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Poly (ADP-ribose) polymerase inhibitors (PARPi) represent a new standard of care in the upfront treatment of advanced epithelial ovarian cancer to the point that the vast majority of patients now receive a PARPi, alone or in combination with the anti-angiogenic bevacizumab, as part of their first-line maintenance therapy. The clinical benefit of PARPi is well established; however, much has changed since their introduction and several relevant questions have been raised and remain unresolved in the post-PARPi era. The decision-making process regarding the most appropriate first-line maintenance therapy could be challenging in clinical practice, especially in the homologous recombination-proficient setting, and several other factors need to be considered apart from the mutational status. Concerns regarding post-PARPi progression treatment have emerged, highlighting an unmet need to define a valid algorithm strategy. PARPi may not only compromise the response to further platinum due to cross-resistance mechanisms but the impact on subsequent non-platinum chemotherapy and surgery also remains unclear. Definitive results on the role of PARPi rechallenge are awaited, especially in the case of oligoprogression managed with locoregional treatment. Moreover, the updated overall survival data from the recurrent setting warrant caution in using PARPi as single agents for unselected patients. Several PARPi combination regimens are emerging for overcoming PARPi resistance and may become our new therapeutic armamentarium. This review discusses a set of clinically relevant issues in the PARPi era and provides a glimpse of future challenges and opportunities in ovarian cancer treatment.

ObjectiveAdult granulosa cell tumors represent less than 5% of all ovarian malignancies. The aim of this study was to analyze the clinicopathological parameters and their impact on progression-free and overall survival.MethodsPatients with primary adult granulosa cell tumors treated in three international referral centers between July 1999 and December 2018 were included. The following data were anonymously exported from the prospective database: age at diagnosis, International Federation of Gynecology and Obstetrics (FIGO) stage, adjuvant therapy, surgical procedures, progression-free survival, and overall survival. Descriptive statistical analysis regarding tumor and treatment characteristics was performed. Survival analyses included Kaplan–Meier functions and Cox proportional hazard ratios (HR).ResultsA total of 168 patients with primary adult granulosa cell tumors were included. Median age was 50 years (range 13–82). With regard to stage distribution, 54.2% (n=91) of patients were FIGO stage IA, 1.2% (n=2) were stage IB, 26.8% (n=45) were stage IC, and 17.9% (n=30) were FIGO stage II–IV. 66.7% (n=112) of patients underwent surgical restaging, of whom 17.9% (n=20) were moved to a higher stage. In addition, 36 (21.4%) patients underwent fertility-sparing surgery. After a median follow-up of 61 months (range 0–209), 10.7% of patients (n=18) had recurrent disease and 4.8% (n=8) died of disease. Five-year progression-free survival was 86.1% and estimated overall survival was 95.7%. Five-year progression-free survival was worse for patients with advanced stages (FIGO stage IA/B vs IC: HR 5.09 (95% CI 1.53 to 16.9); FIGO stage IA/B vs II–IV: HR 5.62 (95% CI 1.58 to 19.9)). Nineteen patients receiving adjuvant chemotherapy had lower estimated 5-year progression-free survival compared with patients not receiving chemotherapy (49.7% vs 91.1%, pConclusionThe prognosis of patients with primary adult granulosa cell tumors is mainly determined by FIGO stage. The outcome of patients with FIGO stage IC is comparable to those with advanced stages. Fertility-sparing surgery seems to be a safe procedure in stage IA. Our data do not support the use of adjuvant chemotherapy in early and advanced stages of adult granulosa cell tumors.

Inhibitors of poly(ADP-ribose) polymerase (PARPi) are increasingly employed as salvage therapy in epithelial ovarian cancer (EOC), but cytotoxic drug exposure along with PARP inhibition may favor development of hematological disorders. In our study, of 182 women with EOC treated with PARPi, 16 (8.7%) developed therapy-related myeloid neoplasms (t-MNs), with 12 cases of myelodysplasia and 4 of acute myeloid leukemia. All experienced persistent cytopenia after PARPi discontinuation. Seven patients had del(5q)/-5 and/or del(7q)/-7, nine had a complex karyotype and TP53 mutations, recently reported as risk factor for t-MNs in EOC post-PARPi, were found in 12 out of 13 tested patients. Four patients had a rapid and fatal outcome, one had stable disease, eleven underwent induction therapy, followed by allogeneic hematopoietic cell transplantation in seven. Three of these 11 patients experienced refractory disease, and 8 had complete remission. During a 6.8 months (range 2.3-49) median observation time, 3 out of 16 patients were alive, with one surviving patient free of both solid and hematological tumors. Ten patients died because of leukemia, two because of transplant-related events, one from heart failure. Five more patients experienced persistent cell blood count abnormalities following PARPi discontinuation, without reaching MDS diagnostic criteria. A customized Myelo-panel showed clonal hematopoiesis in all five patients. These findings confirm the actual risk of t-MNs in EOC patients after chemotherapy and prolonged PARPi therapy. The management of these patients is complex and outcomes are extremely poor. Careful diagnostic procedures are strongly recommended whenever unusual cytopenias develop in patients receiving PARPi therapy.

The incidence of myeloid neoplasms following treatment with poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with ovarian cancer has been gradually increasing over the last few years. The cumulative exposure to PARPi and the improved overall survival of patients with ovarian cancer may represent key underlying explanations behind such trend. Fortunately, the earlier introduction of PARPi in the frontline setting reduces the risk of developing secondary myeloid neoplasms. The etiopathogenesis is still unclear but is likely to be multifactorial. The first 2 years of PARPi exposure seem to be the critical window for the onset of myeloid neoplasms post PARPi, with persistent cytopenia recognized as an early warning sign. Despite intensive treatment strategies, the outcome remains poor. There is an unmet clinical need to learn how to minimize risk, make an early diagnosis, and manage myeloid neoplasms post PARPi. First, decision making regarding the optimal maintenance treatment should avoid a ‘PARPi-for-all’ strategy. PARPi should be used cautiously in cases of high baseline risk for myeloid neoplasms and/or patients who are less likely to have a benefit. Active surveillance, accurate differential diagnosis, and prompt hematological referral are key management pillars. This review discusses what is known on this emerging issue as well as unresolved questions.

5560 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, maintenance olaparib + bevacizumab (bev) provided a significant progression-free survival (PFS) benefit vs placebo (pbo) + bev in patients (pts) with newly diagnosed advanced ovarian cancer in response to platinum-based chemotherapy. Subgroup analyses revealed a substantial PFS benefit in homologous recombination deficiency (HRD)-positive (including BRCA1/2 mutation) pts, leading to US/EU labels for this combination. Preliminary analyses reported that olaparib did not alter global health-related quality of life (G-HQoL; Ray-Coquard I et al. NEJM 2019). We analyzed HQoL by domains and molecular subgroups and explored the impact of disease progression (DP) on HQoL in the 1L setting. Methods: Eligible pts with newly diagnosed advanced (FIGO stage III–IV) HGOC were randomized 2:1 to maintenance olaparib + bev or pbo + bev. Pts completed European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 HQoL questionnaires at baseline and every 12 weeks for 2 years’ follow-up, irrespective of DP. The minimal important difference for clinically relevant change was fixed at 10 points. Longitudinal data were analyzed by mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD). Analyses were in the intent-to-treat population and HRD-positive subgroup. HQoL analyses at DP (± 60 days) were explored. Results: 806 pts were randomized to olaparib + bev (n=537) or pbo + bev (n=269). 465 pts had DP over 2 years’ follow-up. Compliance to HQoL questionnaires was high at baseline (95%) and over time (>70%). MMRM models by HQoL domain did not reveal a clinically relevant difference between treatment arms over time. TUDD of G-HQoL did not differ between arms (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.72–1.07). In the HRD-positive subgroup (n=372), we observed no difference by HQoL domain between treatment arms. Interestingly, TUDD of G-HQoL was statistically significantly in favor of olaparib + bev compared with pbo + bev (HR 0.70, 95% CI 0.52–0.93). We also observed a clinically significant deterioration in emotional (mean change −12.30 points, 95% CI −16.46 to −8.13) and social (−11.17 points, 95% CI −16.21 to −6.12) functioning in both treatment arms at DP, among 103 pts with HQoL questionnaires at DP. Conclusions: The substantial PFS benefit provided by maintenance olaparib + bev in the newly diagnosed setting was achieved without detrimental effect on HQoL domains, even with longer TUDD of G-HQoL in the HRD-positive subgroup. Use of an effective maintenance therapy (ie one with a significant PFS benefit) in HGOC patients in the 1L setting is likely to delay the clinically significant deterioration in emotional and social functioning we identified in patients at DP across PAOLA-1 treatments arms. Clinical trial information: NCT02477644.

5571 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, the addition of maintenance olaparib (ola) to bevacizumab (bev) in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for pts with HRD-positive tumors including a BRCA1/ BRCA2 mutation (BRCAm; Ray-Coquard et al. NEJM 2019). Preclinical data suggest that pts with mutations (mut) in the RING domain of BRCA1 are less sensitive to ola. The magnitude of benefit from ola + bev, according to the location of mut in the functional domains (FD) of BRCA , remains to be explored. Methods: Pts with newly diagnosed advanced HGOC in response after platinum-based chemotherapy + bev received maintenance bev (15 mg/kg q3w for 15 months [mo]) + either ola (300 mg bid for 24 mo) or placebo (pbo). In this post hoc exploratory analysis, PFS was analyzed in pts with BRCAm according to mut location in the FDs of BRCA1 (RING, DNA-binding domain [DNA-BD], or BRCA1 C terminus [BRCT]) and BRCA2 (RAD51-BD; DNA-BD). Results: Among the 806 randomized pts, 235 (29.2%) harbored a BRCAm: 160 (19.9%) with a BRCA1 mut and 76 (9.4%) with a BRCA2 mut. BRCA1 mut in FDs of RING, DNA-BD and BRCT were detected in 19 (11.8%), 41 (25.6%) and 34 (21.2%) pts, respectively. BRCA2 mut were detected in FDs of RAD51-BD and DNA-BD in 37 (48.7%) and 14 (18.4%) pts, respectively. With a median follow-up of 25.5 mo, 24-mo PFS rates and hazard ratios (HRs) according to mut locations are reported in the Table. In pts with a BRCA1 DNA-BD mut, 24-mo PFS was 89% and 14% (ola + bev vs pbo + bev; HR 0.08, 95% confidence interval [CI] 0.02–0.26) compared with 64% and 24% for pts with mut in RING + BRCT + other domains (HR 0.33, 95% CI 0.19–0.57). In pts with BRCA2 mut, 24-mo PFS for pts with mut in the DNA-BD was 91% vs 100% (ola + bev vs pbo + bev) compared with 82% and 44% for pts with mut in RAD51-BD + other domains (HR 0.21, 95% CI 0.08–0.54). Conclusions: In this exploratory analysis, pts with newly diagnosed advanced HGOC and a BRCAm had a PFS benefit from maintenance ola + bev regardless of mut locations in BRCA1/BRCA2. Sensitivity to ola + bev maintenance was particularly high for pts with mut in the DNA-BD of BRCA1. Pts with a mut in the DNA-BD of BRCA2 commonly had excellent outcomes. Clinical trial information: NCT02477644. [Table: see text]

Background Pegylated liposomal doxorubicin (PLD) is an established treatment for relapsed ovarian cancer. Preclinical and clinical evidences in other tumor types suggest that the proteasome inhibitor bortezomib can act synergistically with PLD. Methods Patients with relapsed ovarian cancer (N = 58), previously treated with platinum (100%) and taxane (95%), received bortezomib, 1.3 mg/m2 intravenous (days 1, 4, 8, and 11), and PLD, 30 mg/m2 intravenous (day 1), every 3 weeks. Tumor responses were assessed using Response Evaluation Criteria In Solid Tumors and Gynecologic Cancer Intergroup criteria. An optimal 2-stage design was implemented. Gene expression profiling in peripheral blood was characterized before and during treatment in 10 platinum-sensitive patients enrolled in stage 2 of the study. Results Median number of bortezomib-PLD cycles was 3.5. Of 38 patients in the platinum-sensitive group, 9 responses were observed (median duration, 4.8 months). The platinum-resistant group was closed at stage 1 owing to lack of response. Toxicity was moderate and mainly consisted of hematologic, gastrointestinal, and mucositis events. Of the total 58 patients, peripheral neuropathy was reported in 9 patients (none were grade 3). Transcription profiling identified the prevalence of genes associated with ribonucleoprotein complexes, RNA processing, and protein translation. The gene expression changes were more robust in patients who responded or had stable disease compared with patients who had progressive disease. Conclusions The combination of bortezomib and PLD was well tolerated, but the antitumor activity is insufficient to warrant further investigation in ovarian cancer.

Ovarian cancer accounts for 4% of all cancers in women and is the leading cause of death from gynaecologic malignancies. Because early-stage ovarian cancer is generally asymptomatic, approximately 75% of women present with advanced disease at diagnosis. Survival is highly dependent on stage of disease: 5-year survival in patients with early-stage is 80-90% compared to 25% for patients with advanced-stage disease. For all patients, a comprehensive surgical staging should be performed to obtain the histological confirmation of diagnosis and to evaluate the extent of disease. Patients with early-stage should both be optimally staged and be treated with adjuvant platinum-based chemotherapy if they have a medium or high-risk tumour. For advanced disease the currently recommended management is primary cytoreductive surgery followed by platinum-paclitaxel combination chemotherapy. Appropriate salvage therapy is based on the timing and nature of recurrence and the extent of prior chemotherapy. Surgical resection should be considered in patients with long-term remission, especially in those with isolated recurrences and good performance status. Platinum-based combination represents the standard second-line chemotherapy in patients with platinum-sensitive relapsed ovarian cancer. Salvage chemotherapy in platinum-refractory patients usually results in low response rates and short survival.

Purpose: To evaluate study feasibility, toxicity, drug concentrations, and activity of escalating doses of the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment. Methods: Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0, 400, 600, and 800 mg/d for 1 to 4 weeks before surgery. Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables (nuclear area, DNA index, and chromatin texture) were determined in ascitic cells. Drug levels were measured by high-performance liquid chromatography. Results: Doses up to 800 mg/d were well tolerated, and no adverse reactions occurred. There was no effect of 4-HPR on changes in serum CA125, Ki67 expression, which were assessed in 75% of subjects, and cytomorphometric variables, which were assessed in 80% of subjects. Plasma retinol levels were significantly lower in affected women than healthy donors. 4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 μmol/L concentration with 800 mg/d. Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower, respectively, than in carcinoma cells treated in vitro with 1 μmol/L 4-HPR. Conclusions: Cell biomarkers can be measured in ascitic cells to assess drug activity. Under our experimental conditions, 4-HPR did not show activity in advanced ovarian cancer cells. However, clinical evidence supports further investigation of fenretinide for ovarian cancer prevention. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1914–9)

Objective: To address the incidence of deep wound dehiscence and incisional hernia formation with two types of mass closure after vertical midline laparotomy performed in patients with gynecologic cancer. Methods: Continuous and interrupted mass closures were compared randomly in 632 patients. Both methods were performed with absorbable material. Of the 614 subjects who could be evaluated, 308 underwent a continuous, non-locking closure with looped polyglyconate suture, and 306 were closed with interrupted polyglycolic acid according to the Smead-Jones technique. Results: Three (1%) subjects with the continuous closure and five (1.6%) with the interrupted closure had an abdominal wound infection (P = .50). One patient whose incision was closed with continuous suturing had a deep wound dehiscence (without evisceration). The follow-up period was 6 months to 3 years. No patient had evidence of chronic sinus drainage. Thirty-two (10.4%) of the patients who had the continuous closure and 45 (14.7%) of those who were closed with the interrupted method had evidence of incisional hernia (P = .14). No hernia developed in any patient with a wound infection. Four (1.3%) hernias after the continuous closure and eight (2.6%) after the interrupted closure required surgical repair because of patient discomfort (P = .38). Conclusion: The interrupted closure was not superior to the continuous closure for short- and long-term wound security. The continuous method was preferable because it was more cost-efficient and faster. (C) 1997 by The American College of Obstetricians and Gynecologists

Purpose To describe the clinical management of ovarian stromal cell tumors, which are a heterogeneous group of neoplasms that develop from the sex cords and the ovarian stroma. Design We reviewed the current evidence on the clinical management of these relatively rare ovarian malignancies, which are typically detected at an early stage and may recur as late as 30 years following the initial treatment. The overall prognosis is favorable with a long-term survival ranging from 75% to 90% for all stages. Adult granulosa cell tumor (GCT) is the most common malignancy among these tumors. Results Surgery is the cornerstone of initial treatment. In women of childbearing age and with disease limited to one ovary, a fertility-sparing surgery can be a reasonable approach. Tumor stage represents the most important clinical parameter of prognostic relevance. The value of postoperative adjuvant therapy for high-risk patients has not been proven by prospective randomized studies. Platinum-based chemotherapy is used currently for patients with advanced stages or recurrent disease, with an overall response rate of 63% to 80%. Taxane and platinum combination chemotherapy seems to be a reasonable candidate for future trials. Little evidence exists for the use of radiation or hormonal therapy, and these modalities should be restricted to selected cases. Given the propensity of GCT for late relapse, prolonged follow-up is required. Conclusion Surgery remains the most effective treatment for ovarian stromal tumors and, whenever feasible, for relapsing disease. Platinum-based chemotherapy is currently used in metastatic or recurrent tumors.

The present retrospective study assessed the prognostic value of serum CA125 assay at relapse in 73 patients with recurrent epithelial ovarian cancer. At the time of relapse, serum CA125 levels ranged from 7 to 7000 U ml -1. The 25%, 50% and 75% quantiles of CA125 levels were 76, 178 and 339 U ml -1, respectively. Antigen values were >35 U ml -1 in 67 (91.8%) of the 73 patients. Median time to recurrence was 16 months (range, 4-62 months). Serum CA125 levels at relapse were not related to site of recurrence, time to recurrence, FIGO stage, histologic type, tumor grade and residual disease after initial surgery. Sixty patients received salvage chemotherapy at relapse. In these patients survival after recurrence was significantly related to time to recurrence (≤ 6 months vs 12 months, P=0.0014; ≤16 months vs >16 months, P=0.0001), but not to CA125 level at relapse (at any cut-off value for the antigen: 35, 76, 178 and 339 U ml -1), site of recurrence, FIGO stage, histologic type, tumor grade and residual disease after initial surgery. In conclusion, time to recurrence was the only variable predictive of further survival in patients undergoing salvage chemotherapy for recurrent ovarian cancer, whereas serum CA125 level at relapse had no prognostic relevance

Summary Objective To evaluate the antitumour activity of paclitaxel in patients with endometrial cancer pretreated with cisplatin, doxorubicin and cyclophosphamide (PAC). Materials and methods Eligible patients had complete initial surgery, expected survival ≥ 3 months, performance status ≤ 1, measurable or evaluable disease. Paclitaxel was given over three hours at the dose of 175 mg/m2, repeated every 3 weeks. Tumour response was first evaluated after 3 cycles. A maximum of 10 cycles was given in responders. Results 19 patients entered the study and a total of 105 cycles were administered. Complete and partial responses were achieved in 2 and 5 patients, respectively, for an overall response rate of 37% (95% CI: 16%–62%). The response rate in patients refractory to platinum was 22%. One patient is alive without evidence of disease 16 months after the start of treatment. The most common side effects were mild to moderate myalgia and peripheral neuropathy, which occurred in 31% and 47% of patients, respectively. In only 1 patient treatment had to be discontinued because of severe myalgia. Conclusion Paclitaxel is active in patients with endometrial cancer pretreated with PAC. Further studies with paclitaxel incorporated in the initial treatment for advanced disease are warranted.

Primary chemotherapy for ovarian cancer has evolved over the past 30 years from the use of single alkylating agent to several combination regimens. Treatment strategies, however, vary greatly both nationally and internationally, since no firm results can be derived from available data. Five questions can be identified: (1) Should primary chemotherapy consist of single agent or combination? (2) Should it include doxorubicin? (3) Is cisplatin or carboplatin preferred? (4) Which is the role of cisplatin dose intensity? (5) Should it include taxol? Available data from the European experience are discussed. Final considerations include: (1) Platinum combinations are more effective than single agent platinum when this drug is used at the same dose (now considered lower than current standard). (2) CAP offers a survival benefit of 7% at 6 years compared to CP. However, in most trials dose intensity was higher in CAP than in CP. (3) Cisplatin and carboplatin are equally effective. (4) There is no survival benefit when doubling the dose intensity of cisplatin over 25 mg/m2/week. (5) A confirmatory study will help define the contribution of Taxol in the first-line treatment of ovarian cancer, when administered at 175 mg/m2 over a 3-hr infusion in association with cisplatin.