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Background: We assess the prognostic value of chemotherapy-induced leukopenia and sensory neuropathy in the CALYPSO trial patients treated with carboplatin–paclitaxel (CP) or carboplatin–liposomal doxorubicin (CPLD). Methods: We performed a landmark analysis at first month after randomisation to correlate leukopenia (nadir white blood cell <4.0 × 10 9 per litre or severe infection) during cycle 1 of chemotherapy with progression-free survival (PFS). Using time-dependent proportional-hazards models, we also investigated the association between neuropathy and PFS. Results: Of 608 patients with nadir blood and did not receive growth factors, 72% (CP=70%, CPLD=73%) had leukopenia. Leukopenia was prognostic for PFS in those receiving CP (adjusted hazard ratio (aHR) 0.66, P =0.01). Carboplatin–liposomal doxorubicin was more effective than CP in patients without leukopenia (aHR 0.51, P =0.001), but not those experiencing leukopenia (aHR 0.93, P =0.54; interaction P =0.008). Of 949 patients, 32% (C P =62%, CPLD=28%) reported neuropathy during landmark. Neuropathy was prognostic for PFS in the CP group only (aHR 0.77, P =0.02). Carboplatin–liposomal doxorubicin appeared to be more effective than CP among patients without neuropathy (aHR 0.70, P <0.0001), but not those with neuropathy (aHR 0.96, P =0.81; interaction P =0.15). Conclusion: First-cycle leukopenia and neuropathy were prognostic for patients treated with CP. Efficacy of CP treatment was similar to CPLD in patients who developed leukopenia. These findings support further research to understand the mechanisms of treatment-related toxicity.

Introduction/BackgroundThe non-interventional NIMES-ROC phase IV trial (NCT02825420) evaluated trabectedin (Yondelis®)+pegylated liposomal doxorubicin (PLD) in real-life clinical practice, given in accordance with the marketing authorization to women with platinum-sensitive recurrent ovarian cancer (PSROC) regardless of prior anti-angiogenic treatment.MethodologyWe report the results of an interim analysis of the data from patients with PSROC treated with trabectedin+PLD within the approved schedule (PLD 30 mg/m² followed by 1.1 mg/m² trabectedin as 3-h/every 3 weeks). Eligible were adults with PSROC who have received ≥1 cycle of trabectedin+PLD before inclusion. The primary endpoint was to assess the progression-free survival (PFS) according to investigator criteria.ResultsOverall, 158 adult patients from 50 sites across Spain, Italy, Germany, France and Belgium were evaluated. Median number of trabectedin+PLD cycles received per patient was 6, with 95 patients (50.6%) receiving ≥6 cycles and up 34 cycles. Median treatment duration and cycle duration were 22.2 weeks (range: 3–124) and 25.5 days (range: 21.0–73.0), respectively, with ≥63% of patients treated on an outpatient basis. Twenty-two patients received prior PLD or doxorubicin with no reported safety issues due to retreatment with trabectedin+PLD. With 73 PFS events and 32 deaths recorded, median PFS and overall survival were 11.4 months (95% CI: 10–14) and not reached (16.8-nr), respectively. The objective response rate was 38%, while 28.5% of patients had disease stabilization for a disease control rate of 66.5%. A total of 108 trabectedin-emergent adverse reactions (TEARs) occurred. Most common grade 3/4 TEARs were neutropenia (25%) and asthenia (4%).ConclusionAcknowledging the interim results from observational studies need to be interpreted with caution, our preliminary data confirm that trabectedin+PLD is effective and safe in patients with PSROC. Our data favourably compare with those of the pivotal OVA-301 trial (NCT00113607; i.e. median PFS 9.2 months), even with more pretreated patient population (NIMES-ROC: 39.9% with ≥3 prior chemotherapy lines).DisclosureNothing to disclose.Abstract P118 Table 1DemographicsNIMES-ROC* Total (n=158) Age at study entry (years) Median (range) 62.0 (39–86) ECOG performance status, n (%) 0; 1; 2; Not available* 67 (42.4); 33 (20.9); 5 (3.2); 53 (33.5) Histopathology, n (%); ≥10% of patients Papillary/serous 115 (72.8) Tumor grade at diagnosis, n (%) High grade; Intermediate grade; Low grade; Not done/Unknown* 111 (70.3); 11 (7.0); 9 (5.7); 27 (17.1) BRCA 1/2 status tested, n (%) Positive; Negative; Unknown*; Not done 20 (12.7); 56 (35.4); 15 (9.5); 67 (42.4) Prior treatments, n (%) Prior surgery; Prior secondary debulking; Prior radiotherapy; Prior chemotherapy; Prior use of antiangiogenics; Prior bevacizumab; Prior platinum-based therapy; Prior PLD/doxorubicin 144 (91.1); 61 (38.6); 6 (3.8); 156 (98.7); 88 (55.7); 86 (54.4); 156 (98.7); 22 (13.9%) Platinum sensitivity, n (%) Partially platinum sensitive; Fully platinum sensitive; Missing* 100 (63.3); 53 (33.5); 5 (3.2) Number of lines of prior chemotherapy, n (%) 0; 1; 2; 3; 4–7 1 (0.6); 40 (25.3); 54 (34.2); 31 (19.6); 32 (20.3) *Data not available at cut-off date. CI: Confidence interval; PLD: Pegylated liposomal doxorubicin.Abstract P118 Table 2Best responsesNIMES-ROC; Interim analysis Total (n=158) Progression-free survival* (PFS); Overall survival** (OS) months (95% CI) 11.4 (10–14); nr (16.8-nr) Best response during NIMES-ROC, n (%) Complete response (CR) 15 (9.5) Partial response (PR) 45 (28.5) Stable disease (SD) 45 (28.5) Progressive disease (PD) 32 (20.3) Not evaluable/Missing* 21 (13,3) ORR (CR+PR); [95% CI] 60 (38.0); [30.4–46.0] DCR (ORR+SD); [95% CI] 105 (66.5); [58.5–73.8] *Patients who have not died and do not have an assessment of disease progression are censored. **Patients who have not been reported as dead are included as censored. CI: confidence interval; DCR: disease control rate; nr: not reached; ORR: objective response rate.

Introduction/BackgroundPatients (pts) with ovarian cancer experiencing a platinum-sensitive (PS) recurrence are generally re-exposed to platinum agents (PCT). The addition of bevacizumab (BEV) or PARP inhibitors (PARPi) as concomitant and/or maintenance therapy has shown to improve progression free survival (PFS). In the absence of direct comparisons coming from randomized trials (RCTs), we have performed a network meta-analysis to evaluate differences in terms of efficacy between BEV and PARPi in pts with PS recurrent ovarian cancer (rOC), according to BRCA status.MethodologyWe searched PubMed, Embase and Medline for RCTs involving pts with PS rOC treated with BEV (n=3, 1563 pts) or PARPi (n=5, 1839 pts). Only trials with PFS as primary endpoint were included. Analyses have been done pooling pts who had received PARPi in three groups, according to the available data on BRCA genes status: all comers (AC), BRCA mutated pts (BRCAm) and BRCA wild-type pts (BRCAwt). A frequentist approach has been used with R statistical software. To rank the effect size of treatments, surface under the cumulative ranking value (SUCRA) has been applied.ResultsIn AC pts, PARPi improved PFS compared to BEV (hazard ratio [HR]=0.70, 95% CI 0.54–0.91). In BRCAm pts the gain in PFS for PARPi was even higher compared to BEV (HR=0.46, 95% CI 0.36–0.59). In BRCAwt pts the benefit of PARPi over BEV was not statistically significant (HR=0.87, 95% CI 0.63–1.20) but PARPi had the highest likelihood of being ranked as the best treatment in terms of efficacy according to SUCRA (90% and 60%, respectively for PARPi and BEV).ConclusionAccording to indirect comparisons, PARPi performed the best for the treatment of PS rOC, especially in BRCAm pts who had not previously received PARPi. BEV could be still an option in BRCAwt pts.DisclosureFabio Puglisi: Roche, AstraZeneca (honoraria and research founding). No conflict of interest is to be declared for the remaining authors. The authors receive no financial support for this study.

Introduction/BackgroundWomen aged ≥65 represent nearly 50% of ovarian cancer (OC) patients (pts). However, elderly OC pts are less likely to receive optimal treatment. Furthermore, they are significantly under-represented in clinical trials and multidimensional geriatric assessment is still underused. The present study aims to provide an overview of real-life treatment strategies for elderly advanced-OC pts and to investigate clinico-pathological features that could potentially drive choice of first-line treatment.MethodologyA retrospective analysis was conducted on a consecutive series of 45 OC pts aged ≥69 treated with first-line chemotherapy (1L_CT) from 2011 to 2018 at CRO Aviano National Cancer Institute (Italy). Factors associated with treatment choice and rate of adverse events were investigated through Fisher-exact test; differences in progression free survival (PFS) and overall survival (OS) were tested by log-rank test.Results67% of pts received 1L_CT with a standard carboplatin-paclitaxel combination (CPC). Conversely, 33% received a monotherapy (MT) (31% with carboplatin, 2% with paclitaxel). ECOG PS ≥1 was the only factor significantly associated with choice of MT (P=0.021). No differences were observed between CPC and CPC with dose reductions (CPCdr), neither in terms of PFS (HR=1.29 P=0.59) nor OS (HR=1.40 P=0.56). On the other hand, MT was associated with shorter PFS (HR=4.35 P=0.001) and OS (HR=4.48 P=0.005). No differences in treatment discontinuation rate, neutropenia, thrombocytopenia, neuropathy, constipation, diarrhoea and asthenia in CPC, CPCdr and MT were detected (P>0.05).ConclusionThe present study confirms CPC as the standard first-line chemotherapy also in advanced OC elderly pts and suggests that CPCdr is preferable to MT regimens. Notwithstanding the limitations due to the small sample size, the evaluated regimens showed a comparable toxicity profile. Notably, clinical decision-making was mainly driven by PS ECOG highlighting the pivotal role of multidimensional geriatric assessment for pts stratification. Further prospective studies are needed to investigate improved tailored strategies.DisclosureNothing to disclose.

Background: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. Patients and Methods: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m 2 or PLD 30 mg/m 2 every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). Results: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). Conclusions: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.

Purpose Treatment of patients with recurrent ovarian cancer remains a challenge, and there is a need for new and more effective agents. A phase I-II study was designed to determine the recommended dose (RD) and the anti-tumour effect of a prolonged administration of elacytarabine, the elaidic ester of cytarabine, in patients with refractory/resistant recurrent ovarian cancer. Experimental design The primary objective of the dose escalation phase I part was to determine the RD for elacytarabine when given twice for five consecutive days in a 4-week schedule, D1-5 and D8(+2)-12(+2) q4w. Three to six patients were to be enrolled at each dose level. The start dose was elacytarabine 75 mg/m 2 /day. The phase II part was designed as a two-step study based on response. Results A total of 28 patients entered the study, 17 patients in the phase I part and 11 # patients in phase II. Three dose levels were tested: 75 mg/m 2 /day in 3 patients, 100 mg/m 2 /day in 7 + 11 # patients, and 125 mg/m 2 /day in 7 patients. Three (17.6%) patients in phase I experienced a dose limiting toxicity (DLT), all at the 125 mg/m 2 /day dose level, establishing the lower dose of 100 mg/m 2 /day as the RD. The DLTs were neutropenia grade 4 according to the Common Terminology Criteria for Adverse Events (CTCAE) and thrombocytopenia grade 4 (2 patients), and vomiting grade 2 with hospitalisation and hypokalaemia grade 3 (1 patient). The best response was a clinically meaningful stabilization observed in 3 patients. In two of them, the disease stabilization exceeded the previous platinum-free interval (PFI). Conclusions The RD for elacytarabine was 100 mg/m 2 /day, D1-5 and D8-12 q4w. The safety profile was comparable to the safety profiles reported in previous clinical studies with elacytarabine in solid tumours. Despite some longer-lasting disease stabilisations, two of them exceeding the previous progression-free interval, further investigations of elacytarabine in the ovarian cancer indication are not warranted.

The purpose of this study was to compare long-term survival in first-line chemotherapy with and without platinum in advanced-stage ovarian cancer. From July 1987 to November 1992, 161 untreated patients with FIGO stage III–IV epithelial ovarian cancer were randomized: 81 patients received no platinum and 80 received platinum combination. Residual disease after surgery was <2 cm in 61 patients without platinum, 59 with platinum. Median age was 58 years in nonplatinum arm and 55 years in platinum arm (range: 15–73). Complete and partial responses were 51% and 10% for nonplatinum arm and 51% and 8% for platinum arm, respectively (P= 0.7960). Stable disease was observed in 18% of patients in nonplatinum arm and 15% of patients in platinum arm and progression in 20% of nonplatinum- and 21% of platinum-treated cases. Ten-year disease-free survival was 37% for therapy without platinum and 31% for platinum combination (P= 0.5679); 10-year overall survival was 23% without platinum and 31% with platinum combination (P= 0.2545). Fifteen-year overall survival showed a trend of short duration in favor of platinum (P= 0.0678). Relapses occurred after 60 months in ten patients (seven with and three without platinum). The overall and disease-free survivals at 5, 10, and 15 years show no statistically significant long-term advantage from the addition of cisplatin; however, there is a slight trend in its favor.

Ifosfamide is an alkylating agent active in various tumor types including breast cancer. The availability of mesna (sodium 2-mercaptoethanesulfonate) has increased its safety, avoiding the main dose-limiting side effect, urotoxicity. Interesting activity as a single agent, with response rates ranging from 7 to 30%, is reported in pretreated patients; more attractive data derived from phase II studies on ifosfamide combined with drugs known to be active in advanced breast cancer show response rates always over 35%. This review has taken in consideration papers published after 1995 and available on PubMed medline: the data indicate a potential usefulness of ifosfamide in the clinical management of advanced breast cancer, even if the exact therapeutic role of the drug in this setting should be derived from randomized studies not yet available.