvant chemotherapy (Fig. 1). This time interval is not described in the NCPP. Thus, we defined days more than the median time to adjuvant chemotherapy from PDS or IDS as a delay in TTC.

      2.2 Statistical Analysis

      Comparisons between groups were performed using Chi-squared tests for categorical data and Mann-Whitney U tests for continuous variables.
      We performed ovarian cancer-specific survival analyses using data from the Danish Register of Causes of Death. Data were available for 2927 patients; nineteen patients (1%) were excluded from cancer-specific survival analyses due to missing data. Cancer-specific survival probabilities for patients with stage IIIC-IV EOC were estimated using the Kaplan-Meier method, assessing the time from diagnosis date until death of EOC or end of follow-up. We stratified on age and whether patients had curatively intended treatment (= PDS and adjuvant chemotherapy or NACT-IDS and adjuvant chemotherapy). Differences between groups were performed using log-rank statistics.
      Multivariate Cox regression analysis, including possible confounders as covariates, was used to estimate hazard ratios (HR) and 95% confidence interval (CI) for the different covariables with the first level as reference. The proportional hazards assumption was tested using Schoenfeld residuals, and the model was found fit for use. Follow-up ended on February 11, 2021, or the date of death, whichever came first.
      Statistical analyses were performed using R version 3.5 (The R Foundation for Statistical Computing). Two-sided p-values of <0.05 were considered statistically significant.

      2.3 Ethics

      The Danish Data Protection Agency (File number: P-2019-738) and the Danish Clinical Quality Program – National Clinical Registries approved access to registry data. No ethical approval was required.

      3. Results

      3.1 Baseline Characteristics

      Overall, we included 2946 patients with EOC; 1663 patients (56%) aged <70 years and 1283 patients (44%) aged ≥70 years. Table 1 displays the baseline characteristics of younger and older patients with a median age of 60 [interquartile range (IQR) 53,66] and 76 [IQR: 72,81] years, respectively. The older patients scored higher in the Charlson comorbidity index (CCI) and performance status (PS) and had more often “serous not graded” histology and undetermined cancer site origin than the younger patients. Furthermore, a higher proportion of older patients had FIGO stage IIIC-IV (Table 2).
      Table 1Baseline characteristics of patients with epithelial ovarian cancer by age and treatment modalities.
      Patients < 70 yearsPatients ≥ 70 years
      OverallPDSIDSNDSpaOverallPDSIDSNDSpa
      n16639774012851283504238541
      Age (median [IQR])60[53,66]59[51,65]62[56,66]63[57,67]<0.00176 [72, 81]75 [72, 79]74 [72, 77]79 [74, 83]<0.001
      BMI (%)<0.0040.930
      < 18.551 (3)25 (3)8 (2)18 (6)58 (5)22 (4)12 (5)24 (4)
      18.5–24.9759 (46)460 (47)197 (49)102 (36)532 (41)228 (45)116 (49)188 (35)
      25–29.9420 (25)247 (25)103 (26)70 (25)315 (25)139 (28)60 (25)116 (21)
      ≥ 30310 (19)184 (19)71 (18)55 (19)164 (13)72 (14)32 (13)60 (11)
      NA123 (7)61 (6)22 (6)40 (14)214 (17)43 (9)18 (8)153 (28)
      CCI (%)0.0130.694
      01256(76)767 (79)289 (72)200 (70)783 (61)313 (62)150 (63)320 (59)
      1182 (11)96 (10)53 (13)33 (12)202 (16)82 (16)31 (13)89 (16)
      ≥2218 (13)112 (11)56 (14)50 (18)287 (22)108 (21)55 (23)124 (23)
      NA7 (0)2 (0)3 (1)2 (1)11 (1)1 (0)2 (1)8 (1)
      Performance status (%)<0.001<0.001
      < 21427(86)892 (91)340 (85)195 (68)890 (69)419 (83)187 (79)284 (52)
      ≥ 2195 (12)67 (7)56 (14)72 (25)329 (26)78 (15)48 (20)203 (38)
      NA41 (2)18 (2)5 (1)18 (6)64 (5)7 (1)3 (1)54 (10)
      Histology (%)b<0.001<0.001
      High-grade serous807 (49)461 (47)254 (64)92 (32)602 (47)283 (56)152 (64)167 (31)
      Low-grade serous77 (5)58 (6)8 (2)11 (4)44 (3)34 (7)0 (0)10 (2)
      Serous not graded284 (17)49 (5)125 (31)110 (39)344 (27)33 (7)74 (31)237 (44)
      Other414 (25)379 (39)11 (3)24 (8)177 (14)150 (30)11 (5)16 (3)
      NA81 (5)30 (3)3 (1)48 (17)116 (9)4 (1)1 (0)111 (21)
      Cancertype (%)c<0.001<0.001
      Ovarian955 (57)708 (72)135 (34)112 (39)576 (45)314 (62)81 (34)181 (33)
      Fallopian tube319 (19)197 (20)111 (28)11 (4)222 (17)137 (27)69 (29)16 (3)
      Peritoneal93 (6)33 (3)37 (9)23 (8)100 (8)30 (6)28 (12)42 (8)
      Undetermined278 (17)31 (3)111 (28)136 (48)375 (29)22 (4)54 (23)299 (55)
      NA18 (1)8 (1)7 (2)3 (1)10 (1)1 (0)6 (3)3 (1)
      Abbreviations: EOC, epithelial ovarian cancer; PDS, primary debulking surgery; IDS, interval debulking surgery; NDS, no debulking surgery; IQR, interquartile range; BMI, body mass index; CCI, Charlson comorbidity index; FIGO, The International Federation of Gynecology and Obstetrics; NA, not applicable.
      a: Missing values (NA) was not included in the estimates of significance tests.
      b: Other: mucinous, endometrioid, clear cell, carcinosarcoma, and other epithelial histological subtypes.
      c: Undetermined origin of cancer site (ovarian, fallopian tubal, or primary peritoneal cancer) by pathologist due to cancer dissemination.
      Table 2Chemotherapy in frontline treatment by age and stage.
      < 70 years≥ 70 years
      OverallChemo +Chemo -paOverallChemo +Chemo -pa
      n16631409(85)254 (15)1283970 (76)313 (24)
      FIGO stage (%)b<0.001<0.001
      IA-B228 (14)86 (38)142 (62)86 (7)29 (34)57 (66)
      IC-II323 (19)275 (85)48 (15)195 (15)140 (72)55 (28)
      IIIA-B143 (9)136 (95)7 (5)107 (8)92 (86)15 (14)
      IIIC-IV952 (57)904 (95)48 (5)824 (64)692 (84)132 (16)
      NA17 (1)8 (47)9 (53)71 (6)17 (24)54 (76)
      Abbreviations: EOC, epithelial ovarian cancer; FIGO, The International Federation of Gynecology and Obstetrics.
      a: Missing values (NA) was not included in the estimates of significance tests.
      b: Column percentages are reported for overall data. Row percentages are reported for Chemo +/− data.

      3.2 Treatment Outcomes

      For the 952 younger patients with advanced-stage disease (IIIC-IV), IDS was the most used surgical treatment (39%), followed by PDS (36%), whereas NDS was the most common (52%) for the 824 older patients with stage IIIC-IV, followed by IDS (26%). Table 3 displays the surgical characteristics of patients with stage IIIC-IV disease treated with either PDS or IDS. Older patients had shorter surgery time, had less extensive surgery done (LAP), and more often had >0 cm residual disease after surgery (PDS/IDS). Also, in the PDS group, fewer older patients had adjuvant chemotherapy. Furthermore, we found a significant difference between age cohorts for 30- and 90-day mortality for patients undergoing PDS in favor of the younger patients.
      Table 3Complexity of surgery and perioperative outcomes by age and surgical modality.
      PDSNACT-IDS
      Overall< 70 years≥ 70 yearspaOverall< 70 years≥ 70 yearspa
      n516338178588371217
      Age (median [IQR])66 [56, 72]60 [51, 65]74 [72, 78]<0.00167 [60, 72]62 [56, 66]74 [72, 76]<0.001
      Surgery time, minutes

      (median [IQR])
      230 [150, 300]240 [163, 310]195 [135, 270]0.001172 [120, 240]180 [120, 251]152 [117, 225]0.002
      LAP<0.0010.017
      119 (4)16 (5)3 (2)53 (9)32 (9)21 (10)
      2108 (21)49 (14)59 (33)155 (26)84 (23)71 (33)
      3380 (74)268 (79)112 (63)369 (63)248 (67)121 (56)
      NA9 (2)5 (1)4 (2)11 (2)7 (2)4 (2)
      Residual disease (%)0.0010.427
      = 0 cm384 (74)268 (79)116 (65)401 (68)258 (70)143 (66)
      > 0 cm125 (24)66 (20)59 (33)185 (32)112 (30)73 (34)
      NA7 (1)4 (1)3 (2)2 (0)1 (0)1 (0)
      30-day mortality (%)8 (2)2 (1)6 (3)0.0401 (0)0 (0)1 (0)0.783
      90-day mortality (%)21 (4)8 (2)13 (7)0.0134 (1)1 (0)3 (1)0.284
      No adjuvant chemo (%)50 (10)19 (6)31 (17)<0.0012 (0)0 (0)2 (1)0.263
      Abbreviations: PDS, primary debulking surgery; NACT, neoadjuvant chemotherapy; IDS, interval debulking surgery; IQR, interquartile range; LAP, laparotomy classification system; BMI, body mass index; NA, not applicable.
      a: Missing values (NA) was not included in the estimates of significance tests.
      Table 4The chemotherapy use and time intervals by age and treatment.
      Overall< 70 years≥ 70 yearspa
      PDS
      n516338178
      Number of chemotherapy cycles

      (median [IQR](range)) b
      6 [6,6] (1,14)6 [6,6] (1,14)6 [5,6] (1,12)0.099
      TTT, days (median [IQR])13 [7, 20]12 [7, 19]14 [8, 21]0.032
      TTC, days (median [IQR])c26 [21, 35]26 [21, 34]26 [21, 36]0.625
      Delay in TTT (%)0.251
      ≥ 25 days73 (14)43 (13)30 (17)
      < 25 days443 (86)295 (87)148 (83)
      NA000
      Delay in TTC (%)1.000
      ≥ 26 days243 (47)167 (49)76 (43)
      < 26 days220 (43)151 (45)69 (39)
      NA53 (10)20 (6)33 (19)
      NACT-IDS
      n588371217
      Number of chemotherapy cycles

      (median [IQR](range))d
      6 [6,7] (1,15)6 [6, 7] (1,14)6 [6, 7] (2,15)0.883
      TTT, days (median [IQR])e21 [16, 28]21 [15, 29]22 [16, 28]0.690
      TTC, days (median [IQR])f23 [20, 29]23 [20, 29]23 [20, 30]0.517
      Delay in TTT (%)1.000
      ≥ 24 days214 (36)135 (36)79 (36)
      < 24 days303 (52)192 (52)111 (51)
      NA71 (12)44 (12)27 (12)
      Delay in TTC (%)0.348
      ≥ 23 days290 (49)176 (47)114 (53)
      < 23 days265 (45)172 (46)93 (43)
      NA33 (6)23 (6)10 (5)
      NDS
      n672243429
      Number of chemotherapy cycles

      (median [IQR](range))
      6 [5,6] (1,14)6 [5,7] (1,14)6 [5,6] (1,14)0.013
      Abbreviations: PDS, primary debulking surgery; NACT, neoadjuvant chemotherapy; IDS, interval debulking surgery; NDS, no debulking surgery; IQR, interquartile range; TTT, time-to-treatment; TTC, time-to-chemotherapy.
      a: Missing values (NA) were not included in the estimates of significance tests.
      b: NA = 72 (14%).
      c: NA = 53 (10%).
      d: NA = 90 (15%).
      e: NA = 71 (12%).
      f: NA = 33 (6%).
      Table 2 presents chemotherapy use in the frontline setting for younger and older patients by the stage. Overall, 85% of the younger cohort versus 76% of the older underwent any chemotherapy treatment (p < 0.001). An almost equal proportion of younger and older patients with low-stage disease (IA-B) had chemotherapy, whereas a higher proportion of younger patients with stage IC-IV had chemotherapy. Overall, the median number of chemotherapy cycles in first-line treatment was six for both age cohorts (Table 4, Supplementary Fig. S1).

      3.3 Time Intervals and Delays in Treatment

      TTT for PDS was two days longer for older patients than for younger (p = 0.032) (Table 4). For patients undergoing NACT, we found no difference between age cohorts regarding the TTT. TTC for both PDS and IDS did not significantly differ between younger and older patients.
      Overall, patients undergoing PDS initiated treatment earlier than patients undergoing NACT (13 days [IQR: 0, 76] versus 21 days [IQR: 3, 82]), whereas TTC was shorter for patients undergoing IDS than for patients undergoing PDS (23 days [IQR: 1, 71] versus 26 days [IQR: 3, 99]).
      There were no significant differences in TTT or TTC delays between the age cohorts.

      3.4 Survival

      Two-year cancer-specific survival for patients with stage IIIC-IV disease differed significantly between age cohorts, with 75% (95% CI: 72, 78) in the younger cohort and 54% (95% CI: 50, 58) in the older cohort. When focusing on patients having curatively intended treatment only, the two-year cancer-specific survival narrowed between age cohorts but still differed significantly (83% (95% CI: 80, 86) in the younger cohort and 75% (95% CI: 71, 80) in the older cohort) (Fig. 2).
      Fig. 2
      Fig. 2Cancer-specific survival for patients with stage IIIC-IV disease by age and treatment
      In a multivariate Cox regression model for patients with advanced-stage disease (IIIC-IV), we adjusted for age, CCI, PS, histology, stage, the extent of surgery (LAP), residual disease after surgery, TTT delay, and TTC delay (Table 5). For patients treated with PDS or NACT-IDS, non-serous histology and residual disease >0 cm were significantly associated with a higher risk of cancer-specific death. For patients treated with PDS, delays in adjuvant chemotherapy greater than the median number of days (26 days) were also significantly associated with an increased risk of death.
      Table 5Factors associated with cancer-specific death for patients with stage IIIC-IV disease, by treatment modality.
      PDS
      n = 453, number of events = 147 (63 observations deleted due to missingness).
      NACT-IDS
      n = 482, number of events = 185 (106 observations deleted due to missingness).
      HR
      Adjusted hazard ratio from multivariable model.
      95% CIHR
      Adjusted hazard ratio from multivariable model.
      95% CI
      Age
      < 70 years11
      ≥ 70 years1.220.84, 1.771.310.96, 1.77
      CCI
      011
      11.240.80, 1.930.920.59, 1.43
      ≥20.880.51, 1.530.950.61, 1.48
      PS
      < 211
      ≥ 21.320.79, 2.200.920.62, 1.37
      Histology
      Other histology: endometrioid, clear cell, mucinous, carcinosarcoma, other epithelial.
      High-grade serous11
      Low-grade serous1.270.63, 2.56,0.300.04, 2.22
      Serous not graded1.010.51, 2.011.551.14, 2.10
      Other1.691.10, 2.592.301.18, 4.48
      FIGO stage
      IIIC11
      IV0.860.58, 1.251.090.81, 1.47
      LAP
      111
      20.520.23, 1.171.040.61, 1.76
      30.600.28, 1.280.850.52, 1.39
      Residual disease after surgery
      0 cm11
      >0 cm2.501.74, 3.591.921.41, 2.61
      Delay in TTT
      < 25 days1
      ≥ 25 days1.120.69, 1.81
      Delay in TTC
      < 26 days1
      ≥ 26 days1.461.04, 2.04
      Delay in TTT
      < 24 days1
      ≥ 24 days1.190.88, 1.59
      Delay in TTC
      < 23 days1
      ≥ 23 days1.160.86, 1.56
      Abbreviations: PDS, primary debulking surgery; NACT, neoadjuvant chemotherapy; IDS, interval debulking surgery; HR, hazard ratio; CI, confidence interval; CCI, Charlson Comorbidity Index; PS, performance status; FIGO, The International Federation of Gynecology and Obstetrics; TTT, time-to-treatment; TTC, time-to-chemotherapy.
      a n = 453, number of events = 147 (63 observations deleted due to missingness).
      b n = 482, number of events = 185 (106 observations deleted due to missingness).
      c Adjusted hazard ratio from multivariable model.
      d Other histology: endometrioid, clear cell, mucinous, carcinosarcoma, other epithelial.

      4. Discussion

      4.1 Main Findings

      This study explores differences in surgical complexity, chemotherapy treatment, and treatment delays for younger and older patients with EOC in a real-world Danish setting. For patients with advanced-stage disease, we predominantly observed differences in favor of the younger patients regarding surgical and chemotherapeutic outcomes. Fifty-two percent of the older patients did not undergo curatively intended surgery, whereas most younger patients did. For patients undergoing curatively intended surgery, the older had less extensive surgery (LAP), shorter surgery time, and more often residual disease >0 cm. Likewise, older patients were less often treated with chemotherapy. We did not find any differences between age cohorts regarding treatment delays. Two-year cancer-specific survival differed significantly between age cohorts.

      4.2 Interpretation

      Consistent with previous findings, one out of two older women with advanced-stage EOC did not undergo PDS or IDS [
      • Ekmann-Gade A.W.
      • Høgdall C.K.
      • Seibæk L.
      • Noer M.C.
      • Fagö-Olsen C.L.
      • Schnack T.H.
      Incidence, treatment, and survival trends in older versus younger women with epithelial ovarian cancer from 2005 to 2018: A nationwide Danish study.
      ]. Patients with NDS had higher age and worse PS at diagnosis than those undergoing debulking surgery. This subgroup was not referred to debulking surgery at diagnosis due to unresectable disease, severe comorbidities, high age, or patient wishes [
      • Danish Gynecological Cancer Group
      Instructions for referral, diagnostics and control of epithelial ovarian-, fallopian tubal and primary peritoneal cancer and borderline tumors.
      ]. We suspect most are initially referred to NACT-IDS and then found unfit for IDS after NACT. However, our knowledge of why these patients do not undergo surgery is limited.
      Our results correlate with two previous studies from the United States (US) and the Netherlands reporting that 44% and 50% of patients >75 years with advanced-stage disease did not receive standard combination treatment, respectively [
      • Shalowitz D.I.
      • Epstein A.J.
      • Ko E.M.
      • Giuntoli 2nd, R.L.
      Non-surgical management of ovarian cancer: Prevalence and implications.
      ,
      • van Altena A.M.
      • Karim-Kos H.E.
      • de Vries E.
      • Kruitwagen R.F.P.M.
      • Massuger L.F.A.G.
      • Kiemeney L.A.
      Trends in therapy and survival of advanced stage epithelial ovarian cancer patients in the Netherlands.
      ]. Recently, another Dutch study found that 37% of patients of all ages with advanced-stage disease did not receive combined cytoreductive surgery and chemotherapy.
      We do not know why Danish patients did not undergo standard treatment. Yet, perhaps a lack of apparent adherence to guidelines does not necessarily constitute a poor treatment strategy and impairment of the prognosis [
      • Erickson B.K.
      • Martin J.Y.
      • Shah M.M.
      • Straughn J.M.J.
      • Leath 3rd., C.A.
      Reasons for failure to deliver National Comprehensive Cancer Network (NCCN)-adherent care in the treatment of epithelial ovarian cancer at an NCCN cancer center.
      ]. Indeed, a subgroup of patients with extensive disease or significant comorbidity might live longer with non-surgical management. Thus, while health professionals should not be too restrictive when offering curatively intended treatment to older patients, possible surgical morbidity needs to be balanced with expected survival benefits, quality of life, and patient preferences.
      Interestingly, a Dutch study surveyed the reasons for no treatment in patients with EOC and found that the main reason was “patient's choice,” followed by “patient's poor condition” as the second most common reason [
      • Zijlstra M.
      • Timmermans M.
      • Fransen H.
      • van der Aa M.
      • Reyners A.
      • Raijmakers N.
      • et al.
      Treatment patterns and associated factors in patients with advanced epithelial ovarian cancer: a population-based study.
      ]. Yet, qualitative studies report a similar wish for curatively intended treatment among older patients with EOC compared to younger [
      • Nordin A.J.
      • Chinn D.J.
      • Moloney I.
      • Naik R.
      • de Barros Lopes A.
      • Monaghan J.M.
      Do elderly cancer patients care about cure? Attitudes to radical gynecologic oncology surgery in the elderly.
      ,
      • Dumas L.
      • Lidington E.
      • Appadu L.
      • Jupp P.
      • Husson O.
      • Banerjee S.
      Exploring older women’s attitudes to and experience of treatment for advanced ovarian cancer: A qualitative phenomenological study.
      ].
      Health professionals face difficulty determining how patients wish to be involved in decision-making [
      • Luketina H.
      • Fotopoulou C.
      • Luketina R.-R.
      • Pilger A.
      • Sehouli J.
      Treatment decision-making processes in the systemic treatment of ovarian cancer: review of the scientific evidence.
      ]. Furthermore, personal experience with EOC treatment seems to be a significant factor in the final decision. Consequently, health professionals and patients need to work together to make the best individual decisions possible by respecting and responding to the patients' unique preferences, needs, and values [
      • Kitson A.
      • Marshall A.
      • Bassett K.
      • Zeitz K.
      What are the core elements of patient-centred care? A narrative review and synthesis of the literature from health policy, medicine and nursing.
      ]. In this context, shared decision-making is vital in making better-informed choices that align with what matters most to the individual patient [
      • Barry M.J.
      • Edgman-Levitan S.
      Shared decision making--pinnacle of patient-centered care.
      ]. Yet, the implementation of shared decision-making still represents a clinical challenge [
      • Steffensen K.D.
      • Vinter M.
      • Crüger D.
      • Dankl K.
      • Coulter A.
      • Stuart B.
      • et al.
      Lessons in integrating shared decision-making into cancer care.
      ].
      PDS is associated with increased postoperative morbidity and mortality compared to IDS [
      • Coleridge S.L.
      • Bryant A.
      • Kehoe S.
      • Morrison J.
      Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer.
      ]. In the current study, we observed a tendency toward higher 30- and 90-day mortality and lack of adjuvant chemotherapy for older patients undergoing PDS compared to younger patients. This should be considered when offering PDS to older patients, as NACT-IDS is a beneficial alternative for many older patients with EOC. The surgical burden seems more balanced for the younger patients undergoing PDS, with the highest surgery time and extent reflected in the largest proportion of patients with no residual disease after surgery.
      Comprehensive geriatric assessment and prehabilitation may improve frail patients' conditions, potentially enabling more older patients to undergo surgery [
      • Beck A.
      • Vind Thaysen H.
      • Hasselholt Soegaard C.
      • Blaakaer J.
      • Seibaek L.
      Prehabilitation in cancer care: patients’ ability to prepare for major abdominal surgery.
      ,
      • van Soolingen N.J.
      • Smorenburg C.H.
      • Hamaker M.E.
      • Groen W.G.
      • Retèl V.P.
      • Lok C.A.R.
      • et al.
      GERiatric Screening in the treatment of elderly patients with Ovarian Carcinoma (GERSOC): study protocol for a pragmatic, cluster randomised controlled trial.
      ]. The International Society of Geriatric Oncology (SIOG) and the American Society of Clinical Oncology (ASCO) recommend these approaches for all patients ≥65 years receiving oncologic treatment [
      • Wildiers H.
      • Heeren P.
      • Puts M.
      • Topinkova E.
      • Janssen-Heijnen M.L.G.
      • Extermann M.
      • et al.
      International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer.
      ,
      • Mohile S.G.
      • Dale W.
      • Somerfield M.R.
      • Schonberg M.A.
      • Boyd C.M.
      • Burhenn P.S.
      • et al.
      Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology.
      ]. Yet, while patients with EOC appear positive toward prehabilitation [
      • Beck A.
      • Vind Thaysen H.
      • Hasselholt Soegaard C.
      • Blaakaer J.
      • Seibaek L.
      What matters to you? An investigation of patients’ perspectives on and acceptability of prehabilitation in major cancer surgery.
      ], randomized controlled trials supporting the benefit are lacking.
      Despite a persistent treatment gap between age cohorts, we report high numbers of patients with advanced-stage disease having chemotherapy in both groups. The higher proportion of older patients not receiving adjuvant chemotherapy might reflect that older patients are more prone to surgical morbidity, thus missing the opportunity to receive chemotherapy due to complications. Unfortunately, we do not have data on postoperative complications. Interestingly, we found a median number of six chemotherapy cycles in both age cohorts, regardless of surgical modality, sharply adhering to international guidelines. Thus, notably, patients with NDS also underwent a median number of six therapy cycles, although they were generally older and had higher PS.
      We found a longer TTT for PDS of two days for older patients than younger patients, perhaps due to further indispensable workup before surgery, since they scored higher in CCI and PS than the younger. Overall, treatment delays could be caused by patient factors (e.g., a cardiac workup), diagnostic factors (e.g., explorative laparoscopy), or system factors (e.g., surgery scheduling or a central line insertion). There was no difference between age cohorts when focusing on TTT delays defined by the NCPP. To our knowledge, this is the first study to address TTT and system delays for older patients with EOC. The Danish Health Authorities use the time frames in the NCPP for quality assurance, leading to constant pressure on the tertiary centers to live up to the framework. Thus, spending time on prehabilitation and geriatric interventions may pose an ethical dilemma for health professionals if these approaches overlap the projected initiation of treatment according to the NCPP. It is known that interventions improving nutritional and physical status increase the proportion of cancer patients completing treatment and minimize the risk of postoperative complications [
      • Nakano J.
      • Fukushima T.
      • Tanaka T.
      • Fu J.B.
      • Morishita S.
      Physical function predicts mortality in patients with cancer: a systematic review and meta-analysis of observational studies.
      ,
      • Kristjansson S.R.
      • Nesbakken A.
      • Jordhøy M.S.
      • Skovlund E.
      • Audisio R.A.
      • Johannessen H.-O.
      • et al.
      Comprehensive geriatric assessment can predict complications in elderly patients after elective surgery for colorectal cancer: a prospective observational cohort study.
      ,
      • Audisio R.A.
      • Pope D.
      • Ramesh H.S.J.
      • Gennari R.
      • van Leeuwen B.L.
      • West C.
      • et al.
      Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help. A SIOG surgical task force prospective study.
      ]. Hence, interventions may improve outcomes regardless of a treatment delay because they enable patients to undergo debulking surgery.
      A study by Noer et al. did not demonstrate any benefit regarding survival when initiating treatment within NCCP limits [
      • Noer M.C.
      • Sperling C.D.
      • Ottesen B.
      • Antonsen S.L.
      • Christensen I.J.
      • Høgdall C.
      Ovarian cancer and comorbidity: Is poor survival explained by choice of primary treatment or system delay?.
      ]. There is no international consensus on an exact time window from diagnosis to the start of therapy. With more older patients needing cancer treatment and preoperative geriatric interventions gaining ground, it seems urgent to address this ethical issue in future research.
      We did not find any differences in TTC or delays greater than the median TTC between age cohorts, expectantly mirroring that only the fittest patients go through surgery and chemotherapy. In a study involving patients ≥65 years with advanced-stage disease, extended surgery and perioperative complications were associated with delayed initiation of adjuvant chemotherapy; but did not affect the risk of omitting chemotherapy [
      • Wright J.D.
      • Herzog T.J.
      • Neugut A.I.
      • Burke W.M.
      • Lu Y.-S.
      • Lewin S.N.
      • et al.
      Effect of radical cytoreductive surgery on omission and delay of chemotherapy for advanced-stage ovarian cancer.
      ]. It remains unclear at what time point delayed initiation of treatment adversely affects prognosis. Studies have explored the prognostic impact of TTC in EOC; with mixed approaches and results [
      • Lydiksen L.
      • Jensen-Fangel S.
      • Blaakaer J.
      Is it possible to define an optimal time for chemotherapy after surgery for ovarian cancer?.
      ,
      • ElNaggar A.C.
      • Hade E.M.
      • O’Malley D.M.
      • Liang M.I.
      • Copeland L.J.
      • Fowler J.M.
      • et al.
      Time to chemotherapy in ovarian cancer: Compliance with ovarian cancer quality indicators at a National Cancer Institute-designated Comprehensive Cancer Center.
      ,
      • Liu X.-D.
      • Liu Y.
      • Gong T.-T.
      • Guo J.-Y.
      • Wang Y.-N.
      • Wang L.
      • et al.
      Prognostic influence of the time interval between surgery and chemotherapy in epithelial ovarian cancer.
      ,
      • Rocher G.
      • Gaillard T.
      • Uzan C.
      • Collinet P.
      • Bolze P.-A.
      • Ballester M.
      • et al.
      Does Time-to-chemotherapy after primary complete macroscopic cytoreductive Surgery influence prognosis for patients with epithelial ovarian cancer? A study of the FRANCOGYN group.
      ]. In a meta-analysis evaluating the effect of TTC on disease recurrence and survival three years after the frontline surgery, TTC was not associated with a higher risk of disease recurrence or death; however, the data were heterogeneous [
      • Usón P.L.S.J.
      • Bugano D.D.G.
      • França M.S.
      • Antunes Y.P.P.V.
      • Taranto P.
      • Kaliks R.A.
      • et al.
      Does time-to-chemotherapy impact the outcomes of resected ovarian cancer? Meta-analysis of randomized and observational data.
      ]. In a study from the US, including patients ≥65 years only with advanced-stage disease receiving PDS and adjuvant chemotherapy, delayed initiation of chemotherapy > six weeks was common and associated with poor survival after adjustment for advanced age, race, stage, histology, comorbidities, teaching hospital, and social factors [
      • Wright J.
      • Doan T.
      • McBride R.
      • Jacobson J.
      • Hershman D.
      Variability in chemotherapy delivery for elderly women with advanced stage ovarian cancer and its impact on survival.
      ]. In our population-based study, TTC over the median of 26 days for PDS patients was associated with an increased risk of death with a hazard ratio of 1.47 (95% CI: 1.05, 2.06) in the multivariate Cox analysis. Unfortunately, we could not adjust for postoperative complications, known to influence the prognosis negatively.
      Strengths and limitations: We based the current study on nationwide prospectively collected data from patients registered in the DGCD with EOC. Since data represent almost all patients diagnosed with EOC in the specified period, the risk of selection bias is low. The linkage to other national registers secures lifelong follow-up adding high power to the statistical analyses.
      Data from the Danish Register of Causes of Death enabled us to analyze cancer-specific survival. Compared to younger patients, older patients have more comorbidities and thus might be at greater risk of dying for other reasons than EOC. Therefore, we find it highly relevant to explore cancer-specific survival when comparing the age cohorts, even though all-cause survival is often thought to be equivalent to cancer-specific survival for EOC. This may pose information bias due to misclassification on death certificates. However, around 20–25% of the Danish Register of Causes of Death is manually validated once a year to ensure accuracy [].
      The proportion of “undetermined” cancer sites reported is most likely due to the large number of patients not undergoing debulking surgery. Thus a pathological examination of surgical tissue is lacking. This is, therefore, not considered missing data.
      Apart from TTT and TTC, our key variables only had small proportions of missing data. Data regarding TTT and TTC were provided from the NPR with dates of chemotherapy treatments, but the NPR only includes data if the patient has received chemotherapy. We have previously validated the chemotherapy data in the NPR and found a high accuracy.

      5. Conclusion

      This study confirms that older patients are managed less aggressively regarding both surgical and oncological treatment, which may contribute to inferior cancer-specific survival compared to younger patients receiving treatment according to guidelines. The large proportion of older patients not receiving treatment and the persistent survival gap between age groups suggest opportunities for further improvements in the care for older patients with EOC. Future studies should focus on the group of patients with no curatively intended treatment by exploring the decision-making process and investigating whether tailored geriatric interventions can equalize the persistent disparities in cancer care delivery.
      Supplementary Fig. S1
      Supplementary Fig. S1The number of chemotherapy cycles in first-line treatment of patients with stage IIIC-IV disease stratified on age and surgical treatment modalitya.
      aCut-off of number of chemotherapy cycles at 12 for this figure; 7 data points above the value of 12 are not plotted.

      Author Contributions

      Anne Weng Ekmann-Gade: Conceptualization, Methodology, Software, Formal analysis, Investigation, Writing original draft, Visualization.
      Lene Seibæk: Conceptualization, Writing - Review & Editing.
      Mette Calundann Noer: Methodology, Writing - Review & Editing.
      Tine Henrichsen Schnack: Conceptualization, Methodology, Writing - Review & Editing.
      Claus Kim Høgdall: Conceptualization, Methodology, Writing - Review & Editing, Supervision.

      Ethics

      The Danish Data Protection Agency (File number: P-2019-738) and the Danish Clinical Quality Program – National Clinical Registries approved access to registry data. The National Committee on Health Research Ethics approved the study (H-22059625).

      Consent for Publication

      All authors approved the final article.

      Availability of Data and Materials

      Data and materials are not available.

      Funding

      This work was supported by a grant from the Danish Cancer Society ( R247-A14758 ).

      Declaration of Competing Interest

      The authors report no conflicts of interest.

      Acknowledgments

      The Danish Gynecological Cancer Database (DGCD) is acknowledged for acquiring all data regarding patients and treatment.

      References

        • Ferlay J.
        • Ervik M.
        • Lam F.
        • Colombet M.
        • Mery L.
        • Piñeros M.
        • et al.
        Global Cancer Observatory: Cancer Today.
        International Agency for Research on Cancer, Lyon, France2020 (accessed May 28, 2021)
        • Sorensen S.M.
        • Schnack T.H.
        • Hogdall C.
        Impact of residual disease on overall survival in women with Federation of Gynecology and Obstetrics stage IIIB-IIIC vs stage IV epithelial ovarian cancer after primary surgery.
        Acta Obstet Gynecol Scand. 2019; 98: 34-43https://doi.org/10.1111/aogs.13453
        • Ekmann-Gade A.W.
        • Høgdall C.K.
        • Seibæk L.
        • Noer M.C.
        • Fagö-Olsen C.L.
        • Schnack T.H.
        Incidence, treatment, and survival trends in older versus younger women with epithelial ovarian cancer from 2005 to 2018: A nationwide Danish study.
        Gynecol Oncol. 2022; 164: 120-128https://doi.org/10.1016/j.ygyno.2021.10.081
        • Cabasag C.J.
        • Butler J.
        • Arnold M.
        • Rutherford M.
        • Bardot A.
        • Ferlay J.
        • et al.
        Exploring variations in ovarian cancer survival by age and stage (ICBP SurvMark-2): A population-based study.
        Gynecol Oncol. 2020; 157: 234-244https://doi.org/10.1016/j.ygyno.2019.12.047
        • Dumas L.
        • Bowen R.
        • Butler J.
        • Banerjee S.
        Under-treatment of older patients with newly diagnosed epithelial ovarian cancer remains an issue.
        Cancers (Basel). 2021; 13https://doi.org/10.3390/cancers13050952
        • Nordin A.J.
        • Chinn D.J.
        • Moloney I.
        • Naik R.
        • de Barros Lopes A.
        • Monaghan J.M.
        Do elderly cancer patients care about cure? Attitudes to radical gynecologic oncology surgery in the elderly.
        Gynecol Oncol. 2001; 81: 447-455https://doi.org/10.1006/gyno.2001.6178
        • Dumas L.
        • Lidington E.
        • Appadu L.
        • Jupp P.
        • Husson O.
        • Banerjee S.
        Exploring older women’s attitudes to and experience of treatment for advanced ovarian cancer: A qualitative phenomenological study.
        Cancers (Basel). 2021; 13https://doi.org/10.3390/cancers13061207
        • Danish Health Authority [Sundhedsstyrelsen]
        Cancer patient pathway for ovarian cancer - for professionals [Pakkeforløb for kræft i æggestokkene - for fagfolk].
        (accessed February 23, 2022)
        • Sorensen S.M.
        • Bjorn S.F.
        • Jochumsen K.M.
        • Jensen P.T.
        • Thranov I.R.
        • Hare-Bruun H.
        • et al.
        Danish gynecological cancer database.
        Clin Epidemiol. 2016; 8: 485-490https://doi.org/10.2147/CLEP.S99479
        • Jensen H.
        • Tørring M.L.
        • Olesen F.
        • Overgaard J.
        • Fenger-Grøn M.
        • Vedsted P.
        Diagnostic intervals before and after implementation of cancer patient pathways - a GP survey and registry based comparison of three cohorts of cancer patients.
        BMC Cancer. 2015; 15: 308https://doi.org/10.1186/s12885-015-1317-7
        • Schmidt M.
        • Schmidt S.A.J.
        • Sandegaard J.L.
        • Ehrenstein V.
        • Pedersen L.
        • Sorensen H.T.
        The Danish National Patient Registry: a review of content, data quality, and research potential.
        Clin Epidemiol. 2015; 7: 449-490https://doi.org/10.2147/CLEP.S91125
        • Sundhedsdatastyrelsen
        Dødsårsagsregisteret (DAR) (The cause of death register).
        (accessed June 10, 2021)
        • Bjørn S.F.
        • Schnack T.H.
        • Lajer H.
        • Christensen I.J.
        • Lundvall L.
        • Thomsen L.N.
        • et al.
        Classification of ovarian cancer surgery facilitates treatment decisions in a gynecological multidisciplinary team.
        Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2017; 27: 382-389https://doi.org/10.1097/IGC.0000000000000876
        • Probst H.B.
        • Hussain Z.B.
        • Andersen O.
        Cancer patient pathways in Denmark as a joint effort between bureaucrats, health professionals and politicians--a national Danish project.
        Health Policy. 2012; 105: 65-70https://doi.org/10.1016/j.healthpol.2011.11.001
        • Danish Gynecological Cancer Group
        Instructions for referral, diagnostics and control of epithelial ovarian-, fallopian tubal and primary peritoneal cancer and borderline tumors.
        8th ed. 2021 (accessed June 22, 2021)
        • Shalowitz D.I.
        • Epstein A.J.
        • Ko E.M.
        • Giuntoli 2nd, R.L.
        Non-surgical management of ovarian cancer: Prevalence and implications.
        Gynecol Oncol. 2016; 142: 30-37https://doi.org/10.1016/j.ygyno.2016.04.026
        • van Altena A.M.
        • Karim-Kos H.E.
        • de Vries E.
        • Kruitwagen R.F.P.M.
        • Massuger L.F.A.G.
        • Kiemeney L.A.
        Trends in therapy and survival of advanced stage epithelial ovarian cancer patients in the Netherlands.
        Gynecol Oncol. 2012; 125: 649-654https://doi.org/10.1016/j.ygyno.2012.02.033
        • Erickson B.K.
        • Martin J.Y.
        • Shah M.M.
        • Straughn J.M.J.
        • Leath 3rd., C.A.
        Reasons for failure to deliver National Comprehensive Cancer Network (NCCN)-adherent care in the treatment of epithelial ovarian cancer at an NCCN cancer center.
        Gynecol Oncol. 2014; 133: 142-146https://doi.org/10.1016/j.ygyno.2014.02.006
        • Zijlstra M.
        • Timmermans M.
        • Fransen H.
        • van der Aa M.
        • Reyners A.
        • Raijmakers N.
        • et al.
        Treatment patterns and associated factors in patients with advanced epithelial ovarian cancer: a population-based study.
        Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2019; 29: 1032-1037https://doi.org/10.1136/ijgc-2019-000489
        • Luketina H.
        • Fotopoulou C.
        • Luketina R.-R.
        • Pilger A.
        • Sehouli J.
        Treatment decision-making processes in the systemic treatment of ovarian cancer: review of the scientific evidence.
        Anticancer Res. 2012; 32: 4085-4090
        • Kitson A.
        • Marshall A.
        • Bassett K.
        • Zeitz K.
        What are the core elements of patient-centred care? A narrative review and synthesis of the literature from health policy, medicine and nursing.
        J Adv Nurs. 2013; 69: 4-15https://doi.org/10.1111/j.1365-2648.2012.06064.x
        • Barry M.J.
        • Edgman-Levitan S.
        Shared decision making--pinnacle of patient-centered care.
        N Engl J Med. 2012; 366: 780-781https://doi.org/10.1056/NEJMp1109283
        • Steffensen K.D.
        • Vinter M.
        • Crüger D.
        • Dankl K.
        • Coulter A.
        • Stuart B.
        • et al.
        Lessons in integrating shared decision-making into cancer care.
        J Oncol Pract. 2018; 14: 229-235https://doi.org/10.1200/JOP.18.00019
        • Coleridge S.L.
        • Bryant A.
        • Kehoe S.
        • Morrison J.
        Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer.
        Cochrane Database Syst Rev. 2021; 2CD005343https://doi.org/10.1002/14651858.CD005343.pub5
        • Beck A.
        • Vind Thaysen H.
        • Hasselholt Soegaard C.
        • Blaakaer J.
        • Seibaek L.
        Prehabilitation in cancer care: patients’ ability to prepare for major abdominal surgery.
        Scand J Caring Sci. 2021; 35: 143-155https://doi.org/10.1111/scs.12828
        • van Soolingen N.J.
        • Smorenburg C.H.
        • Hamaker M.E.
        • Groen W.G.
        • Retèl V.P.
        • Lok C.A.R.
        • et al.
        GERiatric Screening in the treatment of elderly patients with Ovarian Carcinoma (GERSOC): study protocol for a pragmatic, cluster randomised controlled trial.
        Trials. 2020; 21: 214https://doi.org/10.1186/s13063-020-4157-y
        • Wildiers H.
        • Heeren P.
        • Puts M.
        • Topinkova E.
        • Janssen-Heijnen M.L.G.
        • Extermann M.
        • et al.
        International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer.
        J Clin Oncol Off J Am Soc Clin Oncol. 2014; 32: 2595-2603https://doi.org/10.1200/JCO.2013.54.8347
        • Mohile S.G.
        • Dale W.
        • Somerfield M.R.
        • Schonberg M.A.
        • Boyd C.M.
        • Burhenn P.S.
        • et al.
        Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology.
        J Clin Oncol Off J Am Soc Clin Oncol. 2018; 36: 2326-2347https://doi.org/10.1200/JCO.2018.78.8687
        • Beck A.
        • Vind Thaysen H.
        • Hasselholt Soegaard C.
        • Blaakaer J.
        • Seibaek L.
        What matters to you? An investigation of patients’ perspectives on and acceptability of prehabilitation in major cancer surgery.
        Eur J Cancer Care (Engl). 2021; e13475https://doi.org/10.1111/ecc.13475
        • Nakano J.
        • Fukushima T.
        • Tanaka T.
        • Fu J.B.
        • Morishita S.
        Physical function predicts mortality in patients with cancer: a systematic review and meta-analysis of observational studies.
        Support Care Cancer Off J Multinatl Assoc Support Care Cancer. 2021; 29: 5623-5634https://doi.org/10.1007/s00520-021-06171-3
        • Kristjansson S.R.
        • Nesbakken A.
        • Jordhøy M.S.
        • Skovlund E.
        • Audisio R.A.
        • Johannessen H.-O.
        • et al.
        Comprehensive geriatric assessment can predict complications in elderly patients after elective surgery for colorectal cancer: a prospective observational cohort study.
        Crit Rev Oncol Hematol. 2010; 76: 208-217https://doi.org/10.1016/j.critrevonc.2009.11.002
        • Audisio R.A.
        • Pope D.
        • Ramesh H.S.J.
        • Gennari R.
        • van Leeuwen B.L.
        • West C.
        • et al.
        Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help. A SIOG surgical task force prospective study.
        Crit Rev Oncol Hematol. 2008; 65: 156-163https://doi.org/10.1016/j.critrevonc.2007.11.001
        • Noer M.C.
        • Sperling C.D.
        • Ottesen B.
        • Antonsen S.L.
        • Christensen I.J.
        • Høgdall C.
        Ovarian cancer and comorbidity: Is poor survival explained by choice of primary treatment or system delay?.
        Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2017; 27: 1123-1133https://doi.org/10.1097/IGC.0000000000001001
        • Wright J.D.
        • Herzog T.J.
        • Neugut A.I.
        • Burke W.M.
        • Lu Y.-S.
        • Lewin S.N.
        • et al.
        Effect of radical cytoreductive surgery on omission and delay of chemotherapy for advanced-stage ovarian cancer.
        Obstet Gynecol. 2012; 120: 871-881https://doi.org/10.1097/AOG.0b013e31826981de
        • Lydiksen L.
        • Jensen-Fangel S.
        • Blaakaer J.
        Is it possible to define an optimal time for chemotherapy after surgery for ovarian cancer?.
        Gynecol Oncol. 2014; 133: 454-459https://doi.org/10.1016/j.ygyno.2014.04.004
        • ElNaggar A.C.
        • Hade E.M.
        • O’Malley D.M.
        • Liang M.I.
        • Copeland L.J.
        • Fowler J.M.
        • et al.
        Time to chemotherapy in ovarian cancer: Compliance with ovarian cancer quality indicators at a National Cancer Institute-designated Comprehensive Cancer Center.
        Gynecol Oncol. 2018; 151: 501-505https://doi.org/10.1016/j.ygyno.2018.09.014
        • Liu X.-D.
        • Liu Y.
        • Gong T.-T.
        • Guo J.-Y.
        • Wang Y.-N.
        • Wang L.
        • et al.
        Prognostic influence of the time interval between surgery and chemotherapy in epithelial ovarian cancer.
        J Cancer. 2018; 9: 4172-4178https://doi.org/10.7150/jca.27409
        • Rocher G.
        • Gaillard T.
        • Uzan C.
        • Collinet P.
        • Bolze P.-A.
        • Ballester M.
        • et al.
        Does Time-to-chemotherapy after primary complete macroscopic cytoreductive Surgery influence prognosis for patients with epithelial ovarian cancer? A study of the FRANCOGYN group.
        J Clin Med. 2021; 10https://doi.org/10.3390/jcm10051058
        • Usón P.L.S.J.
        • Bugano D.D.G.
        • França M.S.
        • Antunes Y.P.P.V.
        • Taranto P.
        • Kaliks R.A.
        • et al.
        Does time-to-chemotherapy impact the outcomes of resected ovarian cancer? Meta-analysis of randomized and observational data.
        Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2017; 27: 274-280https://doi.org/10.1097/IGC.0000000000000923
        • Wright J.
        • Doan T.
        • McBride R.
        • Jacobson J.
        • Hershman D.
        Variability in chemotherapy delivery for elderly women with advanced stage ovarian cancer and its impact on survival.
        Br J Cancer. 2008; 98: 1197-1203https://doi.org/10.1038/sj.bjc.6604298