bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: Final analysis of AGO DESKTOP III/ENGOT-ov20.
Authors: Du Bois Andreas , Sehouli Jalid , Vergote Ignace , Ferron Gwenael , Reuss Alexander , Meier Werner , Greggi Stefano , Jensen Pernille Tina , Selle Frederic , Guyon Frederic , Pomel Christophe , Lecuru Fabrice , Zang Rongyu , Avall-Lundqvist Elisabeth , Kim Jae-Weon , Ponce Jordi , Raspagliesi Francesco , Ghaem-Maghami Sadaf , Reinthaller Alexander , Harter Philipp 
Published: May 2020

6000 Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (ROC) has been under debate for decades. A recent trial in unselected patients (pts) failed to show an OS benefit. Methods: Pts with ROC and 1st relapse after 6+ months (mos) platinum-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were prospectively randomized to second-line chemotherapy alone vs. cytoreductive surgery followed by the same chemotherapy; platinum combination therapy was recommended. OS was primary endpoint in this superiority trial. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% of pts. 206 pts were allocated to the surgery arm of whom finally 187 (91%) were operated. A complete resection was achieved in 75%; almost 90% in both arms received a platinum-containing second-line chemo. Primary endpoint analysis showed median OS of 53.7 mos with and 46.2 mos without surgery (HR 0.76, 95%CI 0.59-0.97, p=0.03); median PFS was 18.4 and 14 mos (HR: 0.66, 95%CI 0.54-0.82, p<0.001), median time to start of first subsequent therapy (TFST) was 17.9 vs. 13.7 mos in favor of the surgery arm (HR 0.65, 95%CI 0.52-0.81, p<0.001). An analysis according to treatment showed an OS benefit exceeding 12 mos for pts with complete resection (CR) compared to pts without surgery (median 60.7 vs. 46.2 mos); pts with surgery and incomplete resection even did worse (median 28.8 mos). 60 d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparotomies were performed in 3.7% of operated pts. Further grade 3/4 adverse events did not differ significantly between arms. Conclusions: This is the first surgical study demonstrating a meaningful survival benefit in OC: Surgery in pts with first relapse and TFIp of 6+ mos and selected by a positive AGO-Score resulted in a significant increase of OS, PFS and TFST with acceptable morbidity and, therefore, should be offered to suitable pts. The benefit was exclusively seen in pts with CR indicating the importance of both the optimal selection of pts (eg. by AGO score) and of centres with expertise and a high chance of achieving a CR. Clinical trial information: NCT01166737.
Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer.
Authors: Matulonis Ursula A. , Shapira Roni , Santin Alessandro , Lisyanskaya Alla Sergeevna , Pignata Sandro , Vergote Ignace , Raspagliesi Francesco , Sonke Gabe S. , Birrer Michael , Sehouli Jalid , Colombo Nicoletta , González-Martín Antonio , Oaknin Ana , Ottevanger P. B. , Rudaitis Vilius , Wu Haiyan , Keefe Stephen Michael , Stein Karen , Ledermann Jonathan A. 
Published: May 2020

6005 Background: Pembrolizumab (pembro) showed modest clinical activity in patients (pts) with recurrent advanced ovarian cancer (AOC) after a median follow-up of 16.9 mo in an interim analysis of KEYNOTE-100 (NCT02674061). We present the protocol-specified final analysis based on a data cutoff of 18-SEP-2019. Methods: Key eligibility criteria included epithelial ovarian, fallopian tube, or primary peritoneal cancer, confirmed recurrence following front-line platinum-based therapy, ECOG PS 0-1, and provision of a tumor sample for biomarker analysis. Pts in cohort A received ≤2 prior chemotherapy lines for recurrent AOC and had a platinum-free or treatment-free interval (PFI/TFI) of ≥3 to 12 mo. Pts in cohort B received 3-5 prior chemotherapy lines and had a PFI/TFI of ≥3 mo. Pts received pembro 200 mg Q3W for 2 yr or until progression, death, or unacceptable toxicity. Tumor imaging was performed every 9 wk for 1 yr and every 12 wk thereafter. Primary study endpoint was ORR per RECIST v1.1 by independent central review in both cohorts and by tumor PD-L1 expression using the combined positive score (CPS). Secondary endpoints included DOR, DCR (CR+PR+SD≥24 wk), PFS, OS, and safety. Results: 376 pts were enrolled and treated, 285 in cohort A and 91 in cohort B. Median age (range) was 61 (25 to 89) yr, 64.4% had ECOG PS 0, and 75.3% had high grade serous disease. In cohorts A and B, ORR (95% CI) was 8.1% (5.2, 11.9) and 9.9% (4.6, 17.9) in the total population, 6.9% (2.8, 13.8) and 10.2% (3.4, 22.2) in pts with CPS ≥1, and 11.6% (3.9, 25.1) and 18.2% (5.2, 40.3) in pts with CPS ≥10. Median DOR (range) was 8.3 (3.9 to 35.4+) mo in cohort A and 23.6 (3.3+ to 32.8+) mo in cohort B. DCR (95% CI) was 22.1% (17.4, 27.4) and 22.0% (14.0, 31.9). Median PFS was 2.1 mo in both cohorts. In cohorts A and B, median OS was 18.7 mo (17.0, 22.5) and 17.6 mo (13.3, 24.4) in the total population, 20.6 mo (15.2, 23.2) and 20.7 mo (13.6, 27.4) in pts with CPS ≥1, and 21.9 mo (12.9, 26.8) and 24.0 mo (14.5, NR) in pts with CPS ≥10. 73.7% of pts had treatment-related AEs and 20.2% were grades 3-4. There were 2 treatment-related deaths (Stevens-Johnson syndrome and hypoaldosteronism). Immune-mediated AEs occurred in 23.7% of pts. Conclusions: Pembro monotherapy was associated with modest antitumor activity in pts with recurrent AOC. There appeared to be a trend toward increased ORR with higher PD-L1 expression in both cohorts. Responses were durable and typically lasted ≥6 months. Median OS was 18.7 months overall, with a trend toward a longer OS with increasing PD-L1 expression in both cohorts. No new safety signals were identified. Clinical trial information: NCT02674061.
Long-term oncological safety of sentinel lymph node biopsy in early-stage cervical cancer.
Authors: Balaya Vincent , Guani Benedetta , Magaud Laurent , Hélène Bonsang-Kitzis , Ngo Charlotte , Mathevet Patrice , Lecuru Fabrice ,   SENTICOL
Published: May 2020

6006 Background: The goal of this study was to assess disease-free survival (DFS) and disease-specific survival (DSS) in patients with early-stage cervical cancer who underwent bilateral sentinel lymph node (BSLN) biopsy alone versus bilateral pelvic lymphadenectomy (BPL). Methods: An ancillary analysis of two prospective multicentric trials on SLN biopsy for cervical cancer (SENTICOL I and II) was performed. All patients with early stage cervical cancer (IA to IIB FIGO stage), negative SLN after ultrastaging and negative non-SLN after final pathologic examination were included. Risk-factors of recurrency and disease-specific deaths were determined by Cox proportional hazard models. Kaplan-Meier survival curves were compared by applying log-rank test. Results: Between January 2005 and July 2012, 259 patients met the inclusion criteria: 85 patients underwent only bilateral SLN biopsy whereas 174 patients underwent BPL. None had positive SLN at ultrastaging or positive non-SLN at final pathologic examination. Between the both groups, there was no differences in histology, final FIGO stage and type of surgical approach. In the BPL group, patients had more frequently tumor size larger than 20 mm (22.9% vs 10.7%, p = 0.02) and postoperative radiochemotherapy (10.7% vs 1.6%, p = 0.01). The median follow-up was 47 months (4-127). During the follow-up, 21 patients (8.1%) experienced reccurencies, including 4 nodal recurrences (1.9%), and 9 patients (3.5%) died of cervical cancer. The 5-year DFS and the DSS were similar between BSLN and BPL groups, 94.1% vs 97.7%, p = 0.14 and 88.2% vs 93.7%, p = 0.14 respectively. After controlling for final FIGO stage and margin status, BSLN compared to BPL was not associated with DFS (HR = 1.76, 95%CI = [0.69 – 4.53], p = 0.24) and DSS (HR = 2.5, 95%CI = [0.64 – 9.83], p = 0.19). Only final FIGO stage was independent predictor of DSS. Conclusions: SLN biopsy alone is oncologically safe in early-stage cervical cancer. Full lymphadenectomy could be omitted in case of bilateral negative SLN. Worse prognosis was associated with higher FIGO stage disease.
Sequential chemoradiation versus radiation alone or concurrent chemoradiation in adjuvant treatment after radical hysterectomy for stage IB1-IIA2 cervical cancer (STARS Study): A randomized, controlled, open-label, phase III trial.
Authors: Huang He , Feng Yanling , Wan Ting , Zhang Yanna , Cao Xinping , Huang Yongwen , Xiong Ying , Huang Xin , Zheng Min , Li Yanfang , Li Jundong , Chen Guandi , Li Hu , Chen Yile , Ma Liguo , Yang Hongying , Li Li , Yao Shuzhong , Liu Qing , Liu Jihong 
Published: May 2020

6007 Background: There are limited data from previous studies regarding whether the addition of chemotherapy to adjuvant radiation after radical surgery improves outcomes among patients with early-stage cervical cancer and adverse pathological factors. Methods: This was a prospective randomized trial including patients with FIGO 2009 stage IB1-IIA2 cervical cancer and squamous-cell, adenocarcinoma, or adenosquamous carcinoma with at least one adverse factor after radical hysterectomy. Patients were randomized 1:1:1 to receive adjuvant radiation alone, concurrent chemoradiation with weekly cisplatin (30-40 mg/m2), or sequential chemoradiation with cisplatin (60-75 mg/m2) plus paclitaxel (135-175 mg/m2) in 21 day cycles, given 2 cycles before and 2 cycles after radiotherapy respectively. The primary outcome was the rate of disease-free survival at 3 years. Results: A total of 1,048 patients were included in the study (350, radiation alone; 345, concurrent chemoradiation; and 353, sequential chemoradiation). Overall, the median follow-up was 56 months and the median age of patients was 48 years. Most patients (75%) had stage IB1 or IIA1 disease. The three groups were similar with respect to histologic subtypes, the rate of lymphovascular invasion, parametrial, surgical margin and deep stromal involvement, tumor grade, rate of use of minimally invasive surgery, and neoadjuvant chemotherapy, except for lymph-node involvement that was lowest in radiation alone arm. In the intention-to-treat population, sequential chemoradiation was associated with a higher rate of disease-free survival than radiation alone (3-year rate, 90·0% vs. 82·0%; HR 0·52; 95% CI, 0·35 to 0·76) and concurrent chemoradiation (90·0% vs. 85·0%; HR 0·65; 95% CI, 0·44 to 0·96), differences remained after adjustment for lymph-node involvement. Sequential chemoradiation was also associated with a higher rate of overall survival than radiation alone (5-year rate, 92·0% vs. 88·0%; HR for death from cancer, 0·58; 95% CI, 0·35 to 0·95). However, neither disease-free survival nor cancer death risk was different between patients treated with concurrent chemoradiation or radiation alone. Conclusions: In this trial, sequential chemoradiation, rather than concurrent chemoradiation, resulted in a higher disease-free survival and lower risk of cancer death than radiation alone among women with early-stage cervical cancer after radical surgery. Clinical trial information: NCT00806117.
A randomized phase II study of cabozantinib and nivolumab versus nivolumab in recurrent endometrial cancer.
Authors: Lheureux Stephanie , Matei Daniela , Konstantinopoulos Panagiotis A. , Block Matthew Stephen , Jewell Andrea , Gaillard Stephanie , McHale Michael S. , McCourt Carolyn K , Temkin Sarah , Girda Eugenia , Backes Floor Jenniskens , Werner Theresa Louise , Duska Linda R. , Kehoe Siobhan Marie , Wang Lisa , Wildman Rachel , Wang Ben X , Ohashi Pamela S , Wright John Joseph , Fleming Gini F. 
Published: May 2020

6010 Background: The efficacy of treatment for recurrent endometrial cancer (EC) remains limited. Vascular endothelial growth factor and inflammatory chemokines are proangiogenic factors and immune modulators involved in immune suppression. Reprogramming the tumor microenvironment by combining antiangiogenic and immunotherapy (IO) could enhance antitumor responses. Methods: A 2:1 randomized phase 2 trial compared the combination of cabozantinib and nivolumab (Arm A) versus nivolumab (Arm B) in recurrent EC. Primary endpoint was progression free survival (PFS) assessed by RECIST 1.1 (NCT03367741). Women with recurrent measurable EC were eligible. There were no limits on prior therapy, but at least one prior platinum-based chemotherapy was required. Patients (pts) were stratified according to MSI status and assessed by CT every 8 weeks. Cabozantinib was given at 40 mg daily (Arm A) and nivolumab at 240 mg, on D1 and D15 of a 28-day cycle for 4 cycles, followed by 480 mg every 4 weeks (Arms A & B). Pts with carcinosarcoma or prior IO were enrolled in an exploratory cohort and received combination treatment (Arm C). A baseline biopsy was required for all pts. CyTOF analysis was performed on fresh biopsies. Results: 76 evaluable pts were enrolled (Arm A: 36, Arm B: 18, Arm C: 9 carcinosarcoma, and 20 post IO including 7 pts crossed over from Arm B). 55% of pts had received ≥3 prior lines of therapy. Two pts were MSI high in Arm A and none in Arm B. The Kaplan-Meier estimated median PFS was 5.3 (95% CI: 3.5-9.5) months in Arm A and 1.9 (95% CI: 1.6-3.8) months in Arm B, with a log-rank p = 0.07, which met the significance level of 0.1 used for sample size calculation. Objective response rate (ORR) was 25% for Arm A and 16.7% for Arm B; stable disease (SD) was seen in 44.4% vs 11.1%, respectively. Clinical benefit (ORR+SD) was significantly higher in arm A vs B (p < 0.001). In Arm C-carcinosarcoma, one patient had a partial response (11.9 months duration) and four SD. In Arm C-prior IO, six pts responded and eight had SD. The most common related AEs in Arm A were diarrhea (47.2%), elevated liver enzymes (44.4%), fatigue (38.9%), anorexia, hypertension, and nausea (30.6%), mainly grade 1/2. Preliminary CyTOF analysis across treatment arms identified multiple immune subsets for further interrogation including activated CD8+ and CD4+ T cells. Conclusions: Cabozantinib plus nivolumab demonstrates improved PFS compared to nivolumab in heavily pre-treated women with recurrent EC. In-depth CyTOF analysis of the tumor microenvironment to identify predictive immune biomarkers of response is ongoing. Clinical trial information: NCT03367741.
Olaparib treatment in patients (pts) with platinum-sensitive relapsed (PSR) ovarian cancer (OC) by BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: Phase II LIGHT study.
Authors: Cadoo Karen Anne , Simpkins Fiona , Mathews Cara Amanda , Kabil Nashwa , Bennett James , Aghajanian Carol 
Published: May 2020

6013 Background: In Study 19 (NCT00753545), olaparib capsules demonstrated improvement in progression-free survival (PFS) vs placebo in the PSR OC maintenance setting, irrespective of BRCAm status (Ledermann et al. Lancet Oncol 2014). LIGHT is the first prospective study to evaluate olaparib tablet treatment in PSR OC pts by BRCAm and HRD status. Methods: This is an open-label, non-randomized study (NCT02983799) that assessed efficacy and safety of olaparib monotherapy (300 mg BID) in pts with PSR, high-grade serous/endometrioid epithelial OC and ≥1 prior line of platinum chemotherapy. Pts were assigned to one of four cohorts: germline (g) BRCAm; somatic (s) BRCAm; HRD+ve (non-BRCAm); HRD–ve; by Myriad BRACAnalysis CDx and myChoice tests. HRD+ve was a score ≥42. Primary endpoint was objective response rate (ORR). Secondary endpoints included: disease control rate (DCR) and investigator-assessed PFS (RECIST v1.1). Primary analysis was to be ~6 months (mo) after the last pt was enrolled. Results: Data cut off was 8/27/19. Of 271 pts treated (median of 31.7 weeks [2.1–96.0]), 270 had measurable disease at baseline and were included in efficacy analyses (Table). The most common treatment-emergent adverse events (AEs) were nausea (66%) and fatigue (62%).Serious AEs and Grade ≥3 AEs were experienced by 25% and 44% of pts, respectively. AEs leading to olaparib dose interruptions, reductions and discontinuations occurred in 33%, 24% and 4% of pts, respectively. Conclusions: Olaparib treatment demonstrated activity across all cohorts. As observed in the maintenance setting, similar efficacy was seen in the gBRCAm and sBRCAm cohorts. For non-BRCAm pts, longer median PFS and higher ORR were observed in the HRD+ve cohort. Olaparib treatment was well tolerated with no new safety signals identified and a safety profile consistent with that seen in the PSR and first-line settings. Clinical trial information: NCT02983799. [Table: see text]
Characterization of patients (pts) with long-term responses to rucaparib in recurrent ovarian cancer (OC).
Authors: Swisher Elizabeth M. , Kristeleit Rebecca Sophie , Oza Amit M. , Tinker Anna , Ray-Coquard Isabelle Laure , Oaknin Ana , Coleman Robert L. , Burris III Howard A. , Aghajanian Carol , O'Malley David M. , Leary Alexandra , Welch Stephen , Provencher Diane M. , Shapiro Geoffrey , Chen Lee-may , Shapira-Frommer Ronnie , Goble Sandra , Maloney Lara , Lin Kevin K. , McNeish Iain A. 
Published: May 2020

6015 Background: Pts who derive durable benefit from PARP inhibitor treatment may provide insights into improving outcomes. Here we describe long-term responders from Study 10 (NCT01482715) and ARIEL2 (NCT01891344), studies of the PARP inhibitor rucaparib for the treatment of high-grade recurrent OC. Methods: This analysis included pts enrolled in Study 10 (Part 2A: BRCA1 or BRCA2 [ BRCA]-mutant OC, platinum sensitive, 2–4 prior chemotherapies; Part 2B: any platinum status, 3–4 prior chemotherapies) and ARIEL2 (Part 1: BRCA-mutant or wild-type OC, platinum sensitive; Part 2: any platinum status, 3–4 prior chemotherapies). Final results from Study 10 (n = 54) and ARIEL2 (n = 491) were pooled. Long-term responders were defined as pts with duration of response (DOR) > 1 y, and short-term responders as pts with DOR ≤ 20 weeks; responses were evaluated using RECIST. Targeted next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. BRCA1 methylation was quantified by digital droplet PCR. Results: Overall, 25% (138/545) of enrolled pts were responders. Of these, 29% (40/138) had long-term responses, including 16/138 (12%) with DOR > 2 y; 21% (29/138) were short-term responders. Both groups received a median of 3 prior anticancer therapies. Among patients with BRCA mutations, BRCA homozygous deletion or rearrangement was detected in 15% (4/27) of long-term responders vs 0% (0/15) of short-term responders. In an expanded analysis of the 95 pts with BRCA mutations and confirmed response, pts with BRCA homozygous deletion or rearrangement had significantly longer DOR than pts with other mutation types (median 3.5 vs 0.6 y; HR = 0.30; p = 0.024). There was no apparent difference in BRCA gene or mutation location for long- vs short-term responders. Ten of the 13 long-term responders with BRCA wild-type OC had high genome-wide LOH (≥16% LOH), a genomic scar indicative of homologous recombination deficiency, including OC associated with BRCA1 hypermethylation (n = 2) and RAD51C/D mutations (n = 2). Conclusions: Long-term responders to rucaparib include OC with BRCA mutation, particularly homozygous deletion or rearrangements, which would not be susceptible to somatic reversion mutations, as well as BRCA1 hypermethylation, and RAD51C/D mutations. Clinical trial information: NCT01482715; NCT01891344.
Beyond Sedlis: A novel, histology-based nomogram for predicting recurrence risk and need for adjuvant radiation in cervical cancer—A NRG/GOG ancillary analysis.
Authors: Levinson Kimberly , Beavis Anna , Purdy Christopher , Rositch Anne , Viswanathan Akila , Wolfson Aaron Howard , Kelly Michael Greg , Tewari Krishnansu , McNally Leah , Guntupalli Saketh R , Ragab Omar , Lee Yi-Chun , Miller David S. , Huh Warner King , Wilkinson Kelly Jeanes , Spirtos Nicola M. , Van Le Linda , Casablanca Yovanni , Holman Laura L. , Nickles Fader Amanda 
Published: May 2020

6019 Background: In GOG 49, factors associated with a 3-year, 30% recurrence risk in squamous cell carcinoma of the cervix (SCC) after surgery alone were defined. These "intermediate" risk factors [tumor size (TS), depth of tumor invasion (DOI), and lymphvascular space invasion (LVSI)] were then studied in GOG 92, which demonstrated the utility of treating patients (pts) with ≥2 intermediate risk factors with adjuvant radiation (RT), Sedlis Criteria. However, pts with < 30% recurrence risk were not eligible and few pts with adenocarcinoma (AC) were included. Our study purpose was 1) to evaluate recurrence risk factors for AC vs SCC, and 2) to define contemporary nomograms for adjuvant treatment in pts with both histologies. Methods: We performed an ancillary analysis of GOG 49, 92, and 141, and included Stage I pts who received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were created separately for AC and SCC to evaluate independent risk factors for recurrence. Model accuracy was tested with ROC curves. Prognostic nomograms were generated for 2-year recurrence risk for AC and SCC. Results: We identified 715 with SCC and 105 pts with AC; 142 with SCC (19.9%) and 18 with AC 17.1%) recurred. For SCC, factors associated independently with recurrence were: LVSI [HR 1.58 (CI 1.12-2.22)], DOI [middle 1/3, HR 4.31 (CI 1.81-10.26); deep 1/3, HR 7.05 (CI 2.99-16.64)] and TS [≥4cm HR 2.67 (CI 1.67-4.29)]. In contrast, for AC, only TS ≥4cm was independently associated with recurrence [HR 4.69 (CI 1.25-17.63)]. At 3 years, ROC curves for these models predicted recurrence with 76% and 75% accuracy for SCC and AC, respectively. Utilizing a nomogram generated from these models, for SCC, DOI had the greatest impact on recurrence, with mid 1/3 conferring an 18% risk and deep 1/3 a 32% risk, while LVSI and TS increased risk by 4-10%, respectively. In contrast, for AC, TS alone had the greatest impact on recurrence risk with TS 2-4cm conferring a 20% risk over 3 years and TS ≥4cm, a 28% risk. Conclusions: Our nomogram differs from the Sedlis Criteria in demonstrating that single, as well as a combination of risk factors predict substantial 3-year recurrence rates in Stage I cervical cancer. Furthermore, these factors differ by AC and SCC subtypes, suggesting that distinct, histology-specific nomograms may have greater utility in identifying pts who will most benefit from adjuvant therapy.