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ARTICLE IN PRESSNCH-1284; No. of Pages 9

Critical Reviews in Oncology/Hematology xxx (2009) xxx–xxx

Poor outcome of elderly patients with platinum-sensitive recurrentovarian cancer: Results from the SOCRATES retrospective study

Sandro Pignata a,∗,1, Gabriella Ferrandina b,1, Giovanna Scarfone c,1, Paolo Scollo d,1,Franco Odicino e,1, Gennaro Cormio f,1, Dionyssios Katsaros g,1, Luigi Frigerio h,1,

Liliana Mereu i,1, Fabio Ghezzi j,1, Luigi Manzione k,1, Rossella Lauria l,1,Enrico Breda m,1, Desiderio Gueli Alletti n,1, Michela Ballardini o,1,

Alessandra Vernaglia p,1, Roberto Sorio q,1, Salvatore Tumolo r,1, Pietro Musso s,1,Giovanna Magni t,1, Carmela Pisano a,1, Alessandro Morabito a,1

a Istituto Nazionale Tumori, Napoli, Italyb Policlinico Agostino Gemelli, Ginecologia Oncologica, Roma, Italy

c Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Clinica Ostetrico-Ginecologica, Milano, Italyd A.O. Cannizzaro, Ginecologia ed Ostetricia, Catania, Italy

e A.O. Ospedali Civili – Università degli Studi di Brescia, II Ginecologia ed Ostetricia, Brescia, Italyf Azienda Ospedaliera Policlinico, II Ginecologia e Ostetricia, Bari, Italy

g Azienda Ospedaliera O.I.R.M.-S. Anna, Ginecologica Oncologica, Università di Torino, Italyh Ospedali Riuniti di Bergamo, U.O. di Ginecologia, Bergamo, Italy

i Ospedale Policlinico S. Matteo, Ostetrica e Ginecologica, Pavia, Italyj Ospedale F. Del Ponte, Clinica Ostetrica e Ginecologica, Università dell’Insubria, Varese, Italy

k Azienda Ospedaliera S. Carlo, Oncologia Medica, Potenza, Italyl Università Federico II, Oncologia Medica, Napoli, Italy

m Ospedale S. Giovanni - Fatebene Fratelli - Isola Tiberina, Oncologia Medica, Roma, Italyn A.O. Vincenzo Cervello, Ostetricia e Ginecologia, Palermo, Italy

o Ist. Onc.Romagnolo c/o Osp. Morgagni-Pierantoni, Forlì, Italyp Casa di cura Malzoni, Ginecologia Oncologica, Avellino, Italy

q CRO AVIANO, Oncologia Medica, Aviano, Italyr Azienda Ospedaliera S.Maria degli Angeli, Oncologia Medica, Pordenone, Italy

s Unità Operativa di Ginecologia Oncologica Ospedale Oncologico M. Ascoli Dipartimento Oncologico A.R.N.A.S. Palermo, Italyt QBGROUP spa, Padova, Italy

Accepted 18 December 2008

ontents

. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Please cite this article in press as: Pignata S, et al. Poor outcome of elderly patients with platinum-sensitive recurrent ovarian cancer:Results from the SOCRATES retrospective study. Crit Rev Oncol/Hematol (2009), doi:10.1016/j.critrevonc.2008.12.010

Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Appendix A. Participating institutions and coauthors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗ Corresponding author at: Divisione di Oncologia Medica B, Istituto Nazionale Tumori, via M. Semmola, 80131 Napoli, Italy. Tel.: +39 081 5903637;ax: +39 081 5903861.

E-mail address: sandro.pignata@fondazionepascale.it (S. Pignata).1 On behalf of the SOCRATES and MITO investigators.

040-8428/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.critrevonc.2008.12.010

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ARTICLE IN PRESSNCH-1284; No. of Pages 9

S. Pignata et al. / Critical Reviews in Oncology/Hematology xxx (2009) xxx–xxx

bstract

ackground: Elderly patients with ovarian carcinoma have a poorer prognosis compared with their younger counterpart, and this depends inost cases on undertreatment. The aim of this study was to evaluate, retrospectively, the pattern of care and the prognosis of elderly patientsith platinum-sensitive recurrent ovarian cancer. The SOCRATES study retrospectively assessed the pattern of care of a cohort of patientsith recurrent platinum-sensitive ovarian cancer observed in the years 2000–2002 in 37 Italian centres. Data were collected between April

nd September 2005.atients and methods: Patients with recurrent ovarian cancer with >6 months of platinum free interval were considered eligible. Four-hundred-inety-three patient files were collected and 425 were considered eligible and analyzed. Ninety-four patients with age ≥70 years and 331atients with age <70 years were analyzed.esults: Recurrence free interval (RFI), PS, and number of disease sites were similar among the two groups. A lower proportion of elderlyatients underwent secondary cytoreduction (8.9% compared to 23.9%; p = 0.0018). The mean number of chemotherapy lines received forecurrence was 2.7 and 2.5 in young and aged patients, respectively. Elderly patients received more frequently at second line single agentlatinum than platinum-combination therapy or other non-platinum chemotherapy. The response rate to the second line chemotherapy wasigher in younger patients than in the elderly population (CR + PR, younger: 67.2%; elderly: 46.5%; p = 0.0004). Median overall survivalrom recurrence was 30.7 months in the younger patients and 23.6 months in the elderly group (p = 0.0037). At multivariate analysis, numberf disease sites (>1 vs. 1), performance status at recurrence (2–3 vs. 0–1), RFI (6–12 months vs. >12 months), age at recurrence, werendependently associated with survival.onclusion: Elderly patients with platinum-sensitive recurrent ovarian cancer receive less surgery and chemotherapy. Response to chemother-py is better in younger patients. Age is an unfavourable factor independently associated to a worst prognosis.

2009 Elsevier Ireland Ltd. All rights reserved.

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eywords: Ovarian cancer; Recurrence; Elderly; Chemotherapy

. Introduction

A continuous demographic change is occurring in theeveloped countries with an increase of the age of the popu-ation [1]. As a consequence of the improvements in the fieldsf health care and nutrition, the significant reduction of preg-ancy rates, the decrease in global mortality and increasingrends of mean-life expectancy, human population is gettinglder and healthier. Because of this phenomenon, and dueo social, medical and demographic changes, the incidencef cancer-bearing patients aged 70 years or over is set toncrease in the western world [2,3]. These data particularlyoncern the female sex, which is predominant among humanlderly population [2,3]. In Europe 58% of all female can-ers occur in women older than 65 years [3,4]. Epidemiologicnalysis reveals that mortality rate from ovarian cancer areontinuously decreasing due to the improvement of surgerynd chemotherapy [1]. However, age-specific analysis indi-ate that the incidence of and mortality rate from ovarianancer are continuously increasing in the elderly population5–7]. In fact, within each stage, significant differences arebserved by age, with younger women surviving longer thanlder women even after adjusting for general life expectancy.

Although data of the literature in this field are really scantyt is thought that the lower survival rate of elderly patientsith ovarian cancer is mainly related to the less intensive

reatment received [8,9]. There is an urgent need of studies inhis field since it is our opinion that a great number of elderlyatients with ovarian cancer are undertreated in order to be

Please cite this article in press as: Pignata S, et al. Poor outcome of eResults from the SOCRATES retrospective study. Crit Rev Oncol/Hema

pared heavy cures which could result in unpredictable side-ffects.

Taken overall, the prognosis of ovarian cancer patients istill unsatisfactory considering that only 30% of the patients

re

re alive after 5 years [10–12]. In fact, although surgery andrst line systemic chemotherapy induce complete and par-

ial response in up to 80% of patients, with about a 25%athological complete remission rate, recurrences occur inhe majority of patients [13]. Most of these patients are sub-ect to repetitive treatment cycles that although palliative inature, can prolong survival.

In platinum-sensitive recurrent disease (recurrenceree interval (RFI) > 6 months) a platinum-based poli-hemotherapy is considered the standard since it was showno be superior to single agent platinum as for progression-freeurvival and overall survival [14,15]. At the following pro-ressions patients often receive several lines of non-platinumhemotherapy agents with the intent to chronicize theisease.

No data is available in the literature regarding treatment oflatinum-sensitive recurrence in elderly patients with ovarianancer.

The SOCRATES (Study of an Ovarian Cancer cohortecurred After first line Treament: a rEstrospectivy Survey)

tudy was planned to retrospectively assess the pattern of caref patients with recurrent platinum-sensitive ovarian cancerbserved in Italy in the years 2000–2002. Using this cohortf patients we evaluated if treatment strategy differs in thelderly population and if this determines a different outcomef the disease.

. Patients and methods

lderly patients with platinum-sensitive recurrent ovarian cancer:tol (2009), doi:10.1016/j.critrevonc.2008.12.010

Patients with recurrent advanced ovarian cancer and aecurrence free interval longer than 6 months were consideredligible for the study.

INONCH-1284; No. of Pages 9

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ARTICLES. Pignata et al. / Critical Reviews in

The patients observed in the years 2000–2002 in 37 Italianentres were analyzed.

Data were collected between April and September 2005.Four-hundred-ninety-three patient files were screened and

25 were considered eligible and analyzed.The descriptive analysis of the data has been performed

oth on the overall series and in two different subgroupsdentified according to age > or < of 70 years.

Clinical, pathological and treatment characteristics at ini-ial diagnosis, as well as at recurrence, including surgical and

edical treatment (up to six lines of chemotherapy) of theecurrence were considered. No data was available regardingpecific comorbidities. Response rate was calculated consid-ring RECIST [16] or Ca 125 criteria [17], or both accordingo centre choice.

Statistical significance of differences between responseo treatment in the different groups was calculated by the2-test. Overall survival was defined as the time elapsedetween recurrence diagnosis and the date of death or theate of last follow-up information for live patients. Medianime to progression and overall survival were calculated byhe Kaplan–Meier product limit method.

Differences among distributions of variables in theifferent groups were analyzed by the Student’s t-test

Please cite this article in press as: Pignata S, et al. Poor outcome of eResults from the SOCRATES retrospective study. Crit Rev Oncol/Hema

nd Wilkoxon test for quantitative variables, and by theantel–Haenszel test and the χ2 method for the qualitative

ariables. Differences were considered statistically signifi-ant when p < 0.05.

rmr

able 1haracteristics of the elderly patients with recurrent ovarian cancer compared to tancer.

Age at recurrence

Younger <70

umber of patients 331

IGO stage at diagnosis 325I 7.4II 7.4III 73.2IV 12.0

ystology 312Serous 70.8%Endometriods 12.8%Mucinous 4.8%Other 14.7%

esult of cytoreductive surgery 265No residual 27.2%Optimal (≤1 cm residual disease) 29.1%Suboptimal (>1 cm residual disease) 43.8%

COG performance status 2890 68.2%1 27.0%2 3.8%3 1.0%

ype of first line chemotherapy 331Platinum single agent 8.2%Platinum-based combination 91.8%

PRESSgy/Hematology xxx (2009) xxx–xxx 3

Association between age and the main prognostic inde-endent variables was assessed by univariate analysis;ariables with a statistically significant association (p < 0.05)ere also tested by multivariate analysis (logistic regressionbackward selection).To analyze risk factors associated to the death outcome the

ox model [18] (backward selection) was used and Hazardatios were calculated.

. Results

Table 1 shows the main clinical characteristics of theatients studied at time of the initial diagnosis (94 patientsver 70 years of age at time of recurrence and 331 youngerhan 70). At time of the analysis 69 (16.3%) patients were losto follow up, 253 (59.7%) were dead, and the remaining 102ere living. Patients lost to follow up were included in the

nalysis considering the last date available in the data base.Performance status, results of primary surgery and histol-

gy were similar between the two groups. In elderly patients,he first line treatment consisted more frequently of singlegent carboplatin than combination chemotherapy (21.3%ompared to 8.2%; p = 0.0003).

lderly patients with platinum-sensitive recurrent ovarian cancer:tol (2009), doi:10.1016/j.critrevonc.2008.12.010

The main characteristics of the patients at time of recur-ence are shown in Table 2. Recurrence free interval was 15.2onths and 14.1 months in the younger and elderly patients,

espectively (p = n.s.). No statistically significant differences

heir younger counterpart at the moment of the initial diagnosis of ovarian

Test

Elderly ≥70

94

916.6 χ2 Mantel–Haenszel p = n.s.7.7

84.61.1

88 χ2

71.6% p = n.s.13.6% p = n.s.5.7% p = n.s.

12.5% p = n.s.

7828.2% χ2 Mantel–Haenszel p = n.s.26.9%44.9%

8366.3% χ2 Mantel–Haenszel p = n.s.26.5%

7.2%

9421.3% χ2 p = 0.000378.7%

ARTICLE IN PRESSONCH-1284; No. of Pages 9

4 S. Pignata et al. / Critical Reviews in Oncology/Hematology xxx (2009) xxx–xxx

Table 2Characteristics of the elderly patients with ovarian cancer with a recurrence free interval >6 months compared to their younger counterpart at the moment ofthe diagnosis of recurrence.

Age at recurrence Test

Younger Elderly

Number of patients 331 94

Age at recurrence (years) 331 94Mean (±s.d.) 55.6 ± 8.8 73.6 ± 3.9Median 56 72Range 28–69 70–97

PS Ecog 309 840 64.4% 54.8% χ2 Mantel–Haenszel p = n.s.1 31.7% 39.3%2 3.9% 6.0%3 – – –

Recurrence free interval (months) 322 94≤12 39.8% 39.4% χ2 Mantel–Haenszel p = n.s.>12 60.2% 60.6%Median (range) 15.2 (5.0–160.0) 14.1 (5.7–141.4) Wilkoxon: p = n.s.

Number of disease sites 306 871 43.1% 41.4% χ2 Mantel-Haenszel p = n.s.>1 56.9% 58.6%

Surgery 322 90Yes 23.9% 8.9% χ2 p = 0.0018No 76.1% 91.1%

Result of cytoreductive surgery 65 7No residual 47.7% 42.9% χ2 p = n.s.Residual disease 52.3% 57.1%

Number of chemotherapy lines received for recurrence 331 94± 1.3

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ere found in PS, and number of disease sites at recurrence.lower proportion of elderly patients underwent secondary

ytoreduction (8.9% compared to 23.9%; p = 0.0018), evenf a similar number of cases were optimally debulked (noesidual disease) in the two groups when the patients wereperated. The mean number of chemotherapy lines receivedor recurrence was 2.7 and 2.5 in young and aged patients,espectively (p = n.s.).

Medical treatment details are shown in Table 3. Elderlyatients received more frequently at second line single agentlatinum than platinum-combination therapy or other non-latinum chemotherapy (p = 0.0025).

The response rate to the second line chemotherapy wasigher in younger patients than in the elderly populationCR + PR, younger: 67.2%; elderly: 46.5%; p = 0.0004). Aigher response rate for younger patients was observed bothor platinum (80.6% compared to 56.5%; p = 0.0002) andon-platinum chemotherapy, although in the latter case with-ut statistical significance (Table 4).

Median time to progression after second line chemother-

Please cite this article in press as: Pignata S, et al. Poor outcome of eResults from the SOCRATES retrospective study. Crit Rev Oncol/Hema

py was worse in the elderly group, although without reachingtatistical significance. Overall survival from recurrence was0.7 months in the younger patients and 23.6 months in thelderly group (p = 0.0037) [Fig. 1].

aci

2.5 ± 1.2 t-test: p = n.s.

At univariate analysis [Table 5] platinum at second lineyes vs. no), platinum in at least one line (yes vs. no), numberf disease sites (>1 vs. 1), performance status at recurrence2–3 vs. 0–1), age at recurrence (<70 vs. ≥70), RFI (6–12onths vs. >12 months), resulted significantly associatedith survival. At multivariate analysis (Table 6), number ofisease sites (>1 vs. 1), performance status at recurrence2–3 vs. 0–1), RFI (6–12 months vs. >12 months), age atecurrence, were the variables independently associated withurvival, while variables linked to medical treatment werexcluded by the backward selection of the model becauseot statistically significant at multivariate analysis.

. Discussion

In this study we found that elderly patients with platinum-ensitive recurrent ovarian cancer receive less surgery, haveworse response to chemotherapy and a poorer prognosis

ompared to their younger counterpart.

lderly patients with platinum-sensitive recurrent ovarian cancer:tol (2009), doi:10.1016/j.critrevonc.2008.12.010

Surgery and carboplatin/paclitaxel first line chemotherapyre considered the standard treatment for advanced ovarianancer. This strategy induces complete and partial responsen up to 80% of patients, with about a 25% pathological

ARTICLE IN PRESSONCH-1284; No. of Pages 9

S. Pignata et al. / Critical Reviews in Oncology/Hematology xxx (2009) xxx–xxx 5

Table 3Distribution of first chemotherapy for recurrencea by age categories.

Type of treatment All patients, n = 420 Younger, n = 327 Elderly n = 93 χ2p

No. % No. % No. %

Single agent platinum 79 18.8 50 15.3 29 31.2Combination platinum-based 199 47.4 161 49.2 38 40.9 0.0025Non-platinum chemotherapy 142 33.8 116 35.5 26 28.0

a Only the initial therapeutic approach is considered.

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Analyzing the reason for the poorer prognosis of elderlypatients, we found that baseline characteristics at recurrencedid not differ significantly within the two groups defined withthe cut off of 70 years. However, when analyzing treatment

Table 4Response to second line chemotherapy in patients with ovarian cancer witha recurrence free interval >6 months according to age.

Younger Elderly Test

N pts. 331 94

Response rate to second lineAll evaluable patients 274 86

CR + PR 67.2% 46.5% χ2 p = 0.004NC + PD 32.8% 53.5%

Platinum-based chemotherapy 180 62CR + PR 80.6% 56.5% χ2 p = 0.002NC + PD 19.4% 43.4%

Non-platinum chemotherapy 94 24

ig. 1. Kaplan–Meyer curves of overall survival of patients with platinum-sen<70 years); white line: elderly (older than 70 years). Crosses represent cen

omplete remission rate. However, recurrences occur in theajority of patients requiring further lines of chemotherapy

n most cases [13].According to the current dogma the potential for plat-

num sensitivity is the most important decision criteria whenlanning treatment of the recurrence [19,20]. Patients whorogress on first line therapy or relapse within 3 monthsre considered to be refractory to a platinum re-treatment.atients who respond to primary treatment and relapse withinmonths are considered platinum resistant. Patients who

elapse more than 6 months after completion of initial ther-py are defined as platinum sensitive. Thus, tumour responseates to platinum are directly related to the recurrence freenterval, time from the last cycle of platinum during first line,nd time of recurrence [20].

Two large randomized studies in platinum-sensitive dis-ase have demonstrated that the addition of a second drug toarboplatin improves the outcome of the patients [14,15]. TheCON4/AGO2.2 trial compared a platinum-based chemother-py (70% carboplatin alone) with a carboplatin and paclitaxelombination. In this study that enrolled 802 patients there wasn absolute difference in 1-year progression-free survival of0% and in 2-year survival of 7%. The combination inducedn acceptable toxicity profile with neurotoxicity (20% G2-4)s major complains [14]. Similar results have been obtainedith the combination of carboplatin and gemcitabine vs. car-

Please cite this article in press as: Pignata S, et al. Poor outcome of eResults from the SOCRATES retrospective study. Crit Rev Oncol/Hema

oplatin. In the AGO study, the combination significantlymproved progression-free survival along with a better qual-ty of life. Toxicity was prevalently haematological, whileeurotoxicity was of lower degree [15].

T

current ovarian cancer according to age at diagnosis. Black line: non-elderlyimes.

No data is available in the literature regarding treatment ofecurrent elderly patients with ovarian cancer. In this study wesed the SOCRATES cohort of patients in order to evaluatef the treatment strategy differs in the elderly population andf this determines a different outcome of the disease.

In this series of patients advanced age was an indepen-ent predictors of survival, along with platinum-free interval,erformance status and number of disease sites.

lderly patients with platinum-sensitive recurrent ovarian cancer:tol (2009), doi:10.1016/j.critrevonc.2008.12.010

CR + PR 41.5% 20.8% χ2 p = n.s.NC + PD 58.5% 79.2%

ime to progression (months) 310 91Median (Kaplan–Meyer) 8.6 8.4 Long-rank: p = n.s.

ARTICLE IN PRESSONCH-1284; No. of Pages 9

6 S. Pignata et al. / Critical Reviews in Oncology/Hematology xxx (2009) xxx–xxx

Table 5Univariable analysis of overall survival.

n p Hazard ratio 95% CI

Platinum at second line (no vs. yes) 744 0.0007 1.577 1.211–2.055Platinum in at least 1 line (no vs. yes) 411 0.0004 1.788 1.299–2.461Multiple sites versus isolated recurrence (more than 1 vs. 1) 384 <0.0001 1.886 1.435–2.478P 384A 416R 408

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erformance status at recurrence (2–3 vs. 0–1)ge at recurrence (≥70 years vs. <70 years)ecurrence free interval (RFI) (6–12 months vs. >12 months)

eceived we observed that elderly patients received less fre-uently secondary surgical cytoreduction and combinationhemotherapy compared to single agent platinum or non-latinum agents at recurrence These data indicate that a lessggressive strategy is used in elderly compared to youngeratients. The retrospective nature of the study does not allowo identify the reason for undertreatment but it is possibleo speculate that in the absence of safety data for surgerynd combination chemotherapy in this setting of patientsany patients have been excluded from a standard treatment

trategy only due to their chronological age.The reduced number of patients that underwent secondary

ytoreduction can be one of the reasons for the poor outcomef elderly patients, considering the recent data suggesting atrong prognostic role for optimal secondary cytoreduction21]. A reason for suboptimal surgical treatment in elderlyatients could be the fear of higher complication rates dueo the presence of multiple co-morbidities in this age group.n the early 1990s, Kirschner et al. [22] and Lawton andacker [23] reported a high rate of severe postoperative com-lications in women aged 65 years or older submitted toelvic surgery. However, in recent years, new developmentsn the field of anaesthesiology, peri-operative care, and surgi-al techniques have significantly improved general safety andate of operability [24] and it is now believed that advancedge should not be considered a contraindication to cytoreduc-ive surgery. In fact, Wright et al. [25] and Sharma et al. [26]ound equal rates of morbidity in younger patients (<70) andn patients over 70 years of age operated with the intent ofptimal cytoreduction.

Regarding chemotherapy we found that elderly patientseceived less frequently combination platinum-basedhemotherapy compared to single agent platinum oron-platinum agents for the treatment of recurrence. It is

Please cite this article in press as: Pignata S, et al. Poor outcome of eResults from the SOCRATES retrospective study. Crit Rev Oncol/Hema

ossible to hypothesize that the high rate of neurotoxicitynd haematological toxicity of the standard chemotherapyith carboplatin/paclitaxel or carboplatin/gemcitabineiscourages the use of combination chemotherapy in this

ta

t

able 6ultivariable analysis of overall survival–Cox model (backward selection) (n = 347

p

ultiple sites versus isolated recurrence (more than 1 vs. 1)erformance status at recurrence (2–3 vs. 0–1) <ecurrence free interval (RFI) (6–12 months vs. >12 months)ge ≥70 versus <70

0.0010 2.479 1.441–4.2640.0051 1.511 1.132–2.016

<0.0001 1.859 1.440–2.400

etting of patients, as previously described [27]. In fact its known that aging can affect the pharmacokinetics andharmacodynamic of antineoplastic therapy [28,29]. As aesult of these changes, the older persons are considered atncreased risk for therapeutic complications [29,30].

However, it is our opinion that chronological age is annsufficient predictor of toxicity from chemotherapy. The usef a multidimensional geriatric evaluation taking into accountamily support, mental status, the type and degree of disabilitynd the presence of co-morbidities [31,32], could be useful inrder to differentiate both frail patients and those at high riskf toxicity from the rest of the elderly population. This evalu-tion, allows a better categorization of elderly cancer patientsompared to performance status alone, also in patients withgood performance status [32], and may help the physician

o choose the best therapeutic strategy. Recommendation forhe use of comprehensive geriatric assessement have beenecently published by the Society of Geriatric Oncology [33].

Another interesting data of the present study is the loweresponse rate to chemotherapy in elderly than in youngeratients, along with a trend versus a worst progression-ree survival. This may depend on the reduced numberf patients treated with combination chemotherapy, butlso on the reduced compliance to treatment of the agedopulation. We do not have data regarding chemotherapyompliance in the present cohort, but in a previous studyn 148 consecutive gynaecologic oncological patients aged70, submitted to first line chemotherapy in Italy during the

ears 1990–2000 [34] we analyzed toxicities, discontinua-ions, dose-reductions and drug delays separately in patientsith 70–74 years of age and in those over 75 years. We

ound that patients older than 75 years showed a higher pro-ortion of drug delays and dose-reductions with respect toatients younger than 75. Only few prospective trials devoted

lderly patients with platinum-sensitive recurrent ovarian cancer:tol (2009), doi:10.1016/j.critrevonc.2008.12.010

o elderly patients have been published [35] and more studiesre clearly needed in this setting.

Our study has some important limitations. First of allhis is a retrospective series. Data on co-morbidities or

pts).

Hazard ratio 95% CI

0.0012 1.648 1.219–2.2290.0001 1.611 1.275–2.0340.0004 1.678 1.261–2.2330.0353 1.424 1.026–1.980

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eriatric assessement are not available due to the design ofhe study and no information is reported regarding physician’sriteria of therapy decisions. Thus, it is not possible to fullynderstand the reasons for the different treatment strategiessed. Furthermore, one could argue that 70 years is not theest cut off to separate elderly patients. However, we thinkhat this cut off, used in several retrospective and prospec-ive trials, was able in our series to separate two groups ofatients where treatment was somehow different. We thinkhat restrospective data like this can help to identify specificetting where a prospective research is needed. In our opinion,edical and surgical treatment of the recurrence in elderly

atients with platinum-sensitive disease merit such prospec-ive studies. In this case it is mandatory that elderly patientsre evaluated by a geriatric multidimensional assessment. Inact, in the few prospective studies previously published inlderly patients with ovarian cancer, it has been shown thatultidimensional geriatric assessment predicts tolerance to

hemotherapy and survival [36]. In particular, among thearameters assessed, the presence of symptoms of depres-ion was found to represent an independent prognostic factorndependently correlated with mortality [36,37].

In conclusion, we found in the SOCRATES cohortf patients that elderly patients with recurrent platinum-

Please cite this article in press as: Pignata S, et al. Poor outcome of eResults from the SOCRATES retrospective study. Crit Rev Oncol/Hema

ensitive ovarian cancer have a poor outcome compared toounger patients. They receive less surgery and chemother-py and response to chemotherapy is lower. We suggesthat properly designed clinical trials should be performed

d

A

Hospital Division

A.O. Spedali Civili di Brescia II ginecologia ed ostetriciaUniversità Cattolica del Sacro Cuore Ginecologia Oncologica

Policlinico Bari II◦ Ginecologia e Ostetricia

Istituto Nazionale Tumori, Napoli Oncologia Medica B,GinecUOC Sperimentazioni Clini

Azienda Ospedaliera O.I.R.M.-S. Anna,Università di Torino

Ginecologia Oncologica

Ospedali Riuniti di Bergamo GinecologiaOspedale Policlinico S. Matteo, Pavia Ostetrica e GinecologicaOspedale F. Del Ponte, Università dell’Insubria,

Varese.Clinica Ostetrica-Ginecolog

Clinica Mangiagalli, Milano Clinica Ostetrico-GinecologAO S. Carlo, Potenza Oncologia MedicaPoliclinico Federico II, Napoli Oncologia Medica

Ospedale S. Giovanni - Fatebene Fratelli - IsolaTiberina, Roma

Oncologia Medica

A.O. Vincenzo Cervello, Palermo Ostetricia - ginecologiaOspedale Morgagni- Pierantoni, Forlì Unità di Biostatistica – Onc

MedicaCasa di cura Malzoni, Avellino Ginecologia Oncologica

PRESSgy/Hematology xxx (2009) xxx–xxx 7

n elderly patients with ovarian cancer, using multidimen-ional geriatric assessment, in order to standardize surgicalnd medical treatment of these patients.

eviewers

Professor Gilles Freyer, Co-Head, Medical Oncologyepartment, Centre Hospitalier Lyon-Sud, F-69495 Pierre-énite Cedex, France.

onflicts of interest

The author(s) indicated no potential conflicts of interest.

cknowledgements

The authors thanks Jane Bryce for editing the paper innglish. The SOCRATES project was supported by an unre-tricted grant from GSK Italy. The MITO group is supportedy a project grant from Associazione Italiana per la Ricercaul Cancro. The authors remember Giovanni Favalli, recentlyeceased, that was a member of the SOCRATES board.

ppendix A. Participating institutions and coauthors

Sergio Pecorelli Franco OdicinoGiovanni Scambia Gabriella Ferrandina

Domenica LorussoLuigi Selvaggi Gennaro Cormio Vera Loizzi

Ambrogio Cazzollaologia,che

Sandro PignataFrancesco Perrone

Alessandro MorabitoCarmela Pisano StefanoGreggi FrancescapaolaMagazzino

Marco MassobbioManuela Puopolo

Dionyssios Katsaros

Luigi Frigerio Antonella VillaEmilio Imparato Saverio Tateo Liliana Mereu

ia Pierfrancesco Bolis Fabio Ghezzi NicolettaDonadello

ica Giorgio Bolis Giovanna ScarfoneLuigi Manzione Rosangela RomanoSabino De Placido Rossella Lauria Emilia

Montagna Emilia BuccinoValeria Forestieri

Vittorina Zagonel Enrico Breda

lderly patients with platinum-sensitive recurrent ovarian cancer:tol (2009), doi:10.1016/j.critrevonc.2008.12.010

A. Lo Presti Giovanna Marforioologia Ruggero Ridolfi Dino Amadori

Carmine Malzoni Alessandra VernagliaLombardi

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ppendix A (Continued )

ospital Division

RO Aviano Oncologia Medicazienda Ospedaliera S.Maria degli Angeli,Pordenone

Oncologia Medica

spedale San Raffaele, Milano Ginecologiaspedale S. Vincenzo, Taormina Oncologia Medica.O. Civico Benfratelli M. Ascoli e G. diCristina, Palermo

Ginecologia Oncolo

zienda Ospedaliera, Parma Ginecologia ed Ostespedale Civile, Voghera Oncologia Ginecolo.O. Bianchi-Melacrino-Morelli, ReggioCalabria

Oncologia Medica

spedale Generale S. Cuore di Gesù, Benevento Oncologia Medicaspedale Mater Salutis, Legnago Oncologia Medicaresidio Ospedaliero di Bentivoglio Oncologia Medica

spedale Belluria di Bologna Oncologia Medicazienda Ospedaliera Cannizzaro, Catania Ginecologia ed Osteasa di Cura La Maddalena, Palermo Oncologia Medicaasa Sollievo della Sofferenza, S.GiovanniRotondo

Ginecologia ed ostet

stituto scientifico oncologico IRCCS, Bari Oncologia Medicaoliclinico Universitario P. Giaccone, Palermo Oncologia Medicazienda Ospedaliera Mariano Santo, Cosenza Oncologia Medicazienda Ospedaliera Civile Maria Paternò,Ragusa

Oncologia Medica

.O. Policlinico Mater Domini, Catanzaro Oncologia Medica.O.C. Belcolle di Viterbo Oncologia Medicaspedale Silvestrini, S.Andrea delle Fratte Oncologia Medica

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iography

Sandro Pignata was born in Naples in 1962. He took theD degree in 1986 at the Naples University and the PhD

egree in gastroenterological science at the University ofome in 1990. Since 1993 he is Staff Physician of the Divi-

ion of Medical Oncology B of the National Cancer Instituten Naples. He is the president of the Multicenter Italian Trial

lderly patients with platinum-sensitive recurrent ovarian cancer:tol (2009), doi:10.1016/j.critrevonc.2008.12.010

n Ovarian cancer (MITO) group that is involved in severalandomized trials on the treatment of gynaecological cancer,hose results have been published in important international

ournals.