bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final survival analysis of NSGO-AVANOVA2/ENGOT-OV24: Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer—A randomized controlled chemotherapy-free study.
Authors: Mirza Mansoor Raza , Nyvang Gitte-Betina , Lund Bente , Christensen Rene dePont , Werner Theresa Louise , Malander Susanne , Bjørge Line , Birrer Michael J. , Anttila Maarit , Lindahl Gabriel , Hietanen Sakari , Dimoula Maria , Peen Ulla , Madsen Kristine , Knudsen Anja , Staff Synnove , Buchner Vinum Nicole , Kjeldsen Maj Kamille , Avall-Lundqvist Elisabeth , Maenpaa Johanna Unelma 
Published: May 2020

6012 Background: We previously reported significantly improved progression-free survival (PFS) with the chemotherapy-free regimen of niraparib and bevacizumab compared to niraparib alone, in women with platinum-sensitive relapsed ovarian cancer (PSROC), regardless of homologous recombination deficiency (HRD) status (MyChoice HRD), duration of chemotherapy-free interval (CFI) and number of previous lines of therapy (Mirza MR et al, Lancet Oncol 2019). We now present the updated PFS, overall survival (OS) and other efficacy and safety endpoints. Methods: In this randomized, open-label, phase 2 study, women with measurable/evaluable, high-grade serous or endometrioid PSROC were randomized to niraparib 300mg once daily or the combination of niraparib 300mg once daily and bevacizumab 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was PFS. Stratification was according to HRD status and CFI (6-12months (mo) vs. > 12mo). First-line maintenance bevacizumab was permitted. Results: Of 97 enrolled patients, 48 were randomized to niraparib monotherapy and 49 to the chemotherapy-free combination. The combined treatment significantly improved PFS compared to niraparib alone: updated median PFS 12.5 mo vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.34; 95% confidence interval (CI) [0.21 to 0.55]; P < 0.0001. Preplanned exploratory subgroup analyses: patients with HRD-positive tumors (n = 54) HR 0.41 (CI, 0.23-0.76); HRD-negative disease (n = 43) HR, 0.40 (CI, 0.20-0.79); Time to First Subsequent Therapy (TFST) (n=97) HR, 0.4 (CI, 0.25-0.64); PFS2 (n=97) HR 0.55 (CI, 0.35-0.88); Time to Second Subsequent Therapy (TSST) (n=97) HR, 0.56 (CI, 0.35-0.90); OS (49 events only) HR, 0.77 (CI, 0.42-1.41). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (22.9% vs. 0%) and neutropenia (8.3% vs. 2.0%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Updated PFS consistently demonstrates that the niraparib-bevacizumab combination had clinically and statistically meaningful activity in PSROC. This phase 2 study was not powered to detect differences in OS or any other efficacy endpoints however TFST, PFS2 & TSST are significantly improved while there is a trend towards OS improvement with niraparib-bevacizumab combination. Clinical trial information: NCT02354131.
Concordance between CA-125 and RECIST progression (PD) in patients with germline BRCA-mutated platinum-sensitive, relapsed ovarian cancer treated with a PARP inhibitor (PARPi) as maintenance therapy after response to chemotherapy.
Authors: Tjokrowidjaja Angelina , Lee Chee Khoon , Friedlander Michael , Gebski Val , Gladieff Laurence , Ledermann Jonathan A. , Penson Richard T. , Oza Amit M. , Korach Jacob , Huzarski Tomasz , Manso Luis , Pisano Carmela , Asher Rebecca , Colombo Nicoletta , Park-Simon Tjoung-Won , Fujiwara Keiichi , Sonke Gabe S. , Vergote Ignace , Kim Jae-Weon , Pujade-Lauraine Eric 
Published: May 2020

6014 Background: There are no data to support CA-125 as a surrogate biomarker for ovarian cancer PD in patients on maintenance therapy with a PARPi. We aimed to assess the concordance of PD by CA-125 with RECIST PD in patients treated with maintenance PARPi. Methods: We extracted data on PD as defined by GCIG CA-125 and investigator-assessed RECIST from the SOLO2/ENGOT-Ov21 (NCT01874353) trial. Patients were categorized into: (i) CA-125 and RECIST non-PD concordant; (ii) CA-125 and RECIST PD concordant; and (iii) CA-125 and RECIST discordant. We excluded those with PD other than by RECIST, PD on date of randomization, and no repeat CA-125 beyond baseline. To assess the concordance of CA-125 PD with RECIST PD and CA-125 non-PD with RECIST non-PD, we computed the positive predictive value (PPV), i.e. the probability that patients with CA-125 PD also had RECIST PD, and negative predictive value (NPV), i.e. probability that patients with no CA-125 PD also did not have RECIST PD, respectively. Results: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included in the primary analysis. 80 (29%) had CA-125 PD and 77 had concordant RECIST PD, resulting in a PPV of 96% (95% CI 90%-99%). Of 195 patients without CA-125 PD, 101 also did not have RECIST PD, resulting in a NPV of 52% (95% CI 45%-59%; Table). Among those with RECIST PD (n = 171), a greater proportion of patients with RECIST-only PD had a normal baseline CA-125 than those with both CA-125 and RECIST PD (94% vs 69%; p< 0.001). Of 94 patients without CA-125 PD but had RECIST PD, 65 (69%) had CA-125 that remained within normal range, while 27 (29%) had rising and elevated CA-125 that did not meet the criteria for GCIG CA125-PD. Discordance between RECIST PD and CA-125 non-PD was similar in early (≤12 weeks) and late ( > 12 weeks) PD (56% vs 55%, respectively; p= 0.96). Conclusions: Almost half the patients with RECIST PD did not have CA-125 PD and most had CA-125 still within the normal range. Regular imaging should be considered as part of surveillance in patients on maintenance olaparib rather than relying on CA-125 alone. [Table: see text]
Association of chronotype and pain at baseline in ovarian cancer survivors participating in a lifestyle intervention (NRG/GOG 0225).
Authors: Crane Tracy E , Miller Austin , Skiba Meghan B , Donzella Sidney , Thomson Cynthia A. 
Published: May 2020

6018 Background: Chronotype is defined as an individual’s propensity to sleep at a specific time in a 24-hour cycle with late chronotype associated with poorer health outcomes including cancer. Chronotype remains relatively undefined in ovarian cancer. The Lifestyle Intervention for oVarian cancer Enhanced Survival (LIVES) study is testing whether 1205 women randomized to a diet and physical activity intervention for 24-months will have longer progression-free survival versus an attention control. Here we determine the association of late and early vs mid chronotypes and patient reported outcomes (PROs), lifestyle behaviors and biomarkers of metabolic health and inflammation in ovarian cancer survivors post-treatment (≤ 6.5 months). Methods: Chronotype was determined using self-reported time to bed (early < 9 pm; mid ≥ 9 pm - ≤12 am; late > 12 am) captured through the Pittsburg Sleep Quality Index and PROs were measured using subscales of the Rand-36 questionnaire. Validated questionnaires for diet and physical activity were used and biomarkers were collected at routine clinic visits. A total subsample of 438 ovarian cancer survivors enrolled in NRG/GOG 0225- LIVES study with all available baseline measures were included in analyses. Descriptive statistics, general linear mixed models, and Pearson correlations were performed. Results: Reported pain was significantly higher in late chronotypes (P < 0.05) when compared to early and mid-chronotypes. Total sleep duration was significant between the 3 chronotypes (P < 0.05) with late chronotype experiencing less sleep (6.77 ± 1.67 hrs) than mid chronotype (7.04 ± 1.31 hrs) and early chronotype (7.56 ± 1.33 hrs). Higher reported pain was significantly correlated to poorer CRP levels (r = -0.198, P < 0.001) suggesting higher systemic inflammation and poorer blood insulin levels (r = -0.116, P < 0.05) independent of chronotype classification. All other subscales of the RAND 36 and physical activity were not associated with chronotype. Diet quality trended towards significance with a positive association observed in early and an inverse association in late chronotypes (P = 0.06). Conclusions: Late chronotypes reported higher levels of pain which was associated with poorer sleep and diet quality and higher levels of inflammation and insulin. More robust data, including actigraphy, are being analyzed and will provide additional insight of the role of circadian rhythm and phenotype on pain and key biomarkers in ovarian cancer survivors. Clinical trial information: NCT00719303.
Effect of high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR) on outcome in ovarian small-cell carcinoma, hypercalcemic type (SCCOHT): Prospective series from the French Rare Gynecologic Malignant Tumors Network (TMRG).
Authors: Blanc Felix , Lefeuvre Claudia , Floquet Anne , Chaltiel Dan , Ray-Coquard Isabelle Laure , Meriaux Emeline , Berton Dominique , Bello Diana , Guillemet Cecile , Dupre Pierre-Francois , Faller Emilie , Alexandre Jérôme , Hardy-Bessard Anne-Claire , Collard Olivier , Fabbro Michel , Provansal Magali , Kalbacher Elsa , Genestie Catherine , Pautier Patricia 
Published: May 2020

6023 Background: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and rapidly lethal disease affecting young women with over half dying within 2 years of diagnosis. We previously reported improved outcomes with cytoreductive surgery followed by HDC-aSCR in a prospective study, but these encouraging results needed to be confirmed in an independent and larger cohort. Methods: Between 2008 and 2019, out of 44 patients (pts) diagnosed with centrally confirmed SCCOHT in 16 referent centers of the TMRG network, 38 were treated prospectively according to the French recommendations of the network with complete surgery (primary or after neoadjuvant chemotherapy), 4 to 6 cycles of PAVEP chemotherapy (cisplatin, doxorubicin, vepeside, and cyclophosphamide), and for pts with complete response (CR), HDC-aSCR, followed by pelvic radiotherapy. The 6 patients who could not receive PAVEP (unfit or diagnostic delay) relapsed and died rapidly. The primary endpoint was the event-free survival (EFS) in the intention-to-treat cohort. Results: Median age at diagnosis was 33 years (14-76). 13 pts presented with FIGO stage I, 17 stage III and 6 stage IV, 2 unknown. Median follow-up was 55.5 months. 34 patients achieved CR with CT + surgery and 30 received HDC-aSCR (40%, 47% and 10% with stages I, III and IV diseases respectively) and 21 received also pelvic radiotherapy. Median overall and event-free survival was 36.4 and 15.9 months respectively, and 2-years event-free survival rate was 40% (CI95% 25-56). Median OS was respectively not reached, 18 and 9.6 months for FIGO I, III and IV patients. Among the pts (N = 14) who did not receive HDC-aSCR (rapid progression during or after PAVEP), the 2-yr EFS was 0% compared to 50.5% for the 30 patients receiving HDC. In multivariate analysis, HDC was significantly correlated with better outcomes (p < 0.001). For the 21 patients receiving also pelvic radiotherapy, 57% (12/21) are free of recurrence at 4 years. Grades 3/4 adverse events were frequent (78%) but, in most cases, manageable, although one toxic death (3%) occurred during HDC (fungal septic shock). Conclusions: Treatment of SCCOHT, with intensive multimodal therapy, is associated with a 40% 2-yr event-free survival. However, this protocol is associated with significant toxicity and should be restricted to good performance status patient and expert centers.
Adjuvant chemotherapy after concurrent chemoradiation therapy for locally advanced cervical cancer.
Authors: Kou Lingna , Zhang Tao , Peng Siyun , Wang Yifei , Yuan Mingyang , Li Minmin 
Published: May 2020

6031 Background: Standard treatment nowadays for locally advanced cervical cancer (LACC) is concurrent chemoradiation therapy (CCRT). However, due to distant metastasis, survival outcomes are still not optimistic. We tried to evaluate the clinical efficacy and safety of adjuvant chemotherapy for patients with LACC after treated with concurrent chemoradiation therapy (CCRT). Methods: Patients diagnosed between May, 2013 to May, 2018 with stage IIA-IIIB LACC were retrospectively analyzed. All the patients received platinum-based radical concurrent chemoradiotherapy and were divided into two groups: adjuvant chemotherapy after CCRT (CCRT+ACT group) and observation after CCRT (CCRT group). Overall survival (OS), progression free survival (PFS) and adverse effects were recorded and analyzed. Kaplan–Meier method and log-rank test were used to calculate and compare differences between survival outcomes. Toxicities were analyzed using chi-square test. Results: In total, 375 patients were included in this study, and 262 patients accepted ACT after CCRT while the remaining 113 patients chose to observe. With a median follow-up of 40 months (range 5-73 months), no significant differences were found in both overall survival (OS) and progression free survival (PFS) between two groups referring as 88.5% vs. 90.3% ( P= 0.904) and 83.2% vs. 87.6% ( P= 0.374). OS rates for patients in CCRT+ACT and CCRT groups at 1 year and 3 years were 97.3% vs. 94.7% ( P= 0.195) and 90.2% vs. 88.4% ( P= 0.694), respectively. Meanwhile, PFS rates at 1 year and 3 years were 92% vs. 94.7% ( P= 0.371) and 87.5% vs. 85.5% ( P= 0.761) for two arms separately. 3-4 grades acute adverse events happened more frequently in CCRT+ACT group than in CCRT group, with significant differences in neutropenia and anemia ( P <0.05). Conclusions: In this study, adjuvant chemotherapy after concomitant chemoradiotherapy did not show benefit of survival but do induce adverse effects. We do not suggest it unless further large scale randomized controlled trials are executed to verify it.
Photodynamic therapy for preinvasive cervical cancer.
Authors: Ivanova Viktoria A. , Verenikina Ekaterina V. , Nikitina Vera P. , Zhenilo Oksana E. , Kruze Polina A. , Nikitin Ivan S. , Kit Oleg I. 
Published: May 2020

6035 Background: Photodynamic therapy (PDT) is an effective treatment for various cancers ensuring maximum preservation of the viability of healthy tissues surrounding the tumor. The purpose of the study was to reveal the effectiveness of PDT in treatment for preinvasive cervical cancer. Methods: The study included 45 patients aged 22-53 years with preinvasive cervical cancer. The patients were divided into two groups depending on the type of the transformation area and the tumor site: group 1–on the exocervix (type I-II), n=24; group 2–on the endocervix (type III), n=21. Infection with high-risk genotypes of HPV (16, 18, 31, 33, 35, 45, 56) was detected with PCR in 37 (82%) women. All patients received PDT with the semiconductor Latus laser up to 3 W, a single-use diffusing fiber for the exocervix irradiation and a single-use cylindrical diffusing fiber for tumors in the cervical canal. Photoditazine and photolon were used as photosensitizers. Effectiveness criteria included the normalization of the colposcopic picture, the absence of atypical cells, and the pathogen elimination confirmed by PCR. Results: A normal cytogram profile was observed after PDT in 84% of group 1 and in 88% of group 2. PCR 3 months after PDT showed a positive HPV reaction in 9.1%. Neither group of patients had negative changes in cytogram after 6 and 12 months. Repeated HPV DNA tests detected HPV DNAs in 2.8% in group 1 and 3.2% in group 2. The effectiveness of PDT did not depend on the photosensitizer. The maximum follow-up period has lasted for 4.5 years, with no recurrences registered. During this period, three young women successfully gave birth to healthy children. Conclusions: PDT is an alternative treatment for pre-tumor and initial tumor pathology of the cervix with preservation of the anatomical and functional integrity of the organ, which is important for the female reproductive function. The results support the use of PDT in treatment for preinvasive cervical cancer.
Delayed adjuvant radiotherapy in early-stage cervical cancer with intermediate-risk features has a detrimental effect on survival that cannot be corrected by adjuvant chemotherapy.
Authors: Kodiyan Joyson , Guirguis Adel , Ashmalla Hani 
Published: May 2020

6037 Background: GOG-0263 is currently investigating the role of adjuvant chemotherapy (CT) concurrently with radiotherapy (RT) in patients with early stage cervical cancer that underwent radical hysterectomy and pelvic lymphadenectomy harboring intermediate risk features. We used a retrospective database to investigate whether adjuvant chemotherapy significantly influenced overall survival (OS), and whether its effectiveness is influenced by delays in radiotherapy. Methods: All data was obtained from the NCDB (National Cancer Database) and initially contained 115,747 cases of cervical cancer diagnosed between 2004 and 2015. Analyzed patients had early stage disease, received radical hysterectomy with pathologic stage I to IIA, and had intermediate risk features including size greater than 4 cm or lymphovascular invasion. All patients received adjuvant RT with or without CT. Cases with positive margin or nodes, with parametrial extension, or metastasis were excluded. Cases were weighted by inverse probability of treatment (CT) using clinical and socioeconomic variables, and analyzed for OS using multivariate models. Predictors of receiving CT were determined using multivariate logistic regression. Results: The final cohort was 557 patients with median follow-up of 43 months (range, 1.54-143.7). Median survival without CT (n = 244) versus with CT (n = 313) was 42.2 versus 43.9 months (HR 0.81, 95%CI 0.661-0.995, p = 0.045). Median time from diagnosis to RT was 91 days (range, 21-691), and predicted for inferior OS (p = 0.007). No significant interaction existed between RT delay and receipt of CT (p = 0.997). Cases with squamous histology were less likely to receive CT than adenocarcinoma histology (OR 0.345, 95%CI 0.159-0.725, p = 0.006). Conclusions: Poor survival outcomes are observed in patients with early stage cervical cancer harboring intermediate risk features when adjuvant radiotherapy is delayed. This outcome was not corrected by addition of chemotherapy.
A phase I trial a FR alpha targeted thymidylate synthase inhibitor CT900 exploring four schedules of treatment in expansion cohorts of patients with high-grade serous ovarian cancer.
Authors: Banerjee Susana N. , Ingles Russo Alvaro , Biondo Andrea , Funingana Ionut-Gabriel , Little Martin , Prout Toby , Parmar Mona , Gurel Bora , Riisnaes Ruth , Jenkins Ben , Hall Emma , Ainscow Ed , McIntosh Stuart , Tunariu Nina , Minchom Anna Rachel , Lopez Juanita Suzanne , De Bono Johann S. , Cook Natalie , Basu Bristi , Banerji Udai 
Published: May 2020

6043 Background: CT900 (BTG945/ONX-0801) is a novel small molecule that binds to folate receptor alpha (FRα), is internalized and causes cytotoxicity by thymidylate synthase inhibition. Methods: The aims of the expansion cohorts were to determine toxicity, response rates and correlation of the response to FRα expression in patients with HGSOC (NCT02360345). Four expansion cohorts were studied which included: schedule A (6 mg/m2/q every 2 weeks), schedule B (12 mg/m2/q every 2 weeks), schedule C (12 mg/m2/q every 2 weeks with 12 mg dexamethasone IV and 8 mg of dexamethasone for 2 days) and schedule D (12 mg/m2/q every 3 weeks). Response rates were assessed by RECIST V1.1 and GCIG CA125 response criteria. Patients who were withdrawn for reasons other than toxicity within 8 weeks (cohorts A, B, C) and 12 weeks (cohort D) were not assessable for efficacy. FRα expression was quantified using immunohistochemistry. Results: A total of 67 patients were treated in the 4 cohorts (14, 25, 15 and 13 for cohorts A, B, C and D). The median age was 62 (IQR 57 - 68) and the median lines of previous treatment was 5 (range 1 to 13). A majority of patients were platinum resistant. The most common toxicities across all expansion cohorts were: fatigue (51%), nausea (36%), anemia (27%), fever (25%), AST elevation (21%), most of which were grade 1 - 2. Toxicity of special interest included radiological changes of pneumonitis and was 15% in all cohorts (7%, 16%, 27% and 8% in cohorts A, B, C and D, respectively). These changes were grade 1 - 2 in all but one case. RECIST response rates in evaluable patients across the different cohorts were: A 1/8 (13%), B 6/21 (29%), C 5/12 (42%) and D 2/12 (17%). FRα expression in archival tumor tissue was measured in 59/67 patients. Expression was found to be high/medium in 43/59 (73%), low in 7/59 (12%) and negative/very low in 9/59 (15%). In patients with high/medium FRα expression, the RECIST response rates in different cohorts were: A 0/9 (0%), B 6/16 (38%), C 4/12 (33%) and D 1/6 (17%). The CA125 response rate in all patients within cohort B was 13/25 (52%) and 10/16 (63%) in patients with high/medium FRα expression. Conclusions: CT900 has shown clinical activity in patients with heavily pre-treated platinum-resistant, high/medium FRα expressing HGSOC. Based on toxicity and efficacy, the schedule of 12 mg/m2/q2 weekly (schedule B) is the recommended phase II dose for further evaluation in patients with relapsed high/medium FRα expressing HGSOC. Clinical trial information: NCT02360345.
Phase I/II trial assessing hydroxychloroquine and itraconazole in women with advanced platinum-resistant epithelial ovarian cancer (EOC) (HYDRA-01).
Authors: Madariaga Ainhoa , Marastoni Stefano , Colombo Ilaria , Mandilaras Victoria , Cabanero Michael , Bruce Jeffrey , Garg Swati , Wang Lisa , Gill Sarbjot , Dhani Neesha C. , Bowering Valerie , Li Xuan , Oza Amit M. , Joshua Anthony M. , Lheureux Stephanie 
Published: May 2020

6049 Background: Autophagy is a mechanism of resistance to platinum chemotherapy. Itraconazole (Itr), an antifungal agent, can alter cholesterol-trafficking, leading to accumulation of cholesterol in endosomes/lysosomes and resulting in cancer cell death. Itr is also involved in regulation of angiogenesis, mTOR and Hedgehog pathways. In preclinical studies the Itr effect can be enhanced by combining it with the autophagy inhibitor hydroxychloroquine (H). Drug repurposing studies with Itr have shown a signal of activity in prostate, lung and basal cell carcinoma. Methods: A rolling-6 phase I design was used to enroll patients (pts) with platinum-resistant/refractory EOC. Pts received Itr 300mg twice daily (BID) with H as per dose escalation schedule (range 200mg BID- 600mg BID), continuously in a 28-day cycle. Primary objective was establishment of MTD; secondary objective was objective response rate, progression free survival (PFS). Pre- and on-treatment biopsies were mandatory to evaluate exploratory objectives assessing effect on apoptosis/proliferation, angiogenesis, cholesterol metabolism and mechanism of cytotoxicity. RNAseq and IHC was performed in the sequential biopsies. Results: 11 pts were enrolled, 9 evaluable for efficacy. Histology was high 91% and low-grade serous 9%. Median lines of prior therapy was 7. RP2D was Itr 300mg BID and H 600mg BID. 1 DLT was seen in dose-level 2 was grade 3 hypertension. Other grade ≥3 related toxicity were grade 3 hypokalemia and grade 4 QTc prolongation (1 pt, dose-level 3). No objective responses were observed and 1 pt had stable disease. Median PFS was 1.6 months (1-1.7). Pre- and on-treatment biopsy was available for 10 pts. Increase in autophagy related protein, LC3, P62 and lysosomal marker, LAMP1, expression by IHC was identified in 3 pts. RNAseq revealed no differences between pre and on treatment samples in cholesterol homeostasis, angiogenesis, lysosomal-autophagy, PI3K-mTOR pathways. Conclusions: The combination of Itr and H was feasible but did not show antitumour activity in this heavily pre-treated platinum resistant EOC population. Increase of IHC expression in autophagy related proteins was detected in 30% of pts but did not correlate with patient benefit. Clinical trial information: NCT03081702. [Table: see text]