bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opsalin: A phase II placebo (Pbo)-controlled randomized study of ombrabulin in patients with platinum-sensitive recurrent ovarian cancer (OC) treated with carboplatin (Cb) and paclitaxel (P).
Authors: Birrer Michael J. , Bondarenko Igor , Tjulandin Sergei , Vergote Ignace , Cibula David , Ray-Coquard Isabelle , Colombo Nicoletta , Allard Aurore , Oprea Corina , Rey Augustin A. , Sessa Cristiana , Pujade-Lauraine Eric 
Published: March 2020

5516 Background: Patients with platinum-sensitive recurrent OC are often retreated with CbP due to limited treatment options. Ombrabulin (AVE8062), a combretastatin A4 analog, is a vascular disrupting agent that damages established tumor vasculature causing tumor necrosis and has synergistic antitumor activity with platinum agents in vivo (Cancer Sci. 2003;94:200). OPSALIN evaluated whether adding ombrabulin to CbP improves outcomes in patients with platinum-sensitive recurrent OC (NCT01332656; EFC10260). Methods: Patients (aged ≥18 yrs, ECOG PS ≤2) with platinum-sensitive measurable ovarian, fallopian tube, or primary peritoneum carcinoma after completion of one line of platinum-based chemotherapy received ombrabulin 35 mg/m² or Pbo plus CbP (AUC 5–6, 175 mg/m²) every 3 weeks. Randomization (1:1) was stratified by time of first disease recurrence (6–12 or >12 months). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate (RR), and safety. An interim analysis after ~54 PFS events (60% of the target 90 PFS events) was planned. Results: From May 2011 to August 2012, 154 patients were randomized (n=77 in each group). Groups were balanced in terms of baseline characteristics. Overall, the median age was 56 yrs (range 34–79), 93% had ovarian primary tumors, and 54% had first disease recurrence >12 months. Planned interim analysis was performed after 53 PFS events (27 ombrabulin; 26 Pbo); median follow-up was 6.8 months. Ombrabulin did not improve PFS vs Pbo in any subgroup (global median 8.4 vs 10.4 months, respectively; HR 1.33; 60%CI 1.06–1.69). Overall, RR was 65% for ombrabulin and 71% for Pbo. Safety profiles were comparable; rates of grade 3–4 adverse events were 51% for ombrabulin and 41% for Pbo, with no particular safety signals. Conclusions: This interim analysis has suggested no safety concerns or efficacy advantage of adding ombrabulin to CbP in patients with platinum-sensitive recurrent OC. The study was discontinued due to limited probability of the ombrabulin arm showing PFS superiority at the final analysis. Study sponsored by Sanofi. Clinical trial information: NCT01332656.
A preoperative window study of metformin for the treatment of endometrial cancer.
Authors: Schuler Kevin M. , Rambally Brooke S. , DiFurio Megan J. , Gehrig Paola A. , Bae-Jump Victoria Lin 
Published: March 2020

5519 Background: Obesity and diabetes have been linked to poorer survival and increased recurrence rates in endometrial cancer. The anti-diabetic medication, metformin, has been shown to have anti-tumorigenic effects in vitro and in vivo, via AMPK activation and inhibition of the mTOR pathway. We conducted a pre-operative window clinical trial of metformin in obese endometrial cancer patients to evaluate short-term in vivo molecular changes. Methods: Women with endometrioid endometrial cancer who were obese (BMI>30) were recruited from a gynecologic oncology clinic. Once enrolled, patients had a repeat pre-treatment endometrial biopsy and then began metformin at a dose of 850 mg PO once daily for 1-4 weeks prior to hysterectomy/surgical staging. A tissue microarray, using triplicate cores from each specimen, was constructed from paired formalin-fixed, paraffin-embedded endometrial biopsy (pre-treatment) and hysterectomy (post-treatment) specimens. The expression of Ki-67, a marker of cell proliferation, was measured by immunohistochemistry. Individual slides were digitized using the Aperio ScanScope (Aperio Technologies, Vista, CA), and digital images were analyzed using Aperio ImageScope software. The Signed Rank Test was used for statistical analysis. Results: Sixteen patients have completed the protocol. The mean duration of treatment was 14.5 days. Percent Ki-67 staining decreased significantly with metformin treatment (mean of 19.5% decrease, p = 0.026). Two patients experienced grade 1 toxicities, including mild abdominal pain and loose stools. Ten of the 16 patients responded to metformin based on decreased proliferation from their pre- to post-treatment specimens. There were no differences in median age, BMI, HgbA1c, or number of doses taken between responders and non-responders to treatment. Pre-treatment Ki-67 levels were statistically higher in the women that responded to metformin treatment (52% versus 27.5%, p = 0.0067). Conclusions: Metformin significantly reduced proliferation in a pre-operative window study in obese endometrial cancer patients, providing further support for therapeutic clinical trials of metformin in this obesity-driven disease.
Chemoresistance in gastric-type mucinous adenocarcinoma of the uterine cervix: Multi-institutional study by Sankai Gynecology Study Group (SGSG).
Authors: Kojima Atsumi , Shimada Muneaki , Nagao Shoji , Takeshima Nobuhiro , Shoji Tadahiro , Sudo Tamotsu , Hirata Eiji , Takehara Kazuhiro , Kanamori Yasunobu , Hayase Ryouji , Teramoto Norihiro , Kiyokawa Takako , Mikami Yoshiki , Kigawa Junzo , Nishimura Ryuichiro ,   Sankai Gynecology Study Group (SGSG)
Published: March 2020

5526 Background: Gastric-type adenocarcinoma (GAS) is a novel variant of mucinous adenocarcinoma of the uterine cervix, characterized by aggressive clinical behavior and absence of high risk HPV detection. However, the cause of its aggressive nature remains unknown. Methods: We have evaluated the chemosensitivity of GASs, which were diagnosed by central pathological review of cases enrolled in the phase II study of neoadjuvant chemotherapy with docetaxel and carboplatin for stage Ib2 to IIb non-squamous cervical cancer (SGSG-005) as an advance study. Results: In a total of 47 cases enrolled in the study, 20 (42.6%), 13 (27.7%), and 12 (25.5%) tumors were diagnosed as usual-type endocervical adenocarcinoma (UEA), GAS, and adenosquamous carcinoma, and each one (2%) as small cell carcinoma and serous adenocarcinoma, respectively. Response rate of UEA and GAS to the protocol was 85.0% and 46.2%, respectively (p = 0.018). Among 47 patients, 33 (70.2%) were assigned FIGO stage II, and 31 of these patients underwent surgery, while remaining 2 were inoperable because of progressive disease or intraabdominal dissemination. By microscopic examination of radical hysterectomy specimens, 12 of 14 (80%) UEAs were down-staged, whereas none of 6 (0%) GASs showed any response with residual vaginal and/or parametrial invasion even after chemotherapy (P<0.001). Two inoperative tumors were GAS. Median follow-up duration was 41 months with a range of 10-65 months. The 3-years progression-free survival rate in cases of UEA and GAS were 73.7% and 35.9%, respectively (p = 0.023), and 3-years overall survival rate were 88.9% and 51.9%, respectively (p <0.001). Conclusions: Our data suggests that GAS is distinguished from UEA by chemoresistance, which appears to be an intrinsic nature of this particular tumor. Alternative treatment strategy should be established for GAS. Clinical trial information: 000000560.
Pathologic complete response to cisplatin with dose-dense paclitaxel as neoadjuvant chemotherapy for locally advanced cervical cancer: Preliminary results of a multicenter phase II study with additional mutation analysis of adeno/adenosquamous carcinoma.
Authors: Tanioka Maki , Yamaguchi Satoshi , Sato Shinya , Nagao Shoji , Takehara Kazuhiro , Nishimura Masato , Sudo Tamotsu , Morita Satoshi , Minami Hironobu , Negoro Shunichi , Shimada Muneaki , Kigawa Junzo , Fujiwara Kiyoshi ,   Sankai Gynecologic Study Group
Published: March 2020

5528 Background: We report efficacy and safety of neoadjuvant cisplatin plus dose-dense paclitaxel (ddTP) within a phase II trial (UMIN-CTR ID: UMIN000006440), designed to investigate recurrence-free survival of neoadjuvant ddTP plus radical hysterectomy followed by adjuvant ddTP without radiotherapy for patients (pts) with stage IB2, IIA2, and IIB cervical cancer, whose driver mutations have been poorly understood. Methods: All enrolled pts received 3 cycles of cisplatin 75 mg/mq on day1 with paclitaxel 80 mg/mq on days 1, 8, and 15 every 21 days. Pathologic complete response (pCR) was defined as no evidence of malignancy in all surgical specimens observed. Using a selected panel of 535 oncogenes (Otogenetics, Norcross, GA), mutations of pretreatment biopsy tissues were analyzed in 6 non-pCR pts with adeno/adenosquamous carcinoma (AC/ASC). Results: Among 51 enrolled pts, 50 were evaluable (40 with squamous cell carcinoma [SCC], 9 with AC/ASC, and 1 with small cell carcinoma). Median age was 52 years (range 30-70), the FIGO stage was IB2 in 14 pts, IIA2 in 3, and IIB in 34. Eighteen pts achieved complete response and 29 pts achieved partial response, with response rate of 94% (47/50). A total of 14 pts (28%; 13 with SCC, 1 with AC) achieved pCR. Grade 3/4 adverse events were neutropenia (34%), nausea (12%), appetite loss (10%), fatigue (6%), and anemia (6%). Febrile neutropenia was uncommon (2%). The analysis of oncogenes revealed that all 6 pts had mutations in the mixed-lineage leukemia (MLL3) gene, a histone methyltransferase, whose mutations have recently been reported in breast, pancreas, and colorectal cancers. Specifically, in MLL3 gene, identical frameshift mutation was found in 2 pts and 2 common non-synonymous point mutations were found in 4 pts, despite no relevance to the ddTP response. No mutations were detected in TP53 and PIK3CA genes. Conclusions: The pCR rate with neoadjuvant ddTP for locally advanced cervical cancer was one of the highest reported in a prospective trial setting. Novel mutations of the MLL3 gene were identified in non-pCR pts with AC/ASC. Clinical trial information: UMIN000006440.
Patient-reported physical, emotional, and social functioning in advanced breast cancer: Insights from BOLERO-2.
Authors: Yardley Denise Aysel , Hortobagyi Gabriel N. , Lebrun Fabienne , Beck J. Thaddeus , Neven Patrick , Baselga José , Petrakova Katarina , Dakhil Shaker R. , Sabatini Silvia , Komorowski Anna , Chouinard Edmond Emilien , Young Robyn R. , Gnant Michael , Pritchard Kathleen I. , Zhang Jie , Ziemiecki Ryan , Panneerselvam Ashok , Taran Tanya , Sahmoud Tarek , Noguchi Shinzaburo 
Published: March 2020

553 Background: The phase 3 BOLERO-2 study at 18 months’ median follow-up showed that everolimus (EVE) + exemestane (EXE) significantly improved progression-free survival (PFS) vs EXE alone in 724 hormone-receptor–positive (HR+) advanced breast cancer (ABC) patients with recurrence/progression during/after nonsteroidal aromatase inhibitor (NSAI) therapy. A higher rate of grade 3/4 adverse events was noted with EVE + EXE, but was not associated with deterioration in quality of life (QOL) based on the EORTC QLQ-C30 Global Health Status scale. Additional patient-reported post hoc analyses of QOL are reported herein. Methods: During BOLERO-2, QOL (EORTC QLQ-C30 and QLQ-BR23) was assessed at baseline and q 6 wk thereafter until progression or discontinuation. Physical, emotional, and social functioning subscales of QLQ-C30 were analyzed. Time to definitive deterioration (TTD) was defined based on either a 5% (protocol specified) or 10-point (more stringent) decrease from baseline for each subscale and analyzed by Kaplan-Meier methods. The difference between treatments was assessed by a log-rank test stratified by randomization factors. Results: QLQ-C30 compliance was > 80% at week 48. Among the 3 protocol-specified QLQ-C30 subscales, analyses based on a 5% decrease in QOL showed a longer TTD for both physical and emotional functioning in the EVE + EXE group vs EXE alone (log-rank P = .0120 and P = .0277, respectively). The TTD for social functioning was similar in both treatment arms (log-rank P = .3374). Analyses based on a 10-point decrease indicated a longer TTD for physical functioning in the EVE + EXE group (15.2 mo) vs EXE alone (9.7 mo; log-rank P = .0211). The TTDs for emotional and social functioning were similar between EVE + EXE and EXE alone: 13.9 vs 13.8, respectively (log-rank P = .4023), and 11.5 vs 9.5, respectively (log-rank P = .2507). Conclusions: The treatment goal for ABC is to maximize clinical benefit with minimal negative effects on QOL. These additional BOLERO-2 QOL analyses confirmed that the more than doubling of PFS with EVE + EXE was accompanied by maintained physical, emotional, and social functioning compared with EXE alone in patients with HR+ ABC progressing after NSAI. Clinical trial information: NCT00863655.
Health-related quality of life (HRQoL) results from the AURELIA trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum-resistant recurrent ovarian cancer (OC).
Authors: Stockler Martin R. , Hilpert Felix , Friedlander Michael , King Madeleine , Wenzel Lari B. , Lee Chee , Joly Florence , De Gregorio Nikolaus , Arranz Arija Jose Angel , Mirza Mansoor Raza , Sorio Roberto , Freudensprung Ulrich , Sneller Vesna , Hales Gill , Pujade Lauraine Eric ,   AURELIA Investigators
Published: March 2020

5542 Background: Adding BEV to CT significantly improved PFS in platinum-resistant OC in the open-label phase III AURELIA trial. As symptom improvement is a major goal of treatment, determining effects on HRQoL was a key secondary aim of AURELIA. Methods: After investigator selection of single-agent CT (pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel), patients (pts) with measurable/assessable platinum-resistant OC were randomized to CT ± BEV. HRQoL and symptoms were assessed at baseline and every 2 or 3 cycles (8/9 wks) until PD using the EORTC OC Module (OV28) and FOSI. The primary HRQoL endpoint was an absolute improvement of ≥15% (≥15 points) on the 100-point OV28 subscale for abdominal (abdo)/GI symptoms (items 1–6) at wk 8/9. Pts with missing questionnaires (Qs) were included and considered not to have improved. A sensitivity analysis excluded pts with Qs missing for reasons other than PD/death or switch from CT to BEV. Subgroup analyses of symptomatic pts included only those with a baseline score ≥15 (sufficient to show ≥15-point improvement). Mixed-model repeated measures (MMRM) analysis was used to compare Qs from all time points until PD/death, not just wk 8/9. The FOSI was analyzed similarly. Results: Baseline Qs were available from 89% of 361 randomized pts. At wk 8/9, 81% of BEV–CT vs 68% of CT pts who were alive and PD-free returned OV28 Qs. For the primary HRQoL endpoint, more BEV–CT than CT pts had a ≥15% improvement in the OV28 abdo/GI symptom subscale at wk 8/9 (21.9% vs 9.3%, 12.7% difference [95% CI 4.4–20.9]; p = 0.002). The sensitivity analysis described above showed a 13.3% difference [95% CI 4.5–22.1]. In the subgroup of 233 pts with a baseline score ≥15, there was a 16.9% difference (95% CI 6.1–27.6) favoring BEV–CT (29.6% vs 12.7%). MMRM analysis of OV28 abdo/GI symptom subscale scores also favored BEV–CT (6.4-point difference [95% CI 1.28–11.6]). More BEV–CT than CT pts had a ≥15% improvement in FOSI score at wk 8/9 (12.2% vs 3.1%, 9.0% difference [95% CI 2.9–15.2]). Conclusions: Adding BEV to CT resulted in more frequent ≥15% improvements in patient-reported abdo/GI symptoms in platinum-resistant OC. Clinical trial information: NCT00976911.
Efficacy and safety of front-line bevacizumab (BEV), weekly paclitaxel (wPAC), and q3w carboplatin (C) in elderly patients (pts) with ovarian cancer (OC): Subgroup analysis of OCTAVIA.
Authors: Gonzalez-Martin Antonio , Gladieff Laurence , Tholander Bengt , Stroyakovsky Daniel , Gore Martin Eric , Oosterkamp Hendrika M , Lisyanskaya Alla , Redondo Andrés , Teissier Eric , Rosenberg Per , Perez Ronco Julian , Freudensprung Ulrich , Pignata Sandro ,   OCTAVIA Investigators
Published: March 2020

5544 Background: Front-line BEV significantly improved PFS when combined with q3w paclitaxel and C in two randomized phase III OC trials. The single-arm OCTAVIA study combined two successful strategies, anti-angiogenic therapy and wPAC administration, demonstrating median PFS of 24 months at the primary analysis [IGCS 2012]. We report exploratory analyses of safety and efficacy in the subgroup of pts aged ≥65 y treated in OCTAVIA. Methods: Pts received 6–8 cycles of BEV (7.5 mg/kg, d1) + wPAC (80 mg/m2 d1, 8, 15) + C (AUC 6, d1) iv q3w, with BEV q3w continued alone for a total of up to 17 cycles (1 y) as front-line therapy for newly diagnosed OC (FIGO stage I–IIa [grade 3/clear cell] or stage IIb–IV [any grade]). The primary endpoint was PFS. Results: Of the189 treated pts, 37 (20%) were aged ≥65 y (11% 65–<70 y; 6% 70–<75 y; 3% ≥75 y). Compared with pts aged <65 y, the subgroup of pts aged ≥65 y included fewer pts with no residual disease after surgery (24% vs 34%) and more pts with grade 3 OC (62% vs 55%) or comorbidities at baseline (hypertension: 38% vs 17%; dyslipidemia: 14% vs 5%). Pts aged ≥65 y received a median of 6 chemotherapy cycles (range 1–8) and 17 BEV cycles (range 0–18). C or wPAC was given for ≥6 cycles to 86% and 68% of pts, respectively. AEs led to early discontinuation of C, wPAC, or BEV in 14%, 38%, and 14% of pts, respectively. After median follow-up of 26.5 months and events in 62%, median PFS was 20.5 mo (95% CI 17.8–29.1 mo) in the elderly subgroup. Seven pts (19%) had died, all from disease progression; the 1-y OS rate was 97.3%. The most common grade ≥3 AEs were hematologic (neutropenia 62%, thrombocytopenia 14%), with no major differences according to age. Overall, there was a numerically higher incidence of grade 3/4 AEs in pts aged ≥65 vs <65 y (86% vs 76%, respectively), driven by non-hematologic AEs. The incidences of grade ≥3 AEs of special interest were similar in older and younger pts, except for hypertension (11% in pts ≥65 y vs 3% in pts <65 y) and bleeding (3% vs 0%, respectively). Conclusions: BEV combined with wPAC and C is a feasible, well-tolerated, active front-line regimen, even in the small subgroup of pts aged ≥65 y, many of whom had comorbidities. Clinical trial information: NCT00937560.
Protein network mapping of platinum-resistant and poor-survival ovarian cancer.
Authors: Sereni Maria Isabella , Baldelli Elisa , Gambara Guido , Zanotti Laura , Bandiera Elisabetta , Bignotti Eliana , Meani Francesco , Ravaggi Antonella , Angioli Roberto , Liotta Lance A. , Pecorelli Sergio L. , Petricoin Emanuel , Pierobon Mariaelena 
Published: March 2020

5560 Background: Epithelial ovarian carcinoma (EOC) is the fifth leading cause of tumor related death in the female population, with only 30% of patients alive at 5 years after diagnosis. Platinum resistance is a major cause of treatment failure. The aim of the study was to perform broad-scale drug target activation mapping of EOC to identify new druggable targets for personalized therapy. Methods: 72 ovarian primary lesions collected from chemo-naïve EOC patients were analyzed. Highly enriched tumor epithelial cells were isolated by laser capture microdissection, lysed and subjected to reverse phase protein microarray analysis for multiplexed protein pathway activation mapping. The activation/phosphorylation level of 156 key signaling proteins was analysed. Based on the disease-free interval to platinum therapy, 61 stage II-IV patients were segregated into platinum-resistant (<6 months), platinum-sensitive (6-12 months), and platinum-supersensitive disease (>12 months). One-way analysis of variance was used to detect significant differences among the three groups in the drug target activation profile. Results: Expression of the drug target PDGF Receptor β and activation of ErbB2/HER2 (Y1248) were significantly higher in patients with resistant disease compared to sensitive groups (respectively, p 0.0033 and p 0.0134), while the expression of Estrogen receptor α was greater in the supersensitive group (p 0.0295). Moreover, overall survival analysis including all stages revealed that the expression level of Cox2 is significantly higher in patients with shorter survival (HR: 2.48, p 0.0179). Conclusions: Functional drug target activation mapping revealed the unique signaling architecture of platinum-resistant EOC. If confirmed in independent study sets, these results suggest that the utilization of drugs targeting PDGF Receptor β and ErbB2/HER2 could be evaluated in platinum resistant EOC and/or in combination with platinum therapy in order to overcome acquired resistance. Finally, this study indicates that Cox2 may play an important role in aggressive EOC, and that the addition of Cox-inhibitors to standard of care could be rationally evaluated as a novel therapeutic regimen for ovarian cancer.
Benefits of neoadjuvant chemotherapy in ovarian, primary peritoneal, or fallopian tube carcinoma.
Authors: Brown Alaina J. , Huang Marilyn , Sun Charlotte C. , Zaid Tarrik M. , Balakrishnan Nyla , Mhadgut Hemendra , Lu Karen H. , Westin Shannon Neville , Bodurka Diane C. 
Published: March 2020

5580 Background: NCCN guidelines recommend consideration of neoadjuvant chemotherapy (NACT) for poor surgical candidates with bulky stage III or IV ovarian, fallopian tube, or primary peritoneal cancer. However, new convincing evidence favoring NACT instead of primary tumor reductive surgery (PTRS) has resulted in shifting practices among gynecologic oncologists. This study compares operative and post-operative outcomes between patients receiving NACT and those undergoing PTRS. Methods: After IRB approval, patients who received NACT or PTRS were identified through the tumor registry and surgical database at a single institution from 2008-2012. Statistical analyses included Wilcoxon Mann-Whitney, Chi square and Fisher’s exact test. Results: Of 163 patients, 109 (67%) received NACT and 54 (33%) underwent PTRS. The majority in both groups was Caucasian (82%) and had ovarian cancer (85%). The median age of all patients was 62 years. There was no difference in median age between groups. High-grade serous histology was most common. In the PTRS group, 72% were stage IIIC. During cytoreductive surgery, NACT cases had significantly shorter total operative and anesthesia time compared to PTRS cases (p = 0.005). NACT patients had significantly less blood loss (p=0.002) than PTRS patients. Based on available data, there was no difference in intraoperative transfusion rate (p = 0.098). However, PTRS cases had a higher rate of postoperative transfusion compared to NACT cases (p = 0.043). There was no difference in the proportion of optimal surgical cytoreduction between groups (p = 0.422). Available data demonstrated that PTRS patients had significantly more complications and intensive care unit (ICU) admissions compared to those receiving NACT (p = 0.024, p = 0.002 respectively). Conclusions: NACT offers advantages regarding operative and anesthesia time, blood loss, postoperative complications, and ICU admissions. NACT may offer a valuable alternative to PTRS. Further studies are warranted to better define the role of NACT in the upfront treatment of advanced ovarian cancer.