bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20.
Authors: Du Bois Andreas , Vergote Ignace , Ferron Gwenael , Reuss Alexander , Meier Werner , Greggi Stefano , Jensen Pernille Tina , Selle Frédéric , 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 , Sehouli Jalid
Published: September 2018

5501

Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (OC) has not been defined by level-1 evidence. Methods: Pts with OC and 1st relapse after 6+ mos platin-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 randomized to 2nd-line chemotherapy alone vs cytoreductive surgery followed by chemo. Chemo regimens were selected according to the institutional standard. We report here results of the predetermined interim analysis. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% and 76% pts in both arms. 8.9% of 203 pts were operated despite of randomization to the no-surgery arm, whereas 6.9% of 204 pts in the surgery arm did not undergo operation. Complete resection was achieved in 67% of pts; 87% and 88% received a platinum-containing 2nd-line therapy. Median PFS was 14 mos without and 19.6 mos with surgery (HR: 0.66, 95%CI 0.52-0.83, p<0.001). Median time to start of first subsequent therapy (TFST) was 21 vs 13.9 mos in favor of the surgery arm (HR 0.61, 95%CI 0.48-0.77, p=p<0.001). PFS-2 between 1st and 2nd relapse equaled or even exceeded PFS-1 before 1strelapse in 26% after surgery and only 16% without-surgery. Analysis of the primary endpoint OS is kept blinded due to immaturity and will be evaluated after extended follow-up (the observed pooled unblinded 2-YSR was 83% instead of the initially in the protocol assumed 55-66%). 60d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparatomies were performed in 7 pts (3.5%) in the surgery arm.With the exception of myelosuppression which occurred more frequently in the no-surgery arm no further significant differences were observed with respect to grade 3+ acute adverse events. Conclusions: Surgery in pts with 1st relapse of OC after a TFIp of 6+ mos and selected by a positive AGO-Score resulted in a clinically meaningful increase of PFS and TFST with acceptable treatment burden. Until final OS data will definitively define the role of secondary cytoreductive surgery it should at least be considered as valuable option in pts with a positive AGO-Score. Clinical trial information: NCT01166737.
A novel genomic rearrangement signature to predict poor survival among women with high grade serous ovarian cancer.
Authors: Hillman Robert Tyler , Lu Karen H. , Futreal Phillip Andrew
Published: September 2018

5509

Background: Resistance to platinum-based chemotherapy is a major cause of disease progression and mortality among women with high grade serous ovarian cancer (HGSOC). It is not known whether patterns of genomic rearrangement are predictive of clinical outcome in HGSOC. Methods: This was a retrospective cohort analysis of whole genome sequences from 80 HGSOC tumors. Genomic rearrangements were identified and categorized by size and type (inversion, duplication, deletion, or translocation). Non-negative matrix factorization was then used to extract rearrangement signatures. Wilcoxon rank-sum test was used for comparison of continuous variables. Univariate and multivariate analyses were performed using Cox proportional hazards models. Results: A rearrangement signature characterized by 10 kilobase to 10 megabase duplications and deletions was identified. The median overall survival (OS) was 22.5 months (95% CI, 20.1 to 33.5 months) in the Sig-High group versus 46.0 months (95% CI, 27.7 to 80.6 months) in the Sig-Low group (hazard ratio, 2.13; 95% CI, 1.27 to 3.55; P=0.004). Exploration of clinical variables showed a significantly higher median signature contribution in platinum-resistant disease than platinum-sensitive disease (20.0% vs 9.1%, p=0.007). Multivariate analysis showed a hazard ratio for death of 2.1 associated with the Sig-High group (Table). Validation of this signature was performed using HGSOC copy number data from the Cancer Genome Atlas. In this cohort, the median OS was 38.8 months (95% CI, 36.7 to 44.5 months) in the Sig-High group versus 49.5 months (95% CI, 45.2 to 56.3 months) in the Sig-Low group (hazard ratio, 1.44; 95% CI, 1.14 to 1.82; P=0.024). Conclusions: A genomic rearrangement signature is associated with chemoresistance and poor prognosis in HGSOC. Prediction of poor survival outcomes could allow early identification of women who may be candidates for clinical trials. [Table: see text]
Pembrolizumab for previously treated advanced cervical squamous cell cancer: Preliminary results from the phase 2 KEYNOTE-158 study.
Authors: Schellens Jan H.M. , Marabelle Aurelien , Zeigenfuss Susan , Ding Jie , Pruitt Scott Knowles , Chung Hyun Cheol
Published: September 2018

5514

Background: In the phase 1b KEYNOTE-028 study, pembrolizumab showed promising activity as monotherapy in patients with advanced cervical cancers that expressed PD-L1. As part of the ongoing, multicohort, phase 2 KEYNOTE-158 study (NCT02628067), we assessed the antitumor activity of pembrolizumab in a larger cohort of patients with previously treated, advanced cervical squamous cell cancer who were enrolled without regard to tumor PD-L1 or other tumor biomarker expression. Methods: Key eligibility criteria for this cohort included age ≥18 years, histologically or cytologically confirmed advanced cervical squamous cell cancer, progression on or intolerance to ≥1 line of standard therapy, ECOG PS 0 or 1, and provision of a tumor sample for biomarker analysis. Patients received pembrolizumab 200 mg Q3W for 2 years or until progression, intolerable toxicity, or physician or patient decision. Clinically stable patients with progression could remain on treatment until progression was confirmed on subsequent assessment. Tumor imaging was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. PD-L1 positivity was evaluated retrospectively by IHC and was defined as a combined positive score ≥1%. Primary end point was ORR assessed per RECIST v1.1 by independent central radiologic review. Planned enrollment is ~100 patients. This efficacy analysis includes patients who had ≥18 weeks of follow-up as of Oct 19, 2016. Results: Among the first 47 patients with advanced cervical cancer who enrolled, ORR was 17% (95% CI, 8%-31%), with 3 confirmed and 5 unconfirmed responses. 41 (87%) patients had PD-L1–positive tumors, and ORR was independent of PD-L1 status. Among the 15 patients who had ≥27 weeks of follow-up, ORR was 27% (95% CI 8%-55%), with 3 confirmed responses and 1 unconfirmed response. Safety and updated efficacy data for 83 patients with ≥27 weeks of follow-up will be available for presentation. Conclusions: Preliminary data from KEYNOTE-158 suggest that pembrolizumab has promising antitumor activity in patients with previously treated advanced cervical squamous cell cancer. The observed ORR with pembrolizumab appears to increase with longer follow-up. Clinical trial information: NCT02628067.
Evaluating the cost-effectiveness of current FDA-approved PARP inhibitors for the treatment of recurrent ovarian cancer.
Authors: Wolford Juliet Elizabeth , Bai Jiaru , Eskander Ramez Hassef , Keller Robin , Minion Lindsey E , Chan John K. , Monk Bradley J. , Tewari Krishnansu Sujata
Published: September 2018

5516

Background: Unlike approved IV administered therapies, Medicare is under no obligation to cover prescription medicines. We sought to evaluate the cost-effectiveness of the two FDA-approved orally administered PARP inhibitors (PARPi), olaparib and rucaparib. Methods: A Markov model was created in TreeAge Pro 2015 with nodes in the chain allowing patients to transition through response, hematological complications, non-hematological complications, progression, and death. Separately, the PARP inhibitors were compared with IV administered drugs approved for recurrent ovarian cancers including platinum-based, non-platinum, and bevacizumab-based regimens. Toxicity and mean PFS rates for the different agents were obtained from registration trial data. Costs of IV chemotherapy, managing toxicities, infusions, and supportive care were estimated using 2015 Medicare data. Incremental cost-effectiveness ratios (ICER) were calculated and survival was reported in quality adjusted life months. Results: Platinum-based combinations were the most cost-effective at $1,672/PFS mo as compared to non-platinum agents ($6,688/mo), bevacizumab-containing regimens ($12,482/mo), olaparib ($13,3731/mo), and rucaparib ($14,034/mo). Considering a cost of $114,478 for olaparib and $137,068 for rucaparib prior to progression, costs associated with PARPi were 7.1 to 8.3X more than platinum combinations. To better compare the registration trial data to PARPi data, probability was adjusted to 2nd line for rucaparib, revealing it’s ICERs’ of per month of life added to be $26,997 for bevacizumab, $17,757 for non-platinum, and $79,585 for platinums. Using the adjusted-to-2nd-line probabilities for olaparib, exhibited ICERs were $16,549 for bevacizumab, $25,637 for non-platinums and $72,083 for platinums. Conclusions: The high costs of PARPi were not balanced by costs of infusion and managing toxicities of IV drugs typically associated with lower response rates and shorter PFS in the recurrent space. Balancing incremental clinical benefit with novel therapies remains problematic and could widen disparities among those with limited access to care.
Phase II clinical and molecular trial of oral ENMD-2076 in clear cell ovarian cancer (CCOC): A study of the Princess Margaret phase II consortium.
Authors: Lheureux Stephanie , Burnier Julia V. , Tan Qian , Kanjanapan Yada , Clarke Blaise , Tinker Anna , Ghatage Prafull , Dhani Neesha C. , Butler Marcus O. , Welch Stephen , Weberpals Johanne Ingrid , Tan David Shao Peng , Brooks Kelly , Ramsahai Janelle , Wang Lisa , Shaw Patricia Ann , Tsao Ming Sound , Garg Swati , Stockley Tracy , Oza Amit M.
Published: September 2018

5522

Background: CCOC is a rare chemoresistant subtype of OC. ENMD-2076 is an oral multi-target kinase inhibitor with antiangiogenic/antiproliferative profile; selective activity against the mitotic kinase Aurora A and VEGFRs, FGFRs. Methods: This is a multi-center Phase II study of ENMD-2076 in pts with recurrent CCOC and prior platinum. Primary endpoints were ORR and 6-m PFS rate. Correlative analyses include ARID1A, PTEN expression by IHC and genome sequencing by custom capture library of 555 genes. Results: Completed study enrolled 40 pts – 37 evaluable, median age of 54 (39-78). 12 pts (31%) received prior radiation and 24 (62%), 11 (28%), 4 (10%) had 1, 2 or 3 lines of chemotherapy. Archival tissue was available for 36/37 pts. Best response was PR for 2 pts (1 unconfirmed), SD for 25 (68%) and PD for 10 (26%) pts. Median PFS was 3.7 months (m) (95%CI: 3.4-4.4). ENMD was well tolerated with main related AE: hypertension (21 pts - 8 G3), nausea (18 pts -1 G3) and diarrhea (17 pts - 4 G3). By IHC, median PFS (95%CI) in ARID1A loss (19 pts) was 4.1m (3.5-10.3) vs 3.6m (1.7-3.9) in ARID1A positive (17 pts) (p = 0.024). Whilst, by IHC, PTEN was loss in 20 pts; intact in 10 and heterogeneous in 6 pts; no difference in PFS was observed. By PI3KCA mutation status, median PFS (95%CI) in wild-type (WT) (12 pts) was 5m (3.4-19.3) vs 3.7m (167-4.4) in mutated group (20 pts) (p = 0.038). Molecular profiling showed variants in PI3KCA (27%), ARID1A (26%), TP53 (7%), BRIP1 (7%), ATM (11%), BRCA1 (5%), BRCA2 (3%), RAD50 (3%), PABL2 (1%), RAD51C (1%), FANCA (1%), CTNNB1 (3%).The patient with the longest treatment duration (22m) was PTEN WT, diploid PTEN, putative bi-allelic inactivation of ARID1A. Conclusions: The PFS at 6 months was 20% for the evaluable patients, 31% in ARID1A loss and 12% in ARID1A positive patients. Loss of ARID1A, a known negative prognostic factor, was correlated with better PFS on ENMD-2076. Additional molecular profiling of the baseline biopsy material is underway. Clinical trial information: NCT01914510.
A phase I study of sequential ipilimumab in the definitive treatment of node positive cervical cancer: GOG 9929.
Authors: Mayadev Jyoti , Brady William E. , Lin Yvonne Gail , Da Silva Diane M , Lankes Heather A. , Fracasso Paula M. , Ghamande Sharad A. , Moore Kathleen N. , Pham Huyen Q. , Wilkinson Kelly Jeanes , Kennedy Vanessa Amy , Aghajanian Carol , Koh Wui-Jin , Monk Bradley J. , Schilder Russell J.
Published: September 2018

5526

Background: The outcome of lymph node positive (LN) cervical cancer (CC) with chemoradiation (CRT) is dismal, especially with involved para-aortic nodes (PAN). The anti-CTLA-4 immune checkpoint inhibitor ipilimumab (ipi) holds promise. We report the safety, tolerability, and efficacy in this GOG phase I study examining sequential ipi after CRT for CC. Methods: Patients (pts) with LN CC were treated with 6 weekly doses of cisplatin (40 mg/m2) and extended field radiation (RT). 2-6 weeks after RT, if there was no progression of disease, sequential ipi was given at the following dose levels: dose level 1: 3mg/kg, level 2: 10mg/kg, and an expansion cohort of 10mg/kg. The primary endpoints (endpts) were the maximum tolerated dose (MTD), and dose-limiting toxicities (DLT) of adjuvant ipi. Secondary endpt included the 1-yr disease free survival (DFS). Translational endpts included the effect of CRT on enumeration and subsets of T-cells, and CTLA4, PD-1 and ICOS expression. Results: 34 pts were enrolled, and 19 pts are evaluable for the endpts: 14 pts went off study to reasons unrelated to the study drug, 1 pt continues in her DLT evaluable period. Of the evaluable pts, all had pelvic LN, with 25% PAN. All pts completed CRT, 90% had 4 cycles of ipi, and the other 10% had 2 cycles of ipi. The ipi MTD was 10 mg/kg. There were 3 pts (16%) with acute grade 3 toxicity (lipase, ↓ANC, rash) which self-resolved. Most of the acute toxicities were grade 1-2 GI distress, rash, endocrinopathies. There were no minor or major RT quality deviations. With a median follow up of 12 months, there were no major late toxicities reported, with a 1-year DFS of 74%. There was no difference in CD4+- and CD8+- T cell levels nor CTLA-4 expression with sequential ipi. CRT itself increased ICOS and PD-1 expression. Conclusions: This study is the first to describe the safety of immunotherapy sequencing with definitive CRT in CC. Our data suggests that immunotherapy is tolerable and shows possible activity in this population with a historical dismal prognosis with standard therapy. CRT increased ICOS and PD-1 expression which was sustained with ipi, illustrative of immune modulation targets for future clinical trials and radioimmunotherapy combinations. Clinical trial information: NCT01711515.
Treatment and outcomes of small cell neuroendocrine carcinoma of the cervix (SCCC).
Authors: Schlappe Brooke , Jordan Emmet , Zhou Qin , Iasonos Alexia , Leitao Mario M. , Park Kay J. , Alektiar Kaled M. , Zivanovic Oliver , Sabbatini Paul , Aghajanian Carol , O'Cearbhaill Roisin Eilish
Published: September 2018

5531

Background: Extrapulmonary small cell carcinoma is rare. SCCC represent 2% of cervical cancers and can portend a poor prognosis. Treatment standardization is challenging given its rarity. We describe management of limited stage (LS; disease could be encompassed within one radiation port) at a large tertiary referral center and the characteristics and outcomes in a cohort of patients (pts) with LS and extensive stage (ES) SCCC. Methods: Pts with SCCC diagnosed from 1/1990-1/2016 were identified following IRB approval. Clinicopathologic, treatment, and follow-up data were recorded. Descriptive statistics were provided. Median PFS/OS or PFS/OS rate were estimated using Kaplan-Meier method. Results: 39 pts were identified, 29 with LS. Select characteristics are shown in table. Tumor molecular profiling revealed MYC amplifications, TP53 mutations, PIK3CA mutation among the small subset of pts who had this performed. LS SCCC was treated with whole pelvic radiation therapy (RT) (4500-5040cGy) and concurrent IV cisplatin (60mg/m2) on day 1 and etoposide (120mg/m2) on days 1, 3, and 5 during RT and days 1-3 post RT to complete a total of 4 cycles. 26 pts, all had LS, underwent initial surgical management. No pt had prophylactic cranial RT. 3 pts (8%), all had LS, developed brain metastases. Median follow-up was 59.5 months (1.9-234.1). Median PFS (95%CI) for LS pts was 39.2 months (15.1-not estimable) vs 2.9 months (0.9-4.6) for ES. Median OS(95%CI) was 31.8 months (16.3-56.0) for the whole cohort, 52.8 months (31.8-not estimable) for LS and 5.9 months(1.8-16.3) for ES. Conclusions: In the LS SCCC cohort treated with concurrent cisplatin/etoposide chemo/RT and outback cis/etoposide +/- post initial radical hysterectomy the 5-year PFS (95%CI) was 37.5% (19.2-55.9%). Clinicopathologic characteristics and risk factors for SCCC appear distinct to cervical cancers and lung small cell cancers. Further investigation of molecular alterations and treatment of this rare tumor is needed to improve pt outcomes. [Table: see text]
A multicenter phase II study of the efficacy and safety of quisinostat (an HDAC inhibitor) in combination with paclitaxel and carboplatin chemotherapy (CT) in patients (pts) with recurrent platinum resistant high grade serous epithelial ovarian, primarily peritoneal or fallopian tube carcinoma cancer (OC).
Authors: Tjulandin Sergei , Fedyanin Mikhail , Vladimirov Vladimir Ivanovich , Kostorov Vladimir , Lisyanskaya Alla Sergeevua , Krikunova Ludmila , Cakana Andrew , Azarova Valeria , Karavaeva Oksana , Vostokova Natalia , Baranovsky Sergey
Published: September 2018

5541

Background: Quisinostat is an orally bioavailable potent pan-histone deacetylase inhibitor. Combinations of HDAC inhibitors with paclitaxel or cisplatin demonstrate promising results in preclinical models with cisplatin and paclitaxel resistant OC. In phase Ib study the dosage of Quisinostat in combination of paclitaxel and carboplatin recommended for the phase II study was 12 mg. We report results of the phase II study of Quisinostat in combination with paclitaxel and carboplatin in pts with recurrent platinum resistantOC. Methods: the main inclusion criteria was tumor progression observed not less than 1 month and no more than 6 months after completion of the planned number of cycles of 1st line platinum/paclitaxel based CT. Quisinostat was administered at dose 12 mg p.o. each 3 week cycle on Days 1, 3, 5, 7, 9, 11 with of paclitaxel (175 mg/m2) and carboplatin (AUC5) on Day 7 of each cycle, for 2ndline. Pts received up to 6 cycles. The primary efficacy endpoint is the objective response rate (ORR) verified by the ICR. The secondary endpoints include safety, progression free survival (PFS) and overall survival. The study design implies the use of the two-stage Simon model: 29 patients who underwent treatment would provide 80% power for hypothesis testing in order to frequency of the ORR 30% (α = 0.05). Results: 31 pts were enrolled (30 pts evaluated). Median age was 57 years. Twenty one pts (67.7%) received all 6 cycles of therapy. ORR was 50.0% (15 pts). Median duration of response was 5 months (4.2-5.7). Median PFS - 6 months (95%CI 4.4-7.6). Any SAE were seen in 16.1% pts, AE of grade 3 and 4 – in 71% and 48.4% pts temporarily discontinued therapy due to AE. Dose reduction of CT due to AE was performed in 22.6% pts. The most common adverse events were neutropenia – 67,7%, nausea – 61.3%, weakness – 29%, thrombocytopenia – 22.6%, neuropathy – 19.4%, vomiting – 19.4%. Conclusions: Quisinostat in combination with paclitaxel and carboplatin in pts with recurrent platinum resistant ovarian cancer showed high efficacy and good tolerability Clinical trial information: NCT02948075.
A phase II clinical trial of metformin as a cancer stem cell targeting agent in stage IIc/III/IV ovarian, fallopian tube, and primary peritoneal cancer.
Authors: Buckanovich Ronald J. , Brown Jason , Shank Jessica , Griffith Kent A. , Reynolds R. Kevin , Johnston Carolyn , McLean Karen , Uppal Shitanshu , Liu J. Rebecca , Cabrera Lourdes , Mehta Geeta
Published: September 2018

5556

Background: Epidemiologic and preclinical studies suggest that Metformin has antitumor effects which may be due to an impact on cancer stem-like cells (CSC). We present a phase II trial of metformin administered in combination with chemotherapy for patients with advanced stage epithelial ovarian cancer (EOC). Primary endpoints were 18 month progression free survival (PFS) and CSC number in Metformin treated tumors. Methods: Thirty-eight patients with confirmed stage IIC(n=1)/III(n=25)/IV(n=12) EOC were treated with either neoadjuvant metformin followed primary debulking surgery and adjuvant Metformin+chemotherapy, or neo-adjuvant metformin+chemotherapy, followed by interval debulking and adjuvant chemotherapy+Metformin. Patients were evaluated for side effects, PFS and overall survival (OS). Metformin treated tumors were evaluated for the presence of CSC via FACS and sphere assays. Results: Thirty-two patients (84%) completed at least six cycles of metformin+chemotherapy. Metformin was well tolerated with only one grade III/IV treatment-related adverse event (3%) noted. Common adverse effects were diarrhea (18%) and nausea (16%). Eighteen month PFS was 65.4% (95% confidence interval 47.9-78.3), Median PFS was 21.7 months (CI-17-26.7). Estimated three year OS was 73.5% (CI-54.7-84.3) with median OS not reached after a media follow-up of 33 months. Finally, tumors treated with metformin were noted to have a 3-fold decrease in ALDH+ CSC at baseline, increased sensitivity to Cisplatin in vitro, and a reduced ability to amplify ALDH+ CSC with passage in vitro. Conclusions: This is the first prospective study of Metformin in EOC patients. Translational studies confirm an impact of metformin on CSC. Metformin was well tolerated and outcome results were favorable, supporting the use of Metformin in phase-III studies. Clinical trial information: NCT01579812.
Circulating free DNA and circulating tumor cells as new serum biomarkers in advanced ovarian cancer.
Authors: Martinez Garcia Jeronimo , Soto Asuncion , Sanchez-Henarejos Pilar , Puertes Boix Ana , Rodriguez Edith , Guirao Maran Marta , Jimenez-Lucas MDolores , Cuellar Miler , Cano Alicia , Alonso Romero Jose Luis , Ruiz Merino Guadalupe , Collados David , Marin Miguel , Ros Silver , Garcia Hernandez Maria Del Rosario , Salgado Rosario
Published: September 2018

5566

Background: Circulating free DNA (cfDNA) and circulating tumor cells (CTC) are new biomarkers for malignant tumors. Its role on ovarian epithelial cancer (OEC) is not yet well stablished. We analyze its role on advanced OEC compared with CA125 and HE4. Methods: Multicentric prospective observational study from November 2013 until February 2017, with OEC patients group (OECG), benign ovarian tumors group (BENIGNG) and health subjects control group (HEALTHG). CTCs were analysed by the CellSearch method and cfDNA by ALU-sequences-based quantitative PCR using two primers (115 and 247 bp); cfDNA integrity was calculated by ALU247/ALU115 ratio. Samples were obtained before treatment (M0), after primary peritoneal surgery (M1), after one cycle of chemotherapy (M2), before (M3) and after interval surgery (M4). This study was approved on May 2013 by the corresponding Central Research Independent Ethics Committee. Results: We analyized 102 subjects from all 3 groups (81 OECG, 14 BENIGNG y 7 HEALTHG); 68% were high grade serous subtype; most frequent staging was IIIC (58%). Within the follow-up (FU) period (average 14 months: min 0, max. 35) 36% relapses and 23% deaths were reported. CTCs were positive on 23% of OECG. In HEALTHG no positive were seen and only 1/14 in the BENIGNG group. Monitoring of cfDNA at the treatment points shows significant differences between M0 and M4 (p = 0.02). No differences were seen in the other determinations. cfDNA-ALU115 was 1.40178 ng / mcL (95% CI 1.18066-1.62290) in the OECG, 0.66383 (95% CI 0.44832-0.87935) in BENIGNG and 0.59923 in HEALTHG ( 95% CI, 0.14449-1.05397). The difference was significant between OECG and BENIGNG (P = 0.017) and near the significance between OECG and HEALTHG (p = 0.69). cfDNA integrity in OECG and HEALTHG was significantly different (P = .012). The area under the curve of Ca125, HE4, CTC, cfDNA and CFDNA integrity was 0.490, 0.526, 0.621, 0.587 and 0.450 respectively. New generation sequencing of circulating TP53 is ongoing. Conclusions: CTC and cfDNA are new biomarkers that might have an important role in the diagnosis and monitoring of OEC.
A phase Ib/II trial of lenvatinib (LEN) plus pembrolizumab (Pembro) in patients (Pts) with endometrial carcinoma.
Authors: Makker Vicky , Rasco Drew W. , Dutcus Corina E , Stepan Daniel E. , Li Di , Schmidt Emmett V. , Shumaker Robert Charles , Taylor Matthew H.
Published: September 2018

5598

Background: LEN is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1−3, fibroblast growth factor receptor 1−4, platelet-derived growth factor receptor α, RET, and KIT. Pembro, an antibody targeting programmed cell death protein 1 (PD-1), prevents T cell deactivation. In addition to its antiangiogenic effects, LEN may act in part by preventing VEGF-mediated immune suppression, suggesting combination with pembro could improve its activity. We report results in pts with endometrial carcinoma from a phase Ib/II trial of LEN + pembro. Methods: In this multicenter, open-label study, pts had confirmed metastatic endometrial cancer that progressed after approved therapy, measurable disease, and ECOG performance status ≤ 1. Pts received oral LEN 20 mg/day plus pembro 200 mg intravenously every 3 weeks. Tumor assessments were by the investigator. The primary phase II endpoint was objective response rate (ORR) based on immune-related RECIST (irRECIST). Secondary endpoints included progression-free survival (PFS), disease-control rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]), clinical-benefit rate (CBR; CR + PR + durable SD), and duration of response (DOR), all by irRECIST, and safety. Results: 23 Pts enrolled (phase II: 21; phase Ib: 2); median age was 64 years (range: 51−80); 87% were white; and all had ≥ 1 prior anticancer therapy. Confirmed ORR was 48% (all PR). Median PFS and DOR were not estimable (NE; see table). All pts had a treatment-emergent adverse event (TEAE). The most common TEAEs were hypertension, fatigue, arthralgia, diarrhea, and nausea. Toxicities were manageable with dose interruption and/or modification and no new safety signals were found. Updated data will be presented. Conclusions: Promising efficacy was observed in pts receiving LEN + pembro. In addition, toxicities were generally expected and manageable with dose modification. These results warrant further study of LEN + pembro in pts with endometrial carcinoma. Clinical trial information: NCT02501096. [Table: see text]
What drives overtreatment? Surgeon and radiation oncologist views on omission of adjuvant radiotherapy for elderly women with early stage breast cancer.
Authors: Shumway Dean Alden , Griffith Kent A. , Sabel Michael S. , Jones Rochelle , Hawley Sarah T. , Jeruss Jacqueline Sara , Jagsi Reshma
Published: September 2018

562

Background: Although trials have shown no survival advantage and only a modest improvement in local control from adjuvant radiotherapy after lumpectomy in older women with stage I, ER+ breast cancer, radiotherapy is commonly administered, raising concerns about overtreatment. Therefore, we sought to evaluate physician attitudes, knowledge, communication, and recommendations in this scenario. Methods: We mailed a survey to a national sample of 713 radiation oncologists and 879 surgeons between June to October 2015. Of these, 913 responded (57%). We assessed physicians’ attitudes, knowledge of pertinent risk information, and responses to clinical scenarios. Results: In patients age > = 70 with stage I, ER+ breast cancer treated with lumpectomy and endocrine therapy, omission of radiotherapy was felt to be unreasonable by 40% of surgeons and 20% of radiation oncologists (p < 0.001). Many surgeons (29%) and radiation oncologists (10%) erroneously associated radiotherapy in older women with improvement in survival. Similarly, 32% of surgeons and 19% of radiation oncologists tended to substantially overestimate the risk of locoregional recurrence in older women with omission of RT. In a scenario with an 81-year-old with multiple comorbidities, 31% of surgeons and 35% of radiation oncologists would still recommend radiotherapy. On multivariable analysis, erroneous attribution of a survival benefit to radiotherapy (OR 6.2; 95% CI 3.9-9.8) and overestimation of remaining life expectancy (OR 6.5; CI 4.2-9.9) were strongly associated with the opinion that radiotherapy omission is unreasonable. Conclusions: Many radiation oncologists and surgeons continue to consider omission of radiotherapy as substandard therapy. A sizeable proportion of surgeons overestimate radiotherapy’s benefits and consider omission of radiotherapy to be an unreasonable departure from the standard of care, suggesting that surgeon involvement in decisions about radiotherapy omission may be a key factor in reducing overuse of aggressive care in this setting.
Locoregional surgery of the primary tumor in stage IV breast cancer patients.
Authors: Wang Ying , Yu Yunfang , Chen Kai , Fu Tuping , Yao Herui
Published: September 2018

566

Background: Existing guidelines lack clear recommendations for the role of locoregional treatment for the primary tumor in women with stage IV breast cancer. We aimed to compare the effectiveness of locoregional surgery with no surgery of the primary tumour in stage IV breast cancer patients. Methods: Eligible studies were randomized clinical trials (RCTs) that investigated the effect of locoregional surgery versus no surgery of the primary tumour in stage IV breast cancer patients. The primary outcome was overall survival (OS), measured as hazard ratios (HRs). Secondly outcomes included 2-year and 3-year OS, expressed as odds ratios (ORs). Meta-analyses and trial sequential analysis (TSA) were conducted. Quality was evaluated using the GRADE. Results: Data were included from four RCTs involving 767 participants, including 377 who underwent locoregional surgery and 390 who with no surgery. The median follow-up was 28.6 months (95% confidence interval (CI) 24.1 to 33.9). In a meta-analysis of these trials, the low-quality evidence indicated that locoregional surgery versus no surgery did not significantly affect OS (HR = 0.87, 95% CI 0.59 to 1.29, P = 0.490), 2-year OS (OR = 1.23, 0.66 to 2.30, P = 0.510), or 3-year OS (OR = 1.08, 0.94 to 1.25, P = 0.263). TSA showed that more trials were needed before reliable conclusions could be drawn regarding in both 2-year and 3-year OS. Across the subgroup analysis of OS, we found the moderate-quality evidence that locoregional surgery followed by chemotherapy versus chemotherapy alone resulted into a significantly improved survival (HR = 0.65, 95% CI 0.49–0.87, P = 0.004); but no statistically significant difference was identified in term of response to chemotherapy with or without locoregional surgery (HR = 1.06, 95% CI 0.83–1.36, P = 0.632). Conclusions: The current evidence suggests that locoregional surgery followed by chemotherapy, compared with chemotherapy alone, was beneficial for prolonging OS in patients with stage IV breast cancer, but surgery did not impact OS among patients who have responded to chemotherapy.
Adjuvant or neoadjuvant chemotherapy in early stage triple negative breast cancer (TNBC) comparison of outcomes in both BRCA positive and BRCA negative patients.
Authors: Clifton Katherine , Gutierrez Barrera Angelica , Ma Junsheng , Bassett Roland L. , Litton Jennifer Keating , Arun Banu
Published: September 2018

576

Background: NSABP Protocol B-18 was a randomized trial which found no statistically significant difference in overall survival (OS) in patients (pts) receiving neoadjuvant (NAC) or adjuvant chemotherapy (AC), however outcome was not analyzed by breast cancer subtypes. Subsequent retrospective studies in TNBC reported conflicting results with an initial study showing a significant OS benefit with AC and later studies showing a trend toward improved survival with NAC. Furthermore, studies have not included a significant number of pts with BRCA mutations. This study aims to analyze outcomes of AC versus NAC in pts with early stage TNBC with and without BRCA germline mutations. Methods: Pts with stage I or II TNBC who had BRCA testing were identified from a prospective cohort study of 4027 pts at MD Anderson Cancer Center. Clinical, demographic, genetic test results, chemotherapy, recurrence, survival data were collected. OS and disease free survival (DFS) were estimated using the Kaplan-Meier method, and log-rank tests were used to compare groups. Results: 305 pts with stage I and II TNBC who met eligibility criteria were included in the analysis. Pts who received both NAC and AC or no chemotherapy were excluded. 181 received AC (59.3%) and 124 received NAC (40.7%). The majority of the pts were less than 50 years old (236, 77.4%) and white (194, 63.8%). 134 were BRCA positive (44.1%) and 170 were BRCA negative (55.9%). The majority of the pts received an anthracycline and taxane regimen (223, 73.1%). There was no significant association between OS or DFS and treatment with NAC versus AC in the overall cohort. Furthermore, there were no significant differences between pt subgroups (NAC BRCA positive, NAC BRCA negative, AC BRCA positive, and AC BRCA negative) with respect to either OS or DFS. Conclusions: NAC versus AC with standard anthracycline and taxane containing regimens results in similar DFS and OS survival amongst pts with stage I and II TNBC regardless of BRCA status. Further studies are needed to evaluate whether similar results are observed with newer agents, such as platinums, PARP inhibitors and other targeted agents.
EarlyR genomic signature to predict pathological complete response following neoadjuvant anthracycline-taxane chemotherapy in estrogen-receptor positive (ER+) breast cancer.
Authors: Buechler Steven Allen , Badve Sunil S. , Gokmen-Polar Yesim
Published: September 2018

579

Background: EarlyR is a prognostic signature computed from expression values of ESPL1, SPAG5, MKI67, PLK1 and PGR that stratifies ER+ breast cancer (BC) into EarlyRLow, EarlyRInt, and EarlyRHigh risk strata. Here, we show that EarlyR is also predictive of pathological complete response (pCR) following neoadjuvant anthracycline-taxane (AT) based chemotherapy. Methods: The ability of EarlyR gene signature to predict pCR was assessed in Affymetrix microarrays datasets (GSE25065, GSE25066, GSE20194, GSE20271; n = 541, pCR = 42 (7.8%) collectively labeled as Cohort A) derived from patients with ER+ breast cancer treated with neoadjuvant TFAC or FEC. For 2 of these datasets (GSE25065, GSE25066 (n = 291)) distant metastasis-free survival (DMFS) results were also available. The DMFS data in cohort A were compared to that of BC patients not treated with chemotherapy (denoted Cohort B, n = 1269) derived from ER+ samples from 7 GEO datasets (GSE3494, GSE7390, GSE12093, GSE6532, GSE2034, GSE11121, GSE17705). Results: In cohort A, EarlyR is a significant predictor of pCR (p = 1.0 x 10-6) (EarlyRLow, n = 273, pCR = 5, 1.8%; EarlyRInt, n = 11, pCR = 1, 9.1% and EarlyRHigh, n = 256, pCR = 36, 14.1%). Notably, 86% of the 42 cases with pCR have EarlyRHigh. Of the 291 patients with 8-year DMFS data from Cohort A, who had received chemotherapy, the survival of EarlyRHigh [0.79 (95%CI 0.70-0.89)] was nearly the same as that of EarlyRLow [0.82 (95%CI 0.74-0.90)]. In contrast, in cohort B, who were not treated with chemotherapy, 8-year DMFS is significantly (p = 5 x 10-15) lower in EarlyRHigh [0.57 (95%CI 0.51-0.64)] than in EarlyRLow[0.81 (95%CI 0.78-0.84)]. Conclusions: EarlyR is a strong predictor of pathological complete response in patients treated with TFAC or FEC. In addition, EarlyR also predicts poor DMFS outcomes for patients in EarlyRHigh not receiving chemotherapy. More importantly, neoadjuvant chemotherapy dramatically improved survival of patients in EarlyRHigh. These results document that EarlyR identifies a set of patients, EarlyRHigh, with a high risk of distant metastasis, who are also likely to respond favorably to chemotherapy.
A multicenter randomized controlled trial (RCT) of adjuvant chemotherapy (CT) in nasopharyngeal carcinoma (NPC) with residual plasma EBV DNA (EBV DNA) following primary radiotherapy (RT) or chemoradiation (CRT).
Authors: Chan Anthony T. C. , Hui Edwin Pun , Ngan Roger K.C. , Tung Stewart Yuk , Cheng Ashley Chi Kin , Ng Wai Tong , Lee Victor HF , Ma Brigette , Cheng Hoi Ching , Wong Frank C.S. , Loong Herbert H. F. , Tong Macy , Poon Daren MC , Ahuja Anil Tejbhan , King Ann Dorothy , Wang Ki , Mo Frankie , Zee Benny C.Y. , Chan Allen K.C. , Lo YM Dennis
Published: September 2018

6002

Background: The benefit of adjuvant CT in NPC is unclear. Post-RT EBV DNA predicts poor survival and may be a biomarker of subclinical residual disease. We conducted a biomarker driven RCT using post-RT EBV DNA to select high risk NPC patients (pts) for adjuvant CT while sparing low risk pts from unnecessary toxicity. Methods: Eligible pts had biopsy proven NPC of AJCC (6th Ed) stage IIB-IVB, detectable EBV DNA ( > 0 copy/ml) at 6-8 weeks post-RT, no persistent locoregional disease or distant metastasis, ECOG 0 or 1, and adequate organ function. Pts were randomized with stratification for primary therapy (RT Vs CRT) and tumor stage (II/III Vs IV) to arm A (adjuvant cisplatin 40 mg/m2 and gemcitabine 1000 mg/m2, both given on D1+8 q3w x 6 cycles) or arm B (clinical follow-up). Primary endpoint was relapse free survival (RFS). With a hazard ratio (HR) of 2, 100 pts were required with a power of 0.8 and an alpha at 0.05. Results: From 9/2006 to 7/2015, 789 pts consented for EBV DNA screening, 218 (27.6%) pts had detectable EBV DNA, and 104 (13.2%) pts were randomized (arm A: 52; arm B: 52). The two arms were well balanced in baseline characteristics. 84.6% received prior neoadjuvant and/or concurrent CT and all received curative RT. Staging distribution: IIB 27.9%, III 37.5%, IVA 19.2%, IVB 15.4%. 8 pts refused adjuvant CT after randomization. Overall 69% and 50% completed 3 and 6 cycles of adjuvant CT respectively. After median follow up of 6.5 years (yr), the 3-yr and 5-yr survival outcomes were summarized in Table. Conclusions: In NPC pts who had residual EBV DNA after curative RT/CRT, adjuvant CT with cisplatin-gemcitabine did not improve survival. Clinical trial information: NCT00370890. [Table: see text]
Randomised phase-III-trial of concurrent chemoradiation (CRT) for locally advanced head and neck cancer (stage III-IVB): Comparing dose reduced radiotherapy (63,6 Gy) with paclitaxel/cisplatinum to standard radiotherapy (70,6 Gy) with fluorouracil/cisplatinum.
Authors: Fietkau Rainer , Iro Heinrich , Hecht Markus , Hofner Benjamin , Gefeller Olaf , Balermpas Panagiotis , Roedel Claus , Hautmann Matthias , Koelbl Oliver , Leber Horst , Salay Attila , Ruebe Christian , Breinl Peter , Krings Waldemar , Gripp Stephan , Wollenberg Barbara , Keerl Rainer , Schreck Ulrike , Siekmeyer Birgit , Grabenbauer Gerhard
Published: September 2018

6016

Background: Concurrent CRT with 70.6 Gy is the standard treatment for locally advanced head and neck cancer (LA-SCCHN). There exist no prospective data on safety and efficacy of a reduced radiation (RT) dose. Methods: Pts with stage III-IVB LA-SCCHN were randomized 1:1 to receive 70.6 Gy with concurrent cisplatinum (20mg/m²/d IV on days 1-5 and 29-33) and fluorouracil (600 mg/m²/d CIV on days 1-5 and 29-33) (standard arm A) versus 63,6 Gy with intensified chemotherapy using concurrent cisplatinum (20mg/m²/d IV on days 1-4 and 29-32) and paclitaxel (20mg/m²/d IV on days 2, 5, 8, 11 and 25, 30, 33, 36) (experimental arm B). After a planned interim analysis recruitment was stopped due to statistical reasons. Results: Between 06/2010 and 02/2015 a total of 221 pts were randomized with 105 pts receiving treatment in arm A and 112 in arm B (4 pts dropped out). Median follow-up was 38 months. Pts’ characteristics: Oral cavity (15%), oropharynx (54%), hypopharynx (28%), larynx (14%); 17 pts had more than one primary site; tumor stage: III (14%), IV (86%); HPV-status (p16) was positive in 20%, negative in 38%, currently pending in 42%. A total of 96 PFS-related events occurred. 3-year PFS (ITT) was 58% in the standard arm A and 48% in experimental arm B (p = 0.454). 3-year OS (ITT) was 64% in arm A and 59% in arm B (p = 0.688). 3-year rates of distant metastases, loco-regional recurrences and death were 10% vs 12%, 17% vs 21% and 15% vs 19% for pts in arm A and B, respectively. As for the p16-positive subgroup, 3-year PFS/OS were 77%/76% in arm A (n = 21) and 69%/80% in arm B (n = 22), respectively. Grade 3+ hematologic adverse events during therapy (arm A/arm B): Anemia 11%/4% (p = 0.038); neutropenia 40%/16% (p < 0.001); thrombocytopenia 8%/3% (p = 0.130). Conclusions: These preliminary results indicate that pts receiving concurrent CRT for LA-SCCHN did not benefit from a lower total RT dose of 63.6Gy despite intensified chemotherapy. However, in the subgroup of p16-positive pts a reduced RT dose may be sufficiently effective. Clinical trial information: NCT01126216.
Randomized, double-blind, placebo-controlled, phase II trial of first-line platinum/docetaxel with or without erlotinib (E) in patients (pts) with recurrent and/or metastatic (R/M) head and neck squamous cell carcinomas (HNSCCs).
Authors: William William Nassib , Feng Lei , Kies Merrill S. , Ahmed Salmaan , Blumenschein George R. , Glisson Bonnie S. , Massarelli Erminia , Johnson Faye M. , Lu Charles , Papadimitrakopoulou Vassiliki , Gold Kathryn A. , Theriault Rachel Leigh , Heymach John , Kim Edward S.
Published: September 2018

6017

Background: In a single-arm, phase 2 study, we previously demonstrated that in pts with R/M HNSCC, cisplatin, docetaxel and E improved progression-free survival (PFS) compared to historical data (Kim et al., ASCO 2006). Herein, we evaluated this regimen in a single center, randomized, phase 2 trial. Methods: Pts with R/M HNSCC, with a performance status (PS) 0-2, were randomized (1:1) to receive up to 6 cycles of first-line chemotherapy with cisplatin 75 mg/m2 (or carboplatin AUC 6) and docetaxel 75 mg/m2 i.v. on day 1 every 21 days, plus placebo (P) vs. E 150 mg p.o. daily, followed by maintenance P or E until disease progression. The primary endpoint was PFS. With 120 pts, the study had 80% power to detect an improvement in median PFS from 3.0 to 4.9 months with a two-sided type I error rate of 0.1. Results: From 05/2010 to 07/2015, 120 pts were randomized to the P (N = 60) or E (N = 60) groups. All pts but one initiated treatment and were eligible for evaluation of the primary endpoint – 92 males; median age 62 years; 52 oropharynx, 40 oral cavity, 19 larynx, 8 hypopharynx cancer pts; 86 current/former smokers; 43 with recurrence within 6 months of completion of local treatment; 27 with prior exposure to EGFR inhibitors. Median PFS was 4.4 vs. 6.1 months for the P and E groups, respectively (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.42-0.95 months, p = 0.026). Response rates were 44% vs. 56% for P vs. E (p = 0.21). Median overall survival (OS) for P- and E-treated pts was 13.7 vs. 17.0 months (HR = 0.67, 95% CI 0.43-1.04, p = 0.07). Benefits from E on PFS and OS were more pronounced in pts with oropharyngeal tumors (p≤0.05 for interaction). In the E group, first-cycle rash grade 2-4 (34% pts) was associated with longer OS (HR = 0.40, p = 0.02). E-treated pts experienced a higher incidence of grade 3-4 adverse events (33.9 vs. 53.3%), including diarrhea (3 vs.17%), dehydration (5 vs. 15%), nausea (5 vs. 14%), rash (0 vs. 12%). Conclusions: This study met its primary endpoint. Addition of E to first-line platinum/docetaxel improved PFS and OS. This regimen may warrant further evaluation in randomized, phase 3 trials. Clinical trial information: NCT01064479.
Results of a phase II randomized controlled clinical trial comparing efficacy of cabazitaxel versus docetaxel as second-line or above therapy in recurrent head and neck cancer.
Authors: Joshi Amit , Patil Vijay Maruti , Noronha Vanita , Dhumal Sachin , Chandrasekharan Arun , Pande Nikhil , MV Chandrakanth , Talreja Vikas , Vallathol Dilip , Srinivas Sujay , Chanana Raajit , Gupta Kushal , Parthiban Sangeetha , Prabhash Kumar
Published: September 2018

6018

Background: Cabazitaxel has shown activity in squamous cancer cell lines and in taxane resistant cell lines. Hence we planned a randomized phase 2 study to evaluate the efficacy and safety of cabazitaxel against docetaxel in recurrent head and neck cancer, post first line treatment. Methods: This was a phase 2 open label, investigator initiated, randomized controlled trial of Docetaxel (75 mg/m2) versus Cabazitaxel (20 mg/m2), in adult patients with head and neck cancer, ECOG performance status 0-2, with measurable disease, who have been exposed to at least one line of chemotherapy (CTRI/2015/06/005848). 1:1 central randomization was performed and chemotherapy was administered till progressive disease or until patient had intolerable side effects. The sample size of 92 (46 per group) was determined based on an assumption for a difference in disease control rate of 25%, an alpha of 0.05 and 80% power. The data was censored for analysis on 3rd March 2017. Primary analysis of disease control at 6 weeks (CR/PR/SD) was assessed and compared using the chi-square test. Progression free survival (PFS) and overall survival (OS) curves were estimated using the Kaplan-Meier method. Cox proportional hazard model was used for comparison of PFS and OS between the 2 arms. Results: 92 patients were accrued in the study with 46 in each arm. The disease control rate at 6 weeks was better in the docetaxel arm which was statistically significant over the cabazitaxel arm (13.6% versus 52.3%, p = 0.017). The median PFS was 21 days (95% CI 5.28-36.72 days) in the cabazitaxel arm versus 61 days (95% CI 16.21 to 105.79 days) in the docetaxel arm (HR = 1.466, 95% CI 0.923-2.328, p = 0.105). The median OS was 172 days (95% CI 111.78 to 232.22 days) in the cabazitaxel arm versus 188 days (95% CI 134.4 to 241.6 days) in the docetaxel arm (HR-1.408, 95% CI 0.738-2.688, p = 0.299). Conclusion: In this phase 2 study, docetaxel had a superior disease control rate at 6 weeks and PFS compared to cabazitaxel. Clinical trial information: CTRI/2015/06/005848.