bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical modeling of a novel clinical trial design using neoadjuvant therapy (NAT) to personalize therapy in patients (pts) with triple-negative breast cancer (TNBC).
Authors: Moulder Stacy L. , Bassett Roland L. , White Jason B , Huo Lei , Damodaran Senthil , Lim Bora , Ueno Naoto T. , Murthy Rashmi Krishna , Arun Banu , Valero Vicente , Tripathy Debu , Hortobagyi Gabriel N. , Litton Jennifer Keating , Thompson Alastair Mark , Mittendorf Elizabeth A. , Ravenberg Elizabeth , Santiago Lumarie , Adrada Beatriz E , Candelaria Rosalind P , Rauch Gaiane M
Published: May 2020

595

Background: 40-50% of pts with TNBC develop pathologic complete response (pCR) with adriamycin/cyclophosphamide (AC)àtaxane (T) NAT; thus, most pts treated in randomized trials (RCTs) adding experimental drugs (ED) to standard NAT do not benefit from trial participation. A personalized trial design that enriches for non-pCR to standard NAT would diminish toxicity from ED in pts who do not need them and enrich ED in high-risk pts that are most likely to benefit. Methods: ARTEMIS (NCT02276443) is a non-randomized trial to study personalization of NAT in TNBC. Tumor biopsies were performed pre-NAT and volumetric change by ultrasound (VCU) after 4 cycles of AC (or upon clinical progression) assessed response. Pts with sensitive TNBC (VCU >=70% after AC) had T as the second phase of NAT. Pts with <70% VCU were offered phase II trials. pCR was assessed at surgical resection. 273 pts had available pCR status and 222 had complete data to generate a model predictive of response using multivariate logistic regression with common clinical factors. Data was randomly divided into training (n=111) and validation (n=111) sets. Results: 85 pts (38%) had pCR and VCU after AC x 4 was the strongest predictor of pCR. Other factors significant on multivariate analysis and included in the model were T stage (T1-4), stromal TIL, Ki67 and PD-L1. When applied to the validation data set, the accuracy of this model for predicting pCR was 76.6%, sensitivity 78.6% and specificity 75.4%. The PPV was 66.0% and the NPV was 85.2% with a ROC curve AUC of 82.4%. Using these data, ED exposure (table) was estimated for the ARTEMIS study design vs a 1:1 or a 2:1 RCT design (with an estimated pCR in control arm=40%), with a demonstrated benefit for personalization. Conclusions: This modeling indicates that personalization of NAT trials has the potential to enrich ED exposure for non-responsive disease as well as diminish ED exposure in pts likely to achieve pCR with standard NAT. Improved prediction of pCR would further enhance personalized trial design. Clinical trial information: NCT02276443 . [Table: see text]
A randomized phase III trial of secondary cytoreductive surgery in later recurrent ovarian cancer: SOC1/SGOG-OV2.
Authors: Zang Rongyu , Zhu Jianqing , Shi Tingyan , Liu Jihong , Tu Dongsheng , Yin Sheng , Jiang Rong , Zhang Ping , Jia Huixun , Luan Yuting , Zhang Yuqin , Chen Xiaojun , Huang Xiao , Tian Wenjuan , Gao Wen , Feng Yanling , Yang Huijuan , Cheng Xi , Cai Yulang ,   Shanghai Gynecologic Oncology Group
Published: May 2020

6001

Background: In China, secondary cytoreductive surgery (SCR) has been standard of care in some high volume cancer centers for ovarian cancer (OC) and most pts prefer surgery over the past two decades. Although GOG213 showed no OS benefit, the debate on selected pts and the conflict with certain local clinical care is still open. Methods: Pts with 1st relapsed OC after 6m+ platinum-free interval (PFI) were eligible if predicted to be a potential R0 by iMODEL score combined with PET-CT image and were randomized to SCR followed by chemotherapy (surgery arm) vs 2nd line chemotherapy alone (no surgery arm). Co-primary endpoint is PFS and OS. The 2nd endpoint is accumulated treatment-free survival (TFSa), which was defined as the overall survival time minus the time of surgery and chemotherapy after randomization. We report analysis of PFS and interim analysis of TFSa. Results: 357 pts were randomized 2012-2019. 6.3% of 175 pts were operated in no surgery arm and cross-over rate was 36.9% in 2nd+ relapsed pts of no surgery arm. 97% and 96% of pts received a platinum-containing 2nd line therapy. Complete resection (R0) rate was 76.7% in overall and 61.1% in pts with iMODEL> 4.7. 60 d mortality rates were 0 % in both surgery and no surgery arm. Postoperative 30 d complication rate with ≥ grade 3 was 5.2%. The median follow-up was 36.0 m. Median PFS was 17.4 m and 11.9 m in surgery and no surgery arm, respectively (HR 0.58, 95% CI 0.45-0.74, p < 0.001). Median time to start of first subsequent therapy (TFST) was 18.1 m vs 13.6 m in favor of the surgery arm (HR 0.59, 95%CI 0.46-0.76). 1.1% and 10.1% of pts underwent Bevacizumab and PARPi maintenance in the 2nd line therapy. The OS and TFSa was immatured. The median TFSa was unreached and 39.5 m in R0 subgroup and no surgery arm, respectively (HR0.59, 95%CI 0.38-0.91). TFSa in surgery arm showed a better long-term survival than that in no surgery group (restricted mean survival time from 60 to 72m: 6.2m vs 4.2m). Conclusions: SCR in selected pts resulted in a dramatically significant extension of PFS. The interim analysis of TFSa indicate that SCR might contribute to long-term survival.
Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation.
Authors: Poveda Andres , Floquet Anne , Ledermann Jonathan A. , Asher Rebecca , Penson Richard T. , Oza Amit M. , Korach Jacob , Huzarski Tomasz , Pignata Sandro , Friedlander Michael , Baldoni Alessandra , Park-Simon Tjoung-Won , Sonke Gabe S. , Lisyanskaya Alla Sergeevna , Kim Jae-Hoon , Filho Elias Abdo , Vergote Ignace , Rowe Phil , Pujade-Lauraine Eric
Published: May 2020

6002

Background: SOLO2 (ENGOT ov-21; NCT01874353) showed that maintenance therapy with the PARP inhibitor olaparib in pts with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation (BRCAm) led to a statistically significant improvement in median progression-free survival (PFS) of 13.6 months vs placebo (hazard ratio [HR] 0.30). Time to second progression or death significantly improved (Pujade-Lauraine et al Lancet Oncol 2017) and a quality-adjusted PFS benefit was seen (Friedlander et al Lancet Oncol 2018) with maintenance olaparib vs placebo. We report the preplanned final OS analysis for SOLO2. Methods: Pts with PSROC and a BRCAm who had received ≥2 lines of treatment and were in response to their most recent platinum-based chemotherapy received maintenance olaparib (300 mg bid tablets) or placebo. Pts were stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6–12 months vs >12 months). OS was a secondary endpoint. The only preplanned OS sensitivity analysis was an OS analysis in the Myriad germline BRCAm subset (Myriad BRAC Analysis test). Results: At final data cut-off (Feb 3, 2020), median follow-up was 65 months in both treatment arms. A long-term treatment benefit was seen with olaparib vs placebo with an OS HR of 0.74 (95% confidence interval [CI] 0.54–1.00) in the full analysis set (FAS; unadjusted for crossover; 38.4% of placebo pts crossed over to a PARP inhibitor) (Table). At 5 years: by Kaplan-Meier estimates, 28.3% of pts in the olaparib arm vs 12.8% of pts in the placebo arm were alive and had still not received subsequent treatment; 42.1% of olaparib pts vs 33.2% of placebo pts were alive. The long-term tolerability profile of olaparib was generally consistent with that reported previously. Conclusions: In the final analysis of SOLO2, maintenance olaparib provided an unprecedented improvement of 12.9 months in median OS vs placebo. This is the first study with olaparib tablets, and the first since Study 19 (NCT00753545), to provide long-term follow-up and final OS data in pts with PSROC and a BRCAm. Clinical trial information: NCT01874353. [Table: see text]
A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer.
Authors: Liu Joyce F. , Brady Mark F. , Matulonis Ursula A. , Miller Austin , Kohn Elise C. , Swisher Elizabeth M. , Tew William P. , Cloven Noelle Gillette , Muller Carolyn , Bender David , Moore Richard G. , Michelin David Paul , Waggoner Steven E. , Geller Melissa Ann , Fujiwara Keiichi , D'Andre Stacy D. , Carney Michael , Secord Angeles Alvarez , Moxley Katherine M. , Bookman Michael A.
Published: May 2020

6003

Background: Combination cediranib (C) and olaparib (O) improved progression-free survival (PFS) in patients (pts) with relapsed platinum (plat)-sensitive high-grade ovarian cancer (ovca) compared to O alone in a Phase 2 trial (NCT01116648). We conducted this randomized, open-label Phase 3 trial (NCT02446600) to assess whether combination C+O, or O alone, was superior to standard of care (SOC) plat-based therapy in relapsed plat-sensitive ovca. Methods: Eligible pts had recurrent plat-sensitive [ > 6-month plat-free interval (PFI)] high-grade serous or endometrioid, or BRCA-related, ovca. One prior non-plat therapy and unlimited prior plat-therapies were allowed; prior anti-angiogenics in the recurrent setting or prior PARP inhibitor were exclusions. Pts were randomized 1:1:1 to SOC (carboplatin/paclitaxel; carboplatin/gemcitabine; or carboplatin/liposomal doxorubicin), O (300mg twice daily), or C+O (C 30mg daily + O 200mg twice daily). Randomization was stratified by g BRCA status, PFI (6-12 vs > 12 months), and prior anti-angiogenic therapy. Target sample size was 549 pts; primary analysis occurred 2 years after the last pt enrolled. The primary endpoint was PFS. Type 1 error = 0.025 was controlled by a gatekeeping hierarchy that assessed C+O vs SOC, then O alone vs SOC, and finally C+O vs O. All maintenance therapy was prohibited. Results: Between 4FEB2016 and 13NOV2017, 565 pts enrolled (187 SOC, 189 O, 189 C+O), and 528 pts initiated treatment (166 SOC, 183 O, 179 C+O). 23.7% of patients had g BRCAmut. Median follow-up was 29.1 months. 53 pts on SOC initiated non-protocol therapy (predominantly PARP inhibitor maintenance) before disease progression. The hazard ratio (HR) for PFS was 0.856 (95% CI 0.66-1.11, p = 0.08, 1-tail) between C+O and SOC and 1.20 (95% CI 0.93-1.54) between O and SOC, with median PFS of 10.3, 8.2, and 10.4 months for SOC, O, and C+O, respectively. Response rates were 71.3% (SOC), 52.4% (O), and 69.4% (C+O). In gBRCA pts, HR for PFS was 0.55 (95% CI 0.73-1.30) for C+O vs SOC, and 0.63 (95% CI 0.37-1.07) for O vs SOC. In non-g BRCA pts, HR for these comparisons was 0.97 (95% CI 0.73-1.30) and 1.41 (1.07-1.86). No OS differences between arms were observed at 44% events. Pts receiving C+O (vs SOC) had more frequent Grade 3 or higher gastrointestinal (30.1% vs 8.4%), hypertension (31.7% vs 1.8%), and fatigue events (17.5% vs 1.8%). Conclusion: C+O demonstrated similar activity to SOC in relapsed plat-sensitive ovca but did not meet the primary endpoint of improved PFS. Clinical trial information: NCT02446600.
Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer.
Authors: Gilbert Lucy , Oaknin Ana , Matulonis Ursula A. , Mantia-Smaldone Gina , Lim Peter C , Castro Cesar Martin , Provencher Diane M. , Memarzadeh Sanaz , Wang Jiuzhou , Esteves Brooke , Zweidler-McKay Patrick A , Moore Kathleen N. , O'Malley David M.
Published: May 2020

6004

Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. As part of the Phase 1b FORWARD II trial (NCT02606305), the combination of MIRV with bevacizumab (BEV) was evaluated in pts with FRα-positive (medium/high expression; ≥ 50%/ ≥75% of cells with PS2+ staining intensity), platinum agnostic ovarian cancer, defined as pts with either platinum resistant (PR) (recurrence within 6 months after last platinum dose) or platinum sensitive (PS) responded to the last platinum therapy received before study entry and did not progress within 6 months) disease for whom a non-platinum based doublet would be appropriate. Methods: Pts received MIRV (6 mg/kg; adjusted ideal body weight) and BEV (15 mg/kg) on Day 1 of a 21-day cycle. Responses were assessed by investigator according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.03. Results: In total, 60 pts received the combination, with a median age of 60 years, and a median of 2 prior lines of systemic therapy (range 1-4). Platinum status was determined for 56 pts, with 30 (50%) considered PR and 26 (43%) considered PS; platinum status data were incomplete for 4 pts. The most common treatment related AEs (percent all grade/grade 3+) were diarrhea (65/2), blurred vision (62/3), nausea (55/0), and fatigue (55/5). The most common treatment related grade 3+ AEs were hypertension and neutropenia, (10% each); all other grade 3+ events occurred in ≤ 5% of pts. Serious AEs regardless of relationship to study drug were infrequent, with the most common events being small intestinal obstruction in 3 pts, 5% (grade 3) and pneumonitis in 3 pts, 5% (2 grade 1; 1 grade 2). Objective responses were seen in 26 pts for a confirmed overall response rate (ORR) of 43% (95% CI, 31, 57). In a subset analysis of pts with high FRα expressing tumors (n = 33), the confirmed ORR was 61% (95% CI, 42, 77), with an ORR of at least 50% in each of the PR and PS subsets. With a median follow-up of 5.5 months, the duration of response and progression free survival data are immature. Conclusions: The combination of MIRV with BEV demonstrates an encouraging ORR with a favorable tolerability profile in pts with recurrent ovarian cancer regardless of platinum sensitivity, particularly in those with tumors that express high levels of FRα. Clinical trial information: NCT02606305.
Final survival analysis of NSGO-AVANOVA2/ENGOT-OV24: Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer—A randomized controlled chemotherapy-free study.
Authors: Mirza Mansoor Raza , Nyvang Gitte-Betina , Lund Bente , Christensen Rene dePont , Werner Theresa Louise , Malander Susanne , Bjørge Line , Birrer Michael J. , Anttila Maarit , Lindahl Gabriel , Hietanen Sakari , Dimoula Maria , Peen Ulla , Madsen Kristine , Knudsen Anja , Staff Synnove , Buchner Vinum Nicole , Kjeldsen Maj Kamille , Avall-Lundqvist Elisabeth , Maenpaa Johanna Unelma
Published: May 2020

6012

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

6014

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

6018

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

6023

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

6031

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

6035

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

6037

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

6043

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

6049

Background: Autophagy is a mechanism of resistance to platinum chemotherapy. Itraconazole (Itr), an antifungal agent, can alter cholesterol-trafficking, leading to accumulation of cholesterol in endosomes/lysosomes and resulting in cancer cell death. Itr is also involved in regulation of angiogenesis, mTOR and Hedgehog pathways. In preclinical studies the Itr effect can be enhanced by combining it with the autophagy inhibitor hydroxychloroquine (H). Drug repurposing studies with Itr have shown a signal of activity in prostate, lung and basal cell carcinoma. Methods: A rolling-6 phase I design was used to enroll patients (pts) with platinum-resistant/refractory EOC. Pts received Itr 300mg twice daily (BID) with H as per dose escalation schedule (range 200mg BID- 600mg BID), continuously in a 28-day cycle. Primary objective was establishment of MTD; secondary objective was objective response rate, progression free survival (PFS). Pre- and on-treatment biopsies were mandatory to evaluate exploratory objectives assessing effect on apoptosis/proliferation, angiogenesis, cholesterol metabolism and mechanism of cytotoxicity. RNAseq and IHC was performed in the sequential biopsies. Results: 11 pts were enrolled, 9 evaluable for efficacy. Histology was high 91% and low-grade serous 9%. Median lines of prior therapy was 7. RP2D was Itr 300mg BID and H 600mg BID. 1 DLT was seen in dose-level 2 was grade 3 hypertension. Other grade ≥3 related toxicity were grade 3 hypokalemia and grade 4 QTc prolongation (1 pt, dose-level 3). No objective responses were observed and 1 pt had stable disease. Median PFS was 1.6 months (1-1.7). Pre- and on-treatment biopsy was available for 10 pts. Increase in autophagy related protein, LC3, P62 and lysosomal marker, LAMP1, expression by IHC was identified in 3 pts. RNAseq revealed no differences between pre and on treatment samples in cholesterol homeostasis, angiogenesis, lysosomal-autophagy, PI3K-mTOR pathways. Conclusions: The combination of Itr and H was feasible but did not show antitumour activity in this heavily pre-treated platinum resistant EOC population. Increase of IHC expression in autophagy related proteins was detected in 30% of pts but did not correlate with patient benefit. Clinical trial information: NCT03081702. [Table: see text]
Laboratory cross-comparison of tumor BRCA1/2 analysis in a multicenter epithelial ovarian cancer series: The BORNEO GEICO60-0 study.
Authors: Romero Ignacio , Oaknin Ana , Garcia-Casado Zaida , Marquez Raul , Yubero Esteban Alfonso , Gallego Alejandro , Sanchez Ana Beatriz , Perez Segura Cristina , Alarcon Jesus , Barretina-Ginesta Maria Pilar , Palacio Vázquez Isabel , Farinas-Madrid Lorena , Cueva Juan Fernando , Matito Judit , Poveda Andres , Lopez Guerrero Jose Antonio , Vivancos Ana
Published: May 2020

6055

Background: Epithelial ovarian cancer (EOC) identification of BRCA1 and BRCA2 mutations is usually carried out in germline, representing around 17% in high grade serous ovarian cancer (HGSOC) and further 5-7% are only identified in the tumor (somatic). The aim of this study was to identify in EOC tumor BRCA mutation frequency and inter-laboratory reproducibility using different Next-generation Sequencing (NGS) approaches. Methods: In an ambispective study design, a population of unselected consecutive non mucinous EOC was clinically annotated and Formalin-Fixed Paraffin-Embedded (FFPE) tumor BRCA1/2 mutation analysis was undertaken in two laboratories (Lab-1 and Lab-2) simultaneously. Both laboratories used their own validated NGS panels; variant allele frequency threshold was 5% for single nucleotide polymorphism and 10% for indels. Each laboratory classified variants into three categories based on ACMG criteria: non-mutated (class 1-2), Variants of Uncertain Significance (VUS: class 3) and likely pathogenic/pathogenic (class 4-5). Germline BRCA analysis was available according to local clinical practice or centralized in Lab-1 if histology was low grade. Results: Ninety FFPE samples were received, 8 had insufficient material to be analyzed in both laboratories and 6 cases were discarded due to tumor cellularity below 20% leaving 76 cases to be sequenced. The population had a median age of 58 (25-84) years, 87% (66/76) of HGSOC histology and 70% of advanced stages (III-IVB: 53) and 14.5% (11) germline BRCA mutations (3 with not available results). Lab-1 identified 17 class 4-5 mutations, 11 correspond to germline, 4 (5.3%) are just somatic and 2 have germline results not available yet. Lab-2 had one not valuable analysis and identified 16 class 4-5 mutations, 10 corresponding to germline and 4 somatic variants. Percentage of concordance between both laboratories was 96% (kappa coefficient 0.883; p value < 0.0001). Three discordant out of 18 class 4-5 mutations included 2 undetected (VAF of 14.9% and 60.3% respectively) and one class 4 in Lab-2 classified as VUS in Lab-1 due to different interpretation criteria. Conclusions: The global BRCA mutation frequency in our series was 22.3% for Lab-1 and 21.0% for Lab-2. Concordance between tumor BRCA mutation analysis was high (96%). Nevertheless, further effort is required on harmonizing the technical and analytical aspects in tumor mutational analysis.
Laparoscopy compared with laparotomy for comprehensive surgical staging of early ovarian cancer: Results of a retrospective multicenter case-control study.
Authors: Radosa Julia Caroline , Radosa Marc P , Mertke Pauline , Hugo Marie-Luise , Radosa Christoph Georg , Brucker Sara , Taran Florin Andrei , Kommoss Stefan , Ulrich Uwe Andreas , Hackethal Andreas , Tuschy Benjamin , Suetterlin Marc , Deeken Martin , Solomayer Erich-Franz
Published: May 2020

6067

Background: The objective of this study was to compare laparoscopy and laparotomy for comprehensive surgical staging of early ovarian cancer in terms of efficacy and oncologic safety. Methods: Patients who had laparoscopic staging for early stage (I/II) ovarian cancer between 01/2000 and 10/2018 at the participating sites (Gynecologic comprehensive cancer centers with respective expertise in minimal invasive surgery) were included in this retrospective case-control study. The control group consisted of all patients treated via laparotomy during the study period. Clinical data were abstracted from medical record and recent follow up information were obtained. Comparisons were made between patients regarding surgical parameters and oncologic outcome and multivariate models were used to identify factors independently associated with disease recurrence. Results: Among 313 patients, staging was performed via laparoscopy in 208 (66 %) patients and via laparotomy in 105 (34 %) patients. Patients staged laparoscopically were younger (median 52 (15-86) vs. 59 (17-92) vears, p≤0.01) and had a lower BMI (24.4 (16.5-46.8) vs. 26 (15.5-53.8), p≤0.01). Regarding surgical parameters, duration of surgery was longer (291 (159-778) vs. 277 (159-690) minutes, p≤0.01), postoperative hospitalization was shorter (7 (0-27) vs. 9 (0-92) days, p≤0.01) and postoperative complications were lower in the laparoscopy group. On univariate analysis there were no differences in rates of tumor stage according to FIGO, intraoperative rupture of ovarian cysts (14 % vs. 13 %, p=0.87), number of lymph nodes removed (24 (0-89) vs. 22 (0-96), p=0.81) or any recurrence of disease (14 % vs. 16 %, p=0.52). At a median follow-up of 46 months (0-227), there were no differences in DFS and OS by surgical technique (5yr DFS 82 % (SE 0.04) vs. 83 % (SE 0.05), p=0.43; OS 91 % (SE 0.03) vs. 87 % (SE 0.04), p=0.87). On multivariate analysis route of surgery was not associated with an increased risk of recurrence. Conclusions: According to this preliminary analysis, laparoscopic surgical staging in patients with early ovarian cancer seems to be adequate and safe, but a longer follow-up and prospective data are needed to enhance evidence on oncologic outcomes.
Efficacy and safety of olaparib according to age in BRCA-1/2 mutated patients with recurrent platinum-sensitive ovarian cancer: Analysis of the phase III SOLO2 (AGO-OVAR 2.23/ENGOT-Ov21) study.
Authors: Trillsch Fabian , Mahner Sven , Ataseven Beyhan , Asher Rebecca , Dubot Coraline , Clamp Andrew R. , Penson Richard T. , Oza Amit M. , Amit Amnon , Huzarski Tomasz , Casado Antonio , Scambia Giovanni , Friedlander Michael , Colombo Nicoletta , Fujiwara Keiichi , Sonke Gabe S. , denys Hannelore , Lowe Elizabeth S. , Pujade-Lauraine Eric
Published: May 2020

6068

Background: Adding olaparib as maintenance treatment to BRCA-1/2 mutated patients (pts) with recurrent platinum-sensitive ovarian cancer (PSOC) has significantly improved progression-free survival (PFS) as well as patient-centered endpoints. As BRCA mutated pts tend to be younger, specific information on efficacy and safety of olaparib for elderly pts is of special interest. Methods: 295 pts from the SOLO2 trial that randomly assigned to olaparib or placebo were categorized according to age cutoff at 65 years. The efficacy and tolerability of olaparib relative to placebo within in each age group was assessed based on PFS and toxicity outcomes. Quality of life (QoL) was assessed using EQ-5D-5L descriptive system score and FACT Trial Outcome Index (TOI) and evaluated using generalized estimating equations (GEE) and time without significant symptoms of toxicity (TWiST) analysis. Results: Baseline characteristics were similar in pts ≥65 years (N=62; 21%) compared to pts <65 years (N=233; 79%), except for more BRCA2 mutations in elderly pts (39% vs. 23%). There was no significant difference in the magnitude of PFS benefit from olaparib in elderly as compared with younger pts (interaction P=0.33). The PFS adjusted hazard ratio (HR) of olaparib vs. placebo arms were respectively HR≥65 0.43 (95%-confidence interval [CI] 0.24-0.81) and HR<65 0.31 (95%-CI 0.22-0.43). Elderly and younger pts also had comparable safety profiles with no significant differences in median time on olaparib treatment (≥65: 27 vs. <65: 33 months), percentage of pts experiencing at least one grade >2 adverse event with olaparib (≥65: 73% vs. <65: 79%), or requiring at least one dose interruption or dose reduction (≥65: 77.5 vs. <65: 77.6%). No differences were found with regards to QoL scores. Quality adjusted TWiST analysis showed only non-significant differences in duration of good QoL under olaparib (≥65: 8.02 vs. <65: 9.24 months, P=0.48). Conclusions: In this large cohort of BRCA mutated PSOC pts treated with a PARP inhibitor within a phase III trial, no significant differences were detected in terms of efficacy, safety, and QoL with olaparib treatment for pts ≥65 years compared to younger pts. This information supports the use of PARP inhibitors as maintenance therapy for PSOC pts irrespective of age. Clinical trial information: NCT01874353.