bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: An NRG Oncology trial.
Authors: Powell Matthew A. , Filiaci Virginia L. , Hensley Martee Leigh , Huang Helen Q , Moore Kathleen N. , Tewari Krishnansu Sujata , Copeland Larry J. , Secord Angeles Alvarez , Mutch David G , Santin Alessandro , Richards William , Warshal David Philip , Spirtos Nicola M. , Disilverstro Paul , Ioffe Olga , Miller David S.
Published: May 2019

5500

Background: Gynecologic carcinosarcomas (CS) are rare yet aggressive epithelial malignancies for which optimal therapy is debated. PI was shown to be superior to I. PC demonstrated compelling phase 2 activity with improved safety and convenience. Methods: Main inclusion: ≥18 y; chemotherapy naïve stage I-IVB or recurrent uterine (U) or ovarian (O) CS. Treatment randomised 1:1 to PC (P 175mg/m2 with C: AUC 6 or 5 if prior RT on D1) or PI (P: 135 mg/m2; I 1.6 g/m2 D1-3; G-CSF support with dose escalation & de-escalation based on nadir counts) q21days for 6-10 cycles. Quality of life (QOL) (FACT-En TOI) and neurotoxicity (FACT/GOG-Ntx subscale) administered at 4 timepoints. A stratified log-rank test compared primary endpoint of overall survival (OS) from entry between treatment groups for non-inferiority (NI) of PC to PI. With 264 events, power was 80% for a null hazard ratio of 1.2 against a 13% greater death rate on PI when type I error is limited to 5% for a one-tail test. NCT00954174. Results: 637 pts accrued with a median follow-up of 61 months. The primary (U, n = 536) and secondary (O, n = 101) cohorts are analyzed separately and included 449 and 90 pts eligible pts, respectively. For the U cohort:PC and PI were randomly assigned to 228 and 221 eligible pts. Stage distribution: I (40%), II (6%), III (31%), IV (15%) and recurrent (8%). The study met its primary objective withPC not inferior to PI (intention-to-treat analysis;Median OS 37 vs. 29 mo, HR = 0.87; 90% CI = 0.70 to 1.075; p < 0.01 for NI, p > 0.1 for superiority (S)).PFS (median on PC 16mo vs PI 12mo; HR = 0.73; p = < 0.01 for NI, p < 0.01 for S). Toxicity (grade 1/2/3/4/5: PC 1/8/40/48/2%; PI 1/32/39/25/1%). Most of increase toxicity for PC was hematologic with G-CSF rarely used (N = 6). Confusion and genitourinary hemorrhage were significantly worse with PI. Both groups had decline in QOL and neurotoxicity scores. Similar trends were noted for the O cohort (OS: PC 30mo vs PI 25mo; and PFS: 15 mo vs 10 respectively). Conclusions: PC was not inferior to PI for OS with longer PFS and similar QOL and neurotoxicity. These results establish a new standard regimen for women with CS. Clinical trial information: NCT00954174.
Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: A multi-institutional analysis of 700 cases.
Authors: Uppal Shitanshu , Gehrig Paola , Vetter Monica Hagan , Davidson Brittany Anne , Lees Brittany F , Brunette Laurie Leigh , Tucker Katherine , Matsuo Koji , Bixel Kristin Leigh , Staley Allison Stuart , Gotlieb Walter H. , Holloway Robert W. , Moore Kathleen N. , Rose Stephen L.
Published: May 2019

5504

Background: Compare outcomes between open and minimally invasive radical hysterectomy. Methods: Retrospective multi-institutional review of patients undergoing radical hysterectomy for stage IA1, IA2 and IB1 squamous, adeno- or adeno-squamous carcinoma between 01/01/2010 - 12/31/2017. Results: From 704 cases that met the inclusion criteria, 185 (26.3%) underwent open and 519 (73.7%) underwent minimally invasive surgery (MIS). Women treated with open surgery were older, had larger tumors on preoperative assessment as well as on final pathology assessment, had higher proportion of patients with IB1 stage and adjuvant therapy. Patients undergoing open surgery had longer median follow-up compared to MIS (44 vs. 30.3 months, p < 0.001). The two groups were similar in regard to race distribution, body mass index, comorbidities and preoperative histology. There were 13/185 (7%) recurrences and 10/185 (5.4%) deaths in the open compared to 42/519 (8.1%) recurrences and 26/519 (5%) deaths in MIS (p = n.s for both). However, on multivariate analysis, after controlling for race, comorbidities, preoperative tumor size, histology, grade and smoking status, MIS had higher odds of recurrence (OR 2.24, 95% CI 1.04 - 4.87, p = 0.04). On a second model, in addition to prior mentioned factors, we included lymphovascular space invasion, receipt of adjuvant therapy and vaginal margin status. Undergoing MIS remained associated with higher odds of recurrence (OR 2.37, 95% CI 1.1 - 5.1, p = 0.031). On sub-group analysis of cases with preoperative tumor size less than equal to 2 cm, there were 5/121 (4.1%) recurrence in open and 25/415 (6%) recurrences in MIS group (p = 0.34). Multivariate analysis did not show a higher rate of recurrence in MIS arm in this subgroup. In 26 cases of MIS where no vaginal manipulator was used, no recurrences were noted. In comparison 19/270 (7%) recurrences were noted in intra-uterine manipulator (V-care/Zumi/Rumi) and 22/210 (11%) in vaginal manipulators (EEA sizer/Colpo Probe) groups (p = 0.119). Conclusions: In this large retrospective analysis, patients undergoing MIS for early stage cervical cancer had higher odds of recurrence. In patients with 2 cm or less tumor on preoperative assessment, recurrence rates were similar between the two groups. Role of manipulator in increasing recurrence should be further studied in this patient population.
Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer: A randomized controlled chemotherapy-free study—NSGO-AVANOVA2/ENGOT-OV24.
Authors: Mirza Mansoor Raza , Avall-Lundqvist Elisabeth , Birrer Michael J. , Christensen Rene dePont , Nyvang Gitte-Bettina , Malander Susanne , Anttila Maarit , Werner Theresa Louise , Lund Bente , Lindahl Gabriel , Hietanen Sakari , Peen Ulla , Dimoula Maria , Roed Henrik , Knudsen Anja Ør , Boufercha Louisa , Staff Synnove , Krog Vistisen Anders , Bjørge Line , Maenpaa Johanna Unelma
Published: May 2019

5505

Background: Standard treatment of platinum-sensitive recurrent ovarian cancer (PSROC) is platinum based combination chemotherapy ± bevacizumab. However, this treatment modality is hardly curative, and is associated with significant toxicity. Both bevacizumab (BEV) and PARP inhibitors (PARPi) have demonstrated efficacy in PSROC. There is preclinical evidence of enhanced activity of the combination. This is the proof-of-concept randomized trial of PARPi-BEV combination against PARPi monotherapy as treatment in PSROC, regardless of number of previous lines of therapies. 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 BEV 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was progression-free survival (PFS). Stratification was according to homologous recombination-deficiency(HRD) status (MyChoice HRD) and chemotherapy-free-interval (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: median 11.9 vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.35; 95% confidence interval (CI),[0.21 to 0.57]; P<0.001. Pre-planned exploratory subgroup analyses: patients with HRD-positive tumors (n=54) HR 0.36 (CI, 0.18-0.69); HRD-negative disease (n=43) HR, 0.47 (CI, 0.24-0.95); g BRCAmut patients (n=34) HR 0.53 (CI, 0.23-1.21); non-g BRCAmut patients (n=63) HR 0.33; CI, 0.18-0.61); CFI of 6 to 12 mo (n=38) HR, 0.29 (CI, 0.14 to 0.62); CFI of ≥12 mo (n=59) HR, 0.42; (CI, 0.22 to 0.80). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (26.5% vs. 0%) and neutropenia (12.2% vs. 2.1%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Both niraparib alone and the combination had meaningful activity in PSROC. Compared to niraparib alone, the chemotherapy-free regimen of niraparib and BEV significantly improved PFS in women with PSROC,regardless of HRD status and duration of CFI. Clinical trial information: NCT02354131.
Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.
Authors: Vanderstichele Adriaan , Van Nieuwenhuysen Els , Han Sileny , Concin Nicole , Van Gorp Toon , Berteloot Patrick , Neven Patrick , Busschaert Pieter , Lambrechts Diether , Vergote Ignace
Published: May 2019

5507

Background: The CLIO trial (NCT02822157) evaluated olaparib single-agent therapy versus standard of care chemotherapy in platinum-resistant (recurrence within 6 months after last platin) ovarian cancer (PROC). Methods: Eligible patients with measurable disease and ≥1 prior line of chemotherapy were randomized 2:1 to Olaparib (OLA) monotherapy (300 mg tablets, BID) or physician’s choice chemotherapy (CT; PLD 40 mg/m2 q 4 wks; Topotecan 1.25 mg/m2 day 1—5 q 3 wks; Paclitaxel 80 mg/m2 day 1, 8,15 q 3 wks; Gemcitabine 1000 mg/m2 day 1, 8 and 15 q 4 wks). Primary endpoint was objective overall response (ORR) per RECIST v1.1. Germline BRCA status was available for all patients. Disease control rate (DCR) was defined as response for at least 12 wks. Results: 100 patients with PROC were randomized 2:1 to OLA (N = 67) or CT (N = 33). Median prior lines of treatment was 3 (range: 1—8). ORR (unconfirmed) was 18% (12/67) for OLA and 6% (2/33) for CT. ORR for OLA was 38% (5/13) in gBRCAm and 13% (7/54) in gBRCAwt patients. Of note, 2 patients with gBRIP1 mutation had no response under OLA. DCR was 35.8% (24/67) for OLA and 42% (14/33) for CT. DCR under OLA in gBRCAm was 62% (8/13) compared to 30% (16/54) in gBRCAwt disease. The median duration of response (DOR) and the median progression-free survival (PFS) was similar: 5.4 months vs 4.5 months (DOR) and 2.9 vs 3.4 months (PFS) for OLA and CT, respectively. Grade ≥3 treatment-related AEs occurred in 60% vs 52% for OLA and CT, respectively. Somatic HRR mutation analysis is ongoing and will be presented. Conclusions: Olaparib monotherapy showed a favorable response rate in PROC compared with chemotherapy also in gBRCAwt patients. Analysis of clinical endpoints in relation to HRR is ongoing and will be presented. Clinical trial information: NCT02822157.
A phase II randomized study of avelumab plus entinostat versus avelumab plus placebo in patients (pts) with advanced epithelial ovarian cancer (EOC).
Authors: Cadoo Karen Anne , Meyers Michael L. , Burger Robert Allen , Armstrong Deborah Kay , Penson Richard T. , Gordon Michael S. , Fleming Gini F. , Moroney John William , Hamilton Erika Paige , Duska Linda R. , Wenham Robert Michael , Sankoh Serap , Brouwer Susan , Ordentlich Peter , Aghajanian Carol , Matulonis Ursula A.
Published: May 2019

5511

Background: Preclinical evidence suggests that combining avelumab (A), a human anti-PD-L1 monoclonal antibody, and entinostat (E), a class I selective histone deacetylase (HDAC) inhibitor, may increase tumor immunogenicity and responsivity to checkpoint inhibition. This study evaluated whether A+E would lead to improved progression free survival (PFS) vs A in pts with advanced EOC. Methods: Pts with EOC which had progressed or recurred after 1st-line platinum-based chemotherapy and received 3- 6 lines of therapy were randomized 2:1 to receive A (10 mg/kg IV Q2W) plus E (5 mg PO QW) or A plus placebo (P). Treatment continued until disease progression (PD) or unacceptable toxicity. The primary endpoint was PFS (investigator-assessed, RECIST 1.1), stratifying on the presence/absence of bulky disease (tumor ≥ 50 mm) and platinum-refractory disease. The hypothesis was that the combination would reduce the hazard of PD or death by 43%, representing a 75% improvement in median PFS. 97 events (from 120 pts) provided 90% power with 1-sided significance level of 0.10. Secondary endpoints included ORR, duration and time to response, toxicity, clinical benefit rate, and OS. Results: 126 pts were enrolled, median age 63 yrs (range 43-82), median 4 prior lines, 83% serous histology. Median PFS was 1.64 and 1.51 mos for A+E and A+P, respectively (p = 0.31; HR 0.90, 95% CI: 0.58-1.39). No significant differences in ORR (6% vs 5%), or OS (NE vs 11.3 mos) were observed. 4 pts (3%) had clear cell EOC, with no responses observed. The incidence of related adverse events (AEs) was higher in the A+E arm compared to A+P (any grade: 93% vs 78%, Grade 3/4: 41% vs 10%), and the most frequent (≥20%) related AEs with A+E were fatigue (46%), nausea (31%), diarrhea (26%), anemia (26%), and chills (20%). Grade 3/4 related AEs occurring in ≥5% with A+E were fatigue (9%), and neutropenia (8%). 47% of pts in A+E arm required E dose holds/reductions. Discontinuations due to AEs were similar between arms (21% vs 17.5% for A+E and A+P, respectively), as was duration of study therapy (median 4 and 5 cycles started). Conclusions: In pts with heavily pretreated EOC, median PFS was not prolonged when E was added to A compared to A alone and the combination resulted in greater toxicity. Clinical trial information: NCT02915523.
Determination of eligibility criteria for salvage hysterectomy after definitive radiotherapy/concurrent chemoradiotherapy for residual cervical disease.
Authors: Takekuma Munetaka , Takahashi Fumiaki , Arimoto Takahide , Ishikawa Mitsuya , Ota Yukinobu , Kagabu Masahiro , Kasamatsu Takahiro , Kanao Hiroyuki , Kawamura Naoki , Kitagawa Ryo , Kudaka Wataru , Suzuki Shiro , Takehara Kazuhiro , Tanikawa Michihiro , Toita Takafumi , Hasumi Yoko , Fujiwara Satoe , Mizuno Mika , Kobayashi Hiroaki , Yaegashi Nobuo
Published: May 2019

5524

Background: Patients with persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy (RT/CCRT) have a poor prognosis. Salvage hysterectomy (HT) is potentially curative, but eligibility criteria therefor have not been determined. Methods: Part 1) Retrospective review of patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions of the Japanese Clinical Oncology Group (JCOG) from 2005–2014. Differences between a salvage HT group and a systemic chemotherapy (CT) group after definitive RT/CCRT for residual tumor were evaluated. Clinical variables influencing a salvage HT treatment decision were evaluated using logistic regression analysis. Part 2) Questionnaire-based survey conducted by JCOG gynecologic oncologists assessing treatment choice for patients with residual cervical disease after definitive RT/CCRT. Patients with residual cervical tumor before, during and after definitive RT/CCRT were surveyed for 86 conditions and appropriate candidates for salvage HT were evaluated using heat map analysis. Results: Part 1) We identified 298 patients who underwent salvage HT or systemic CT. Median overall survival was 3.8 and 0.9 year in the HT and CT groups, respectively (HR 0.4341, 95% CI 0.336-0.559, p < 0.01). FIGO stage and lymph node metastasis at initial treatment, performance status (PS) at diagnosis of residual cervical tumor and parametrial invasion of residual cervical tumor significantly influenced a salvage HT treatment decision. Part 2) Heat map analysis showed that surveyed variables segregated into 3 groups: i) in favor of salvage HT, ii) in favor of systemic CT, and iii) either. Conditions such as FIGO stage IB-IIB, PS of 0-1, residual tumor < 4 cm, no parametrial invasion and no residual lymph node metastasis were included in group i, in favor of salvage HT. Conclusions: Eligibility criteria could be determined based on the results of the current study, and a prospective clinical trial evaluating the survival benefit of salvage HT for residual cervical tumor after definitive RT/CCRT is being planned by JCOG.
Comparative benefit of interstitial needles in addition to intracavitary applicators in the treatment of locally advanced cervical cancer.
Authors: Lombe Dorothy Chilambe , Crook Juanita M. , Bachand Francois , Batchelar Deidre , Moore Jocelyn , Rose Tracey , Sherin Danielle
Published: May 2019

5528

Background: Cervical cancer is the leading cause of cancer mortality of women in Low and Middle Income Countries (LMIC). Interstitial needles (IN) have improved outcomes but the resources required in comparison to intracavitary brachytherapy (IC) alone has impeded uptake in endemic regions. We conducted a retrospective review of the utilisation of IN in the management of locally advanced cervical cancer and simulated 2D planning by loading the applicators using standard Manchester loading (ML) to explore the magnitude of benefit that interstitial needles provide. Methods: 72 brachytherapy plans of 18 patients who had undergone treatment using tandem and ring and had interstitial brachytherapy between 04/2016 and 10/2018 were reviewed. ML plans prescribed to point A were generated to represent a 2D scenario but the known HR-CTV was taken into consideration and its dosimetric outcomes were compared to those of the 3D based plans. Results: The median tumour volume was 23 cm3. IN was used in 82 % of the insertions. The median number of IN was 2 (range 0 – 6) with median percentage of IN dwell time 6.6 % (range 0.68 – 38.5). V100 was excellent 98.2% for ML 97.3% for 3D IN and 98.7% for 3D non-IN plans. The median HRCTV D90 was 8.5 Gy/fraction (cumulative EQD210101.4 Gy) for ML plans and 8.0 Gy/fraction (cumulative EQD210 91.4 Gy) for 3D plans. The ML plans failed to meet the OAR goals except for the rectum, which was optimally distanced by the rectal paddle. The median bladder, sigmoid and small bowel doses were 24% above the recommended constraint in the individual plans and 15% cumulative EQD2. A statistically significant relationship was found between the number of needles utilised, tumour volume (p < 0.001) and coverage (p = 0.006) but not delivered dose (p < 0.068). Conclusions: 2D brachytherapy can provide adequate dose coverage for most tumours but IN provide a benefit in reducing the doses to OARs in a significant number of patients. This justifies investment in resources for uptake of interstitial needles to increase access to optimal treatment of cervical cancer for women in LMIC. This research was made possible an ASCO Conquer Cancer Foundation grant.
Comparison of definitive cervical cancer management with concurrent chemotherapy and radiation between two centers with variable resources and opportunities for improved treatment delivery.
Authors: Asamoah Francis Adumata , Scott Pearl Aba Anoa , Yuan Zhigang , Fernandez Daniel Celestino , Boateng Samuel Anoa , Montejo Michael E. , Agyeman Mervin Anoa , Aidoo Charles , Shahzad Mian M. , Chern Jing-Yi , Chon Hye Sook , Wenham Robert Michael , Vanderpuye Verna D. , Yarney Joel , Yamoah Kosj , Ahmed Kamran A.
Published: May 2019

5534

Background: Cervical cancer remains a global health challenge particularly in low to middle income countries with under resourced healthcare systems. We present the experiences of two centers practicing in variable resource environments to determine predictors of improved radiochemotherapy outcomes. Methods: This retrospective review describes baseline demographic and clinicopathologic characteristics of cervical cancer patients treated with concurrent chemotherapy and radiation between 2014 and 2017 at the National Radiotherapy Oncology and Nuclear Medicine Center (NRONMC) in Korle Bu Teaching Hospital, Accra, Ghana and Moffitt Cancer Center, Tampa, Florida, USA. Results: Ghanaian patients presented at an older median age (56 vs. 49 years, p < 0.001), with predominantly stage IIIB disease (43% vs. 16%, p < 0.001) and squamous cell histology (89% vs. 79%, p < 0.001). Median treatment duration was longer for Ghanaian patients (58 vs. 52 days, p < 0.001). Ghanaian patients were less likely to receive concurrent chemotherapy (68% vs. 100%, p < 0.001) and interstitial brachytherapy implants (0 vs 19%, p < 0.001). No Ghanaian patients received a radiation boost to pelvic or paraortic lymph nodes (p < 0.001). Ghanaian patients had lower local control (64% vs. 93%, p < 0.001) and overall survival (82% vs. 95%, p = 0.02) at 24 months, respectively. For stages IB, IIA, IIB, IIIB, 24 month local control rates for NRONMC vs. Moffitt patients were (60% vs. 93%; p = 0.05), (89% vs. 100%; p = 0.35), (91% vs. 91%; p = 0.89), (53% vs. 91%; p = 0.02) and 24 month OS rates were (85% vs. 100%; p = 0.06), (100% vs. 100%; p = 0.48), (85% vs. 96%; p = 0.2), (73% vs. 91%; p = 0.24), respectively. Treatment duration > 55 days predicted poorer overall survival on multivariable analysis (MVA). Stage ≥III disease predicted poorer local control on MVA. Conclusions: Significant differences were noted in treatment and disease characteristics between the two centers. Feasible improvements for patients treated at NRONMC include removing financial barriers to chemotherapy access, improving radiotherapy delivery capacity to reduce treatment delays, and screening programs to reduce advanced disease presentation.
Recurrence and survival after robotic-assisted radical hysterectomy (RRH) for early-stage cervical cancer (CC): Experience may matter.
Authors: Fitzsimmons Christine K. , Stephens Amanda J. , Kennard Jessica A. , Manyam Madhavi , Pepe Julie W. , DeCoff Kayla M. , Ahmad Sarfraz , McKenzie Nathalie Dauphin , Kendrick James Erasmus , Holloway Robert W.
Published: May 2019

5535

Background: The phase III LACC Trial found that minimally invasive surgery (MIS) / radical hysterectomy was inferior to open radical hysterectomy (ORH) with reduced disease-free survival (86% v 96.5%) and a higher disease-specific death rate (DSDR) (4.4% v 0.6%). We evaluated our experience with attention to the learning curve. Methods: Patients (pts) with early-stage CC (4/2007-12/2017) who underwent RRH with a uterine manipulator were evaluated in a contemporaneously maintained database. First 10 learning curve cases per surgeon (Group A) were compared to all subsequent cases (Group B). Inclusion criteria mirrored the LACC trial: > one-year follow-up, adenocarcinoma, adenosquamous, or squamous carcinoma, stage IA2 or IB1 using FIGO 2014 guidelines, and pathologic tumor size (TS) of 4 cm or less. Atypical histologies and lesions > 4 cm were excluded. Study parameters assessed included recurrence free survival (RFS), DSDR, and pattern of recurrence. Results: 144 RRH pts were identified and 90 met inclusion criteria with mean age of 45.6±14.3 years. Exclusions included stage 1A1 without LVSI (n = 13), atypical histology (n = 10), lost to follow-up (n = 13), and occult stage 1B2 (n = 18). 40 pts met Group A and 50 met Group B criteria. Median follow-up was 61±34.3 months (A = 71.5, B = 52.5). The 5-year RFS was 92% (95 CI ±4%) and the DSDR 5.5% (n = 5). There were 7 (7.8%) recurrences with median time to recurrence of 12±8.3 mos. Recurrence in Group A (n = 6, 15%) exceeded Group B (n = 1, 2%), p= 0.025. DSDR was 10% Group A v 2% B ( p= 0.184). The 4.5 yr RFS was 84.8% (95 CI ±7%) in Group A v 98% (95 CI ±3%) in Group B. There were no differences in risk factors for recurrence between A & B (TS > 2 cm, LN (+), adjuvant therapy (AT), and LVSI p> 0.05), except (+) vaginal margin status (A = 10% v B = 0%, p= 0.034). Three recurrences involved carcinomatosis, which may be insufflation related. All recurrent cases had TS > 2 cm and 5 received AT. Conclusions: In this study, recurrence of disease in early-stage CC clustered in the first 10 cases per surgeon and occurred in TS > 2 cm. This data suggests a possible learning curve effect and argues against a uterine manipulator cause. Carcinomatosis may be insufflation related, unique to MIS, and deserves further study.
Ofranergene obadenovec (VB-111) in platinum resistant ovarian cancer: with an immunotherapeutic effect.
Authors: Cohen Yael Chava , Berlin Suzanne T. , Birrer Michael J. , Campos Susana M. , Rachmilewitz Minei Tamar , Harats Dror , Penson Richard T.
Published: May 2019

5542

Background: VB-111 is a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response. We report final results of a phase I/II study of VB-111 in combination with paclitaxel in patients with platinum-resistant ovarian cancer. Methods: Study NCT01711970 was a prospective, open label, dose escalating study assessing combination treatment of VB-111 Q8W and weekly Paclitaxel. In the phase I part of the study patients were treated with escalating doses of intravenous VB-111 and Paclitaxel. In phase 2 patients were treated with therapeutic doses of VB-111 1x1013 Viral Particles and paclitaxel 80mg/m2. Assessments included safety, overall survival (OS), PFS, tumor response (CA-125 and RECIST) and histopathology. Results: 21 patients with recurrent platinum-resistant ovarian cancer were enrolled and treated in 2 US sites. Patients received a mean of 2.3 ±1.8 repeat doses of VB-111. 17/21 received the therapeutic dose. Median age was 65 (41-79) with a median of 3 (1-4) prior lines of therapy. Half of the subjects were Platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and was associated with generally mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients including durable responses, and responses in patients with platinum refractory disease and post anti-angiogenic failure . The median OS was 498 days in patients treated with Therapeutic Dose compared to 173 days in Sub-therapueutic dose (p = 0.028). Tumor Specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells and regions of apoptotic cancer cells. Conclusions: Treatment with VB-111 in combination with weekly Paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect manifested as tumor infiltration with CD-8 T cells. Encouraging results are the basis for further exploration in the ongoing, placebo controlled, pivotal OVAL study. Clinical trial information: NCT01711970.
Recurrence of ovarian cancer in BRCAwt patients without maintenance therapy: Real-world evidence.
Authors: Louie-Gao Melinda , Aydin Ebru , Thaker Premal H.
Published: May 2019

5547

Background: Development of platinum resistance is a major clinical challenge in ovarian cancer (OC) treatment. In the phase 3 ENGOT-OV16/NOVA trial of the poly(ADP-ribose) polymerase inhibitor (PARPi) niraparib, 55% of BRCA wild-type ( BRCAwt) patients (pts) receiving placebo developed platinum resistance after their last platinum-based therapy (ie, progressive disease within 6 months of their last chemotherapy [CT] dose). Niraparib, a PARPi approved for the maintenance treatment of adult pts with recurrent OC following platinum-based CT, significantly prolongs progression-free survival (PFS). This real-world data analysis investigated the risk of platinum eligibility loss for BRCAwt pts who did not receive maintenance therapy after platinum treatment. Methods: This retrospective study identified 5,535 pts with OC from January 2011–October 2018 using data from Flatiron, a longitudinal, demographically and geographically diverse database derived from records of > 265 cancer clinics and > 2 million US cancer pts. BRCAwt pts who had received ≥2 lines of platinum-based CT, had disease progression ≥6 months after their previous line of therapy, and had no maintenance therapy (PARPi, bevacizumab, or CT agents) after their current treatment were included. Kaplan-Meier analysis was used to estimate the probability of pts initiating next treatment or death, whichever occurred first, within 6 months. Results: Of 5,535 pts diagnosed with OC, 147 BRCAwt pts met the inclusion/exclusion criteria of this analysis (similar to ENGOT-OV16/NOVA placebo arm). An estimated 56% of pts received the next treatment or died within 6 months after their last platinum-based therapy. Median time to next therapy or death was 5.1 months (95% confidence interval, 3.1–7.2). Conclusions: Our real-world data analysis shows that 56% of BRCAwt pts who received platinum-based treatment without maintenance therapy had recurrent OC within 6 months, classifying them as platinum resistant. Use of maintenance treatment options, such as niraparib, has been shown to significantly prolong PFS after platinum-based CT and may be beneficial in extending the platinum-free interval, enabling pts to remain eligible for further platinum therapy.
Comparative performance of Breast Cancer Index (BCIN+) and CTS5 in hormone receptor-positive (HR+) lymph node-positive (N+) breast cancer patients with one to three positive nodes (N1).
Authors: Sgroi Dennis , Zhang Yi , Schnabel Catherine A.
Published: May 2019

555

Background: Identification of N+ breast cancer patients with a limited risk of recurrence improves selection of those for which chemotherapy and/or extended endocrine therapy (EET) may be most appropriate to reduce overtreatment. BCIN+ integrates gene expression with tumor size and grade, and is highly prognostic for overall (0-10yr) and late (5-10yr) distant recurrence (DR) in N1 patients. Clinical Treatment Score post-5-years (CTS5) is a prognostic model based on clinicopathological factors (nodes, age, tumor size and grade) and significantly prognostic for late DR. The current analysis compares BCIN+ and CTS5 for risk of late DR in N1 patients. Methods: 349 women with HR+, N1 disease and recurrence-free for ≥5 years were included. BCIN+ results were determined blinded to clinical outcome. CTS5 was calculated as previously described (Dowsett et al, JCO 2018; 36:1941). Kaplan-Meier analysis and Cox proportional hazards regression for late DR (5-15y) were evaluated. Results: 64% of patients were > 50 years old, 34% with tumors > 2cm, 79% received adjuvant chemotherapy and 64% received up to 5 years of ET. BCIN+ stratified 23% of patients as low-risk with 1.3% risk for late DR vs those classified as high-risk with 16.1% [HR 12.4 (1.7-90.4), p = 0.0014]. CTS5 classified patients into 3 risk groups: 29% of patients as low-risk (4.2% DR), 37% as intermediate-risk (10.6% DR), and 34% as high-risk (22.1% DR) [HR intermediate vs. low: 2.3 (0.7-7.0), p = 0.16; high vs. low: 5.3 (1.8-15.5), p = 0.002]. In a subset of patients who completed 5 years of ET (N = 223), BCIN+ identified 22% of patients as low-risk with a late DR rate of 2.1%, while CTS5 identified 29% and 37% of patients as low- and intermediate-risk with late DR rates of 5.2% and 10.3%, respectively. Conclusions: BCIN+ classified N1 patients into binary risk groups and identified 20% patients with limited risk of late DR ( < 2%) that may be advised to forego EET and its attendant toxicities/side effects. In comparison, CTS5 classified patients into 3 risk groups, with low- and intermediate-risk of late DR of 4-5% and 10%, wherein the risk-benefit profile for extension of endocrine therapy is less clear.
Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients (pts) by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial.
Authors: Friedlander Michael , Moore Kathleen N. , Colombo Nicoletta , Scambia Giovanni , Kim Byoung-Gie , Oaknin Ana , Lisyanskaya Alla Sergeevna , Floquet Anne , Leary Alexandra , Sonke Gabe S. , Gourley Charlie , Banerjee Susana N. , Oza Amit M. , González-Martín Antonio , Aghajanian Carol , Bradley William Hampton , Lowe Elizabeth S. , Bloomfield Ralph , Disilvestro Paul
Published: May 2019

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Background: In SOLO1 (NCT01844986), maintenance olaparib resulted in a significant improvement in progression-free survival (PFS) for newly diagnosed, BRCA1- and/or BRCA2-mutated, advanced ovarian cancer pts compared with placebo (HR 0.30, 95% CI 0.23–0.41; median not reached vs 13.8 months; Moore et al. N Engl J Med 2018). We investigated PFS in SOLO1 for the subgroups of pts with BRCA1 mutations ( BRCA1m) or BRCA2 mutations ( BRCA2m). Methods: All pts were in clinical complete or partial response to platinum-based chemotherapy and were randomized to maintenance olaparib (300 mg twice daily; tablets) or placebo. After 2 years, pts with no evidence of disease discontinued study treatment, but pts with evidence of disease could continue study treatment. PFS by BRCAm was a predefined analysis. BRCAm were identified by central germline (Myriad or BGI) or local testing; Foundation Medicine testing confirmed tumor BRCAm. Results: Median follow-up for PFS was ~41 months in the olaparib and placebo arms. Of 391 randomized pts, 282 had BRCA1m (72%), 106 had BRCA2m (27%) and three (1%) had both (Table). Two pts in the olaparib arm had somatic BRCAm (one BRCA1m, one BRCA2m); all others had germline BRCAm. At the primary data cut-off, 155 pts in the BRCA1-mutated group (55%), 43 in the BRCA2-mutated group (41%) and none in the BRCA1/2 -mutated group had disease progression. The percentage of BRCA1-mutated pts who received olaparib and were progression-free at 1, 2 and 3 years was 86%, 69% and 53% (vs 52%, 36% and 26% receiving placebo) and for BRCA2-mutated pts was 92%, 85% and 80% (vs 50%, 32% and 29%, respectively). Conclusions: Significant PFS benefit with olaparib versus placebo was demonstrated for all pts, regardless of whether they had BRCA1m or BRCA2m. Statistical tests were not used to compare BRCA1- and BRCA2-mutated pts, but those with BRCA2m appeared to receive greater benefit from maintenance olaparib than those with BRCA1m. Clinical trial information: NCT01844986. [Table: see text]
Molecular stratification of endometrioid ovarian carcinomas.
Authors: Stanley Barbara , Thomson John P , Hollis Robert L , Meynert Alison , Rye Tzyvia , Iida Yasushi , Nussey Fiona , Mackean Melanie J , Churchman Michael , Semple Colin , Okamoto Aikou , Gourley Charlie , Herrington C Simon
Published: May 2019

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Background: Endometrioid ovarian carcinomas (EC) have been historically under-investigated. We sought to determine the molecular landscape of contemporarily defined EC using whole exome sequencing (WES). Methods: Tumours diagnosed as EC between May 1980 and December 2013 were identified through the Edinburgh Ovarian Cancer Database. Pathology review was performed according to WHO 2014. Other pathologies including WT1 positive HGSOC were excluded. A selected cohort underwent WES and were analysed for single nucleotide and copy number variants across a panel of genes previously reported as mutated in endometrial, ovarian or pan cancer studies. Tissue microarrays were stained for ER, PR and AR. Multivariable analysis for disease specific survival (DSS) was performed. Results: 125 tumours were included. 61 tumours of all grades underwent WES. 5 molecular groups were identified based on the presence of TP53 mutations (45.9%); or an EClike profile (one or more mutations in ARID1A (41.0%); CTNNB1 (31.1%), PTEN (24.6%) or PIK3CA (23.0%)). Tumours with no mutations in EClike genes were termed ECnull. Each group demonstrated differential DSS (table). Some ECnull: TP53mut tumours also displayed mutations in KRAS, APC and mismatch repair genes. Unsupervised clustering analysis based on the top 100 differentially mutated genes across the dataset validated these groups. Somatic copy number alterations were significantly higher in the TP53mu t groups than the TP53wt groups (P<0.0001), and were identified across EClike genes in the ECnull groups. A PR histoscore of >150, but not ER or AR, was more frequent in the TP53wt group compared to the TP53mut groups (P=0.003). TP53mut status (P=0.0182) and PR histoscore ≤150 (P=0.0115) were independently associated with DSS. Conclusions: EC is a heterogeneous disease comprising 5 molecular subgroups each demonstrating differential clinical outcome. TP53 mutations and PR histoscore ≤150 are independently associated with poor prognosis. [Table: see text]
Olaparib maintenance therapy in patients (pts) with a BRCA1 and/or BRCA2 mutation (BRCAm) and newly diagnosed advanced ovarian cancer (OC): SOLO1 China cohort.
Authors: Wu Lingying , Zhu Jianqing , Yin Rutie , Wu Xiaohua , Lou Ge , Wang Jing , Gao Yunong , Kong Beihua , Lu Xin , Zhou Qi , Wang Yueling , Chen Youguo , Lu Weiguo , Li Wei , Cheng Ying , Liu Jihong , Ma Xin , Zhang Jing
Published: May 2019

5554

Background: SOLO1 (NCT01844986) is a randomized, double-blind, Phase III trial evaluating the efficacy and safety of the PARP inhibitor, olaparib, as maintenance monotherapy in newly diagnosed advanced OC pts with a BRCAm. A separate pt cohort evaluated the efficacy and safety of olaparib in Chinese pts in this setting. Methods: The China cohort of SOLO1 planned to enroll ~53 newly diagnosed OC pts who had completed first-line platinum-based chemotherapy and were in clinical complete or partial response. This sample size provided around a 90% chance to observe an HR < 1, assuming a true HR = 0.62. Pts were randomized 2:1 to olaparib (300 mg bid; tablet) vs placebo. The primary endpoint was investigator-assessed progression-free survival (PFS; modified RECIST v1.1). Sensitivity analysis of PFS was performed by blinded independent central review (BICR). Results: All 64 randomized pts received study treatment (olaparib, n = 44; placebo n = 20). Median follow-up was ~30 months in both arms. Median PFS was not reached in the olaparib arm and was 9.3 months in the placebo arm (Table). The most common AEs in the olaparib group were nausea (n = 28, 63.6%), anemia (n = 25, 56.8%) and vomiting (n = 18, 40.9%). Grade ≥3 AEs occurred in 56.8% of olaparib pts vs 30.0% of placebo pts; the most common grade ≥3 AE was anemia (n = 16, 36.4%). Olaparib dose interruptions, reductions and discontinuations occurred in 56.8%, 27.3% and 6.8% of pts, respectively (vs in 30.0%, 10% and 0% of pts in the placebo arm). Conclusions: In the China cohort of SOLO1, a clinically relevant improvement in investigator-assessed PFS was observed in newly diagnosed OC pts receiving olaparib maintenance therapy. Olaparib treatment led to a 54% reduction in risk of progression or death vs placebo. The safety results were consistent with the known profile of olaparib in Chinese pts. Clinical trial information: NCT01844986. [Table: see text]
Menopausal symptoms in epithelial ovarian cancer survivors: The GINECO VIVROVAIRE2 study.
Authors: Joly Florence , Pautier Patricia , Kalbacher Elsa , Gernier François , Fauvet Raffaele , Floquet Anne , Berton-Rigaud Dominique , Tredan Olivier , Follana Philippe , Alexandre Jerome , Zannetti Alain , Dohollou Nadine , Trager Stephanie , Licaj Idlir , Grellard Jean-Michel , Clarisse Bénédicte , Ahmed-Lecheheb Djihane , Rousset-Jablonski Christine , Gompel Anne
Published: May 2019

5555

Background: We have previously shown that Epithelial Ovarian Cancer and its treatments have significant negative effects on Quality of Life (QoL) and long term fatigue. The aim of the present multicentric VIVROVAIRE2 study was to report the main menopausal, VasoMotor Symptoms (VMS) of Epithelial Ovarian Cancer survivors (EOCS). Methods: 166 patients of the 322 EOCS without relapse ≥3 years after first line of treatment accepted to participate to a gynecological consultation carried out by a gynecologist, including a questionnaire related to menopausal symptoms, a clinical examination, and an osteodensitometry. VMS (hot flashes and/or night sweats) were described according to natural menopause (NM) or surgically induced menopause (SIM). QoL and Fatigue were measured with the validated questionnaires FACT-G and FACT Fatigue. Results: Median age was 62 years [20-83], FIGO stage III/IV (48%) and < 10% BRCA1&2 mutated. Histological subtypes were: high grade serous 31%, low grade serous 23%, endometrioid G2-3 (14%) endometriod G1( 4%), clear-cell 21%, mucinous 5%. All EOCS had surgery, 97% of patients received platinum and taxane chemotherapy, median delay from treatment was 5 years [3-24] and 59 (36%) had SIM. 14% of EOCS had osteoporosis; this rate was similar to the general population. 52% of patients (85) reported either hot flashes (47%) or night sweats (32%). 72% with SIM had VMS compared to 41% with NM (p < 0.001). VMS were not associated with poor global QoL or fatigue. At the time of the survey, only 8 (5 SIM & 3 NM) EOCS received hormone replacement therapy (HRT). Among the 85 EOCS with VMS, 80 (94%) (38 SIM (93%) 42 NM (95%)) did not benefit from HRT after cancer treatment. Among 80 EOCS with VMS and no HRT, 25 (66%) with SIM and 34 (81%) of NM had high grade serous, endometriod G2-3, clear cell and mucinous histology. Conclusions: Vasomotor symptoms are frequently reported by EOCS, particularly among surgically induced menopause patients. A majority of EOCS with these symptoms might have beneficiated from hormone replacement therapy.
Cost-effectiveness analysis of laparoscopic disease assessment in ovarian cancer.
Authors: Harrison Ross , Cantor Scott B. , Villanueva Mariana , Suidan Rudy Sam , Sun Charlotte C. , Rauh-Hain Jose Alejandro , Westin Shannon Neville , Fleming Nicole D. , Sood Anil K , Lu Karen H. , Meyer Larissa
Published: May 2019

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Background: Laparoscopic assessment of disease resectability can be useful for treatment planning for patients [pts] with advanced ovarian cancer [OC] but may be associated with added cost. Methods: We performed a cost-effectiveness analysis from a payer perspective to compare (1) a conventional strategy, where standard new pt evaluation was used to assign pts to either primary cytoreduction [PCS] or neoadjuvant chemotherapy with interval cytoreduction [NACT], and (2) an alternative approach, where pts considered candidates for PCS would undergo laparoscopy to evaluate disease resectability using a validated scoring system, who were then triaged to either PCS or NACT based on this evaluation. Diagnostic work-up, surgical and adjuvant treatment, perioperative complications, and progression-free survival [PFS] were included in the model. We derived model parameters from the literature and our institution’s experience with laparoscopic triage. Utility estimates for health states related to primary treatment were assessed prospectively and taken from the literature. Costs were estimated using Medicare reimbursement. Effectiveness was defined in quality-adjusted progression-free life years [QPFLYs]. We performed multiple sensitivity analyses. Results: Under baseline model parameters, the expected cost of treating one pt under the conventional and alternative strategies was $26,539 and $26,653, respectively. The expected quality-adjusted progression-free survival for pts in the conventional and alternative strategies was 0.70 and 0.94 QPFLYs, respectively. The calculated incremental cost-effectiveness was $473.97 per QPFLY saved. The alternative strategy became cost saving if pts found to have resectable disease by laparoscopy underwent cytoreduction during the same procedure. The conventional strategy may be preferred if PCS increased PFS over NACT by ≥5 months. Conclusions: For newly-diagnosed advanced stage OC pts, laparoscopic assessment of disease resectability prior to PCS was a cost-effective strategy. A conventional strategy may be preferred if PCS produced substantially longer PFS. Sensitivity analysis suggests the benefit of utilizing laparoscopic triage is influenced by mitigation of serious perioperative morbidity and associated costs.
Immunologic responses in triple-negative breast cancer patients in a randomized phase IIb trial of nelipepimut-S plus trastuzumab versus trastuzumab alone to prevent recurrence.
Authors: Campf Jessica , Clifton Guy T. , Hale Diane F. , Vreeland Timothy J. , Hickerson Annelies , Holmes Jarrod P. , Litton Jennifer Keating , Murthy Rashmi Krishna , Lukas Jason Jerome , Mittendorf Elizabeth A. , Peoples George Earl
Published: May 2019

556

Background: Breast cancer (BC) patients (pts) expressing low levels of HER2 by (immunohistochemistry (IHC) 1-2+) are not eligible for trastuzumab (Tz). However, in a randomized phase 2b trial, triple negative BC (TNBC) pts demonstrated a significantly better DFS with nelipepimut-S (NPS) + Tz vs Tz alone. Here, we assess the ex vivo and in vivo immune responses (IR) in both arms. Methods: Disease-free pts (n = 275) with HER2 IHC 1-2+, non-amplified BC who were node positive and/or had TNBC were randomized 1:1 to granulocyte-macrophage-colony stimulating factor (GM-CSF) or NPS+GM-CSF. ±NPS was given every 3 weeks x 6 followed by 4 boosters every 6 months (mo). All pts received Tz concurrently for 1 year per label regimen and were followed for recurrence. IR were evaluated ex vivo by clonal expansion of NPS-specific cytotoxic T lymphocytes (CTL) by dextramer-staining/flow cytometry at time points over 3 years. In vivo IR were assessed by delayed type hypersensitivity (DTH) reactions periodically. Results: The trial enrolled 97 TNBC pts; 60 had 4 timepoints available for analysis (37 NPS + Tz pts; 23 Tz pts). The NPS+Tz group exhibited increases in CTL frequencies vs baseline: 208%, 303%, 379% at 18, 24 and 30 mo, respectively. NPS+Tz pts’ mean CTL frequencies increased from 0.029 ±0.001% at baseline to 0.112±0.026% at 30 mo (p = 0.01) compared to Tz pts who were 0.027 ±0.001% at baseline and 0.057 ±0.016% at 30 mo (p = 0.71). Only 4 NPS+Tz pts recurred as compared to 13 in the Tz arm. While limited by low numbers, recurrent NPS + Tz pt did not mount an IR by ex vivo assessment (range: 0.0 - 0.026%) or by DTH (all measurements: 0 mm), while non-recurrent pts mounted both clonal CTL expansion (range: 0.000- 0.33%) and enhanced DTH (range: 0.0- 80.5mm). Conclusions: NPS+Tz combination is more efficacious in generating time-dependent antigen (NPS)-specific CTL by both ex vivo and in vivo measures vs Tz. Based on these preliminary data, it appears that both ex vivo and in vivo IR to NPS were attenuated in pts with TNBC recurrence. Further analysis of read-outs from these assays to validate the relationship of IRs to clinical effect seen with NPS+Tz in TNBC pts is underway. Clinical trial information: NCT02297698.
Impact of BRCA mutation status and time to platinum resistance on patients with advanced ovarian cancer.
Authors: Tyulyandina Alexandra , Filipenko Maxim , Rumyantsev Alexey , Pokataev Ilya , Nechushkina Valentina , Morkhov Konstantin , Bulanov Anatoly , Stenina Marina , Tjulandin Sergei
Published: May 2019

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Background: The influence of germline BRCA1/2 mutations (gBRCAmt) on ovarian cancer patients (pts) long-term survival remains controversial. Methods: 228 pts with serous and endometrial ovarian cancer stage Ic-IV were enrolled in the retrospective study. Next-generation sequencing testing of BRCA1/2 in blood was employed. Progression-free survival (PFS), overall survival (OS) and time to platinum resistance (TPR) were analyzed. TPR was defined as time from first line chemotherapy to registration of platinum resistance relapse. Results: The rate of pathogenic gBRCAmt was defined in 29.4% (67/228) pts. There was no any significant difference between BRCA1/2 mutation carries and non-carries in both PFS (18.3 and 16.7 months, p = 0.27, HR 0.79, 95%CI 0.52-1.20) and OS (71.9 and 79.1 months, p = 0.69, HR 0.88, 95%CI 0.46-1.68). However, TPR was significantly longer in pts with gBRCAmt than in germline BRCA wild type (gBRCAwt) pts (51.4 and 34.4 months, p = 0.05, HR 0.60, 95% CI 0.36-0.98). Pts with gBRCAmt had poor prognosis after registration of platinum resistance. gBRCAwt pts had longer survival than gBRCAmt after platinum-resistance relapse: 33.7 and 16.9 months respectively (p = 0.05; HR 1.85, 95%CI 1.02-4.08). Conclusions: Our finding provided possible explanation of equal survival of pts with or without BRCA1/2 mutations. Long-term sensitivity to platinum-based chemotherapy allowed pts with gBRCA1/2mt to control the disease for a long period of time. However the non-platinum regimens had less efficacy in pts with gBRCAmt than gBRCAwt after platinum resistance.