bluuebunny/crossref_metadata_2025 huggingface dataset:
Pembrolizumab in patients (pts) with PD-L1–positive (PD-L1+) advanced ovarian cancer: Updated analysis of KEYNOTE-028.
Authors: Varga Andrea , Piha-Paul Sarina Anne , Ott Patrick Alexander , Mehnert Janice M. , Berton-Rigaud Dominique , Morosky Anne , Zhao Guo Qing , Rangwala Reshma A. , Matei Daniela
Published: September 2018

5513

Background: Overexpression of the PD-1 ligand PD-L1 has been demonstrated in ovarian cancer and may hinder an effective antitumor immune response. A preliminary analysis of the ovarian cancer cohort of the KEYNOTE-028 study (NCT02054806) suggested that the PD-1 inhibitor pembrolizumab has promising antitumor activity in pts with PD-L1+advanced ovarian cancer. An updated analysis of the ovarian cancer cohort based on 15.5 months of follow-up is presented. Methods: Key eligibility criteria for the ovarian cohort of this nonrandomized, multicohort phase Ib trial were advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of prior therapy; PD-L1 positivity defined as membranous staining on ≥1% of tumor and associated inflammatory cells or positive staining in stroma; and ECOG PS 0/1. Pembrolizumab (10 mg/kg every 2 wk) was given for ≤2 y or until confirmed progression/unacceptable toxicity. Response was assessed per RECIST v1.1 by investigators every 8 wk for the first 6 mo and every 12 wk thereafter. Primary end points were safety, tolerability, and confirmed ORR. Results: 26 pts (median age, 57.5 y) were enrolled; 61.5% were white, 38.5% received ≥5 therapies for recurrent/metastatic disease, and 53.8% received prior neoadjuvant/adjuvant therapies. As of the October 10, 2016, data cutoff, the median follow-up duration was 15.5 mo (range, 2.4-30.8 mo). 1 pt had a complete response and 2 had partial responses; 6 pts had stable disease as best response. ORR was 11.5% (95% CI, 2.4%-30.2%). Tumor reduction was observed in 6/26 (23.1%); all 3 patients who responded completed 2 years of treatment. Median duration of response was not reached (range, 24.9+ to 26.5+ mo). Median (95% CI) PFS and OS were 1.9 mo (1.8-3.2 mo) and 13.1 mo (6.7-17.5 mo) respectively. Treatment-related AEs occurred in 73.1% of pts, and the most common were arthralgia (19.2%), nausea (15.4%), pruritus (15.4%), rash (11.5%), and diarrhea (11.5%). 1 patient had a grade 3 drug-related adverse event (transaminase increased). Conclusions: With 15.5 mo of follow-up, pembrolizumab continued to be well tolerated and demonstrated durable antitumor activity in pts with advanced ovarian cancer. Clinical trial information: NCT02054806.
Aromatase inhibitor maintenance therapy in high grade advanced ovarian cancer to delay first recurrence.
Authors: Knipprath-Mészáros Alexandra Maria , Vetter Marcus , Montavon Celine , Vigo Francesco , Schoetzau Andreas , Heinzelmann-Schwarz Viola A. ,   Gynecological Cancer Centre, University Hospital Basel
Published: September 2018

5515

Background: Ovarian cancer (OC) is mostly diagnosed as G3 serous advanced stage disease with survival of only 20% in 5 years. Maintenance therapy after 1st line chemotherapy is increasingly used, particularly with Bevacizumab or PARP inhibitors. However, the effect of antihormonal treatment in breast cancer but also in relapsed gynecological cancers has been shown. Also in low grade OC, data are highly supportive of antihormonal treatment. In a previous study of ours, also high grade serous cancers express high amounts of estrogen receptor (ER). The aim of this study was to analyze whether a maintenance antihormonal therapy in advanced OC adds a benefit in relation to the time of recurrence. Methods: All newly diagnosed G3 FIGO III/IV OC cases at our Hospital were assessed prospectively for ER expression. Patients with positive ER status (> 10%) were treated as maintenance therapy with Letrozol 2.5mg 1x/d or not. Progression free survival was recorded and analyzed according to Kaplan-Meier. Patients with macroscopic residual disease post surgery receiving Bevacizumab maintenance treatment were also included. Results: We identified 51 patients with G3 serous OC FIGO III/IV expressing ER. Hereby, 24 patients received and 27 patients did not receive Letrozol after adjuvant chemotherapy. Time to progression ranged from 4 to 121 months. The use of Letrozol was associated with a significant prolonged progression free interval. After 12 months, only 65% of women in the control group vs 84% in the Letrozol group were progression-free. After 24 months, the effect was even stronger (46% in the control group vs 74% with Letrozol (p= 0.02)). Within the subgroup of patients with residual disease treated with Bevacizumab a similar effect was seen with 41% of patients progression free after 12 months vs 89% when taking Letrozol in addition to Bevacizumab. Conclusions: The use of Letrozol as a maintenance therapy after the 1st line treatment in G3 advanced stage serous OC patients was associated with a longer recurrence free interval in our cohort. These findings warrant a randomized controlled trial comparing all existing maintenance regimen as this might have a major influence on cost development in OC treatment.
Efficacy of niraparib on progression-free survival (PFS) in patients (pts) with recurrent ovarian cancer (OC) with partial response (PR) to the last platinum-based chemotherapy.
Authors: Mirza Mansoor Raza , Monk Bradley J. , Gil-Martin Marta , Gilbert Lucy , Canzler Ulrich , Follana Philippe , Waters Justin S. , Kridelka Frederic , Levy Tally , Benigno Benedict B. , Woie Kathrine , Provencher Diane M. , Lueck Hans-Joachim , Casado Herraez Antonio , Lesoin Anne , Buscema Joseph , Hellman Kristina , Rimel Bj , Hazard Sebastien , Matulonis Ursula A. ,   For the ENGOT-OV16/NOVA Investigators
Published: September 2018

5517

Background: Therapeutic paradigms for recurrent OC vary by geography. Maintenance following response to platinum-based chemotherapy (Plat) is standard in Europe, whereas in the US maintenance is considered following complete response (CR) vs treatment for partial response (PR). Niraparib is a highly selective PARP 1/2 inhibitor (PARPi). In preclinical studies it concentrates in the tumor relative to plasma, delivering > 90% durable PARP inhibition and antitumor effects. Niraparib demonstrated significantly longer PFS vs placebo (P) in pts with recurrent OC following a CR or PR to Plat in the randomized, controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. Methods: Pts with recurrent OC, no prior PARPi use, ≥2 prior courses of Plat, and response to most recent Plat were eligible. Pts were assigned to 1 of 2 cohorts on the basis of g BRCA testing (g BRCAmut or non-g BRCAmut) and randomized 2:1 within each cohort to niraparib 300 mg or P qd until progressive disease (PD). Randomization occurred up to 8 weeks after last dose of the most recent Plat. Pts were stratified by time to progression after penultimate Plat (6 to < 12 months or ≥12 months), prior use of bevacizumab (yes/no), and response to most recent Plat (CR or PR). PFS was measured from time of randomization to death or earliest PD as assessed by independent review committee. Results: 49% of pts (niraparib: 67/138; P: 32/65) in the g BRCAmut and ~49% of pts (niraparib: 117/234 [50%]; P: 56/116 [48%]) in the non-g BRCAmut cohorts entered NOVA with a PR following their most recent Plat. At time of unblinding, 30 (45%) niraparib and 23 (72%) P pts in the g BRCAmut and 65 (56%) niraparib and 45 (80%) P pts in the non-g BRCAmut cohorts had PFS events. PFS hazard ratios (95% CI) were 0.24 (0.131–0.441) in g BRCAmut and 0.35 (0.230–0.532) in non-g BRCAmut cohorts for pts who had a PR to their most recent platinum regimen. This compared favorably to the overall NOVA study results, where PFS hazard ratios (95% CI) were 0.27 (0.173–0.410) in g BRCAmut and 0.45 (0.338–0.607) in non-g BRCAmut cohorts. Conclusions: Niraparib treatment provided significant benefit to pts with recurrent OC who achieved a PR following Plat. Clinical trial information: NCT01847274.
A phase 3 trial of hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer.
Authors: Van Driel Willemien , Sikorska Karolina , Schagen van Leeuwen Jules , Schreuder Henk , Hermans Ralph , de Hingh Ignace , Van Der Velden Jacobus , Arts Henriëtte J.G. , Leon Massuger , Aalbers Arend , Victor J. Verwaal , van der Vijver Koen , Aaronson Neil K , Sonke Gabe S.
Published: September 2018

5519

Background: Cytoreductive surgery and systemic therapy are essential for newly diagnosed ovarian cancer. We conducted a multicenter phase 3 trial to study whether the addition of intraperitoneal chemotherapy under hyperthermic conditions (HIPEC) to interval cytoreductive surgery would improve outcome among patients receiving neo-adjuvant chemotherapy for stage III epithelial ovarian cancer. Methods: We randomly assigned patients who showed at least stable disease after three cycles of carboplatin (area under the curve 6) and paclitaxel (175 mg/m2) to receive interval cytoreductive surgery with or without HIPEC using cisplatin (100 mg/m2). Randomization was performed per-operatively and eligible patients had no residual mass greater than 2.5 mm. Three additional cycles of carboplatin and paclitaxel were given post-operatively. The primary endpoint was recurrence-free survival. Overall survival, toxicity, and quality-of-life were key secondary endpoints. Results: A total of 245 patients were randomly assigned to one of the two treatment strategies. In an intention-to-treat analysis, interval cytoreductive surgery with HIPEC was associated with longer recurrence-free survival than interval cytoreductive surgery alone (15 vs. 11 months, respectively; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49 to 0.86; P=0.003). At the time of analysis, 49% of patients were alive, with a significant improvement in overall survival favoring HIPEC (48 vs. 34 months; HR, 0.64; 95% CI, 0.45 to 0.91, P=0.01). The number of patients with grade 3-4 adverse events was similar in both treatment arms (28% vs. 24%, p=0.61). Quality-of-life analysis will follow. Conclusions: The addition of HIPEC to interval cytoreductive surgery is well tolerated and improves recurrence free and overall survival in patients with stage III epithelial ovarian cancer. Clinical trial information: NCT00426257.
A randomized phase III trial of cisplatin with or without S-1 in patients with FIGO IVB, recurrent, or persistent cervical cancer: An Asian study.
Authors: Lim Soyi , Ochiai Kazunori , Aoki Yoichi , Aoki Daisuke , Kamiura Shoji , Lin Hao , Fujiwara Yasuhiro , Cha Soon Do , Kim Jae Hoon , Kim Byoung , Hirashima Yasuyuki , Fujiwara Keiichi , Kim Young Tak , Kim Seok-Mo , Chung Hyun Hoon , Chang Ting-Chang , Kamura Toshiharu , Takizawa Ken , Takeuchi Masahiro , Kang Soon-Beom
Published: September 2018

5527

Background: A combination of S-1, an oral fluoropyrimidine, plus cisplatin has been used for advanced gastric cancer in Asia and EU, and lung cancer in Japan. It also evaluated in advanced or recurrent cervical cancer in a phase II setting. We conducted a randomized phase III trial to compare the efficacy and safety of S-1 plus cisplatin with those of cisplatin alone in recurrent or persistent after treatment and FIGO IVB cervical cancer patients. Methods: Stage IVB, recurrent or persistent cervical cancer patients aged ≥ 20 years, ECOG PS 0–1 and adequate organ function were randomly assigned (1:1) to receive S-1 (80–120 mg daily, according to BSA, day 1–14) plus cisplatin (50 mg/m2 on day 1) (study group) or cisplatin alone (50 mg/m2 on day 1) (control group) every 3 weeks. Treatment was continued until disease progression. In all, 360 patients (at least 296 events) with a hazard ratio (HR) for death of 0.72 were required for a two-sided alpha of 5% and power of 80% under 2 years of recruitment and 1.5 years of follow-up. Stratification factors included recurrence in previously irradiated field, previous platinum-based therapy, and institution. Primary endpoint was OS based on intent-to-treat principle, and secondary endpoints were PFS, overall response rate (ORR), and safety. Results: In all, 375 patients were assigned to the study (n = 189) and control (n = 186) groups. Rate of previous platinum-based therapy was 64%. The median survival time was 21.9 and 19.5 months (95% CI, 18.6–25.8 and 17.0–24.3) with the use of unstratified log-rank test in the study and control groups, respectively (log-rank P = 0.125; HR, 0.84; 95% CI, 0.67–1.05). Significant increases in median PFS (7.3 vs. 4.9 months; log-rank P < 0.001; HR, 0.62) and ORR (43.8 vs. 20.1%, P < 0.001) were observed in the study group. Adverse events (grade≥3) were frequent in the study group (80.9 vs. 41.7%) with neutropenia (52.7%), anemia (34.6%), and leukopenia (32.4%) being the most common events. Conclusions: Compared with cisplatin alone, S-1 plus cisplatin did not significantly improve OS but increased ORR, prolonged PFS, and had tolerable safety of patients with stage IVB, recurrent or persistent cervical cancer. Clinical trial information: NCT00770874.
Clinically significant long-term maintenance treatment with olaparib in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC).
Authors: Gourley Charlie , Friedlander Michael , Matulonis Ursula A. , Shirinkin Vadim , Selle Frédéric , Scott Clare L. , Safra Tamar , Fielding Anitra , Rowe Philip , Ledermann Jonathan A.
Published: September 2018

5533

Background: In Study 19 (NCT00753545), a RCT in 265 pts with PSR SOC, the oral PARP inhibitor olaparib significantly improved progression-free survival (PFS) vs placebo (PBO), with the greatest benefit seen in pts with a BRCA1/2 mutation ( BRCAm); an interim overall survival (OS) analysis suggested an advantage for olaparib-treated pts (DCO: Sep 30, 2015; Ledermann et al, 2016). We report a planned final analysis of the long-term benefit of olaparib in pts with PSR SOC in Study 19. Methods: Pts who had received ≥2 prior regimens of platinum-based chemotherapy and were in response to their most recent regimen received olaparib (400 mg bid; capsules) or PBO until disease progression. Retrospective germline or tumor testing resulted in a known BRCAm status for 254/265 pts (96%). Results: At final DCO (May 9, 2016) median OS follow-up was 78.0 months. A long-term treatment benefit and the final hazard ratio (HR) for OS vs PBO (unadjusted for crossover: 13% of PBO pts – full analysis set [FAS]; 23% of PBO pts – BRCAm subgroup) is shown (Table). Details of BRCAwt pts on treatment for ≥6 years will be presented. No new safety signals or changes in olaparib tolerability profile were seen. Conclusions: The Study 19 final analysis shows that olaparib provides clinically significant, long-term treatment benefit in pts with PSR SOC. A durable benefit was seen in ≥10% of BRCAm and BRCAwt pts, who continued to receive and benefit from olaparib for ≥6 years–unprecedented in the relapsed ovarian cancer setting. Olaparib is well tolerated in this pt population and the analysis suggests olaparib confers an OS benefit in BRCAm pts. Clinical trial information: NCT00753545. [Table: see text]
Long-term benefit of niraparib treatment of recurrent ovarian cancer (OC).
Authors: Matulonis Ursula A. , Herrstedt Jorn , Tinker Anna , Marme Frederik , Redondo Andres , Kalbacher Elsa , Ledermann Jonathan A. , Pikiel Joanna , Christensen Rene dePont , Berek Jonathan S. , Juhler-Nøttrup Trine , Oza Amit M. , Meier Werner , Gil-Martin Marta , Hardy-Bessard Anne-Claire , Monk Bradley J. , Rosenberg Per , Wenham Robert Michael , Hazard Sebastien , Mirza Mansoor Raza ,   For the ENGOT-OV16/NOVA Investigators
Published: September 2018

5534

Background: Current therapies for recurrent OC include chemotherapy (C) or bevacizumab (B) in combination with C followed by continuous B, which showed improved progression-free survival (PFS) compared with C followed by placebo (P) over 3.4 months (GOG-0213) or 4.0 months (OCEANS). Potential impact of B on effectiveness of subsequent therapies has not been described. Niraparib (N) is a highly selective PARP 1/2 inhibitor (PARPi). In preclinical studies, N concentrates in the tumor; N showed significantly longer PFS vs P in patients (pts) with recurrent OC following complete/partial response (CR/PR) to platinum based chemotherapy (Plat) in the randomized, controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. We report the long term effect of treatment with N and its impact on subsequent therapy. Methods: Eligibility for NOVA included recurrent OC, fallopian tube or peritoneal cancer, no prior PARPi use, and completion of ≥2 prior courses of Plat, with a CR or PR following the most recent Plat. Pts were enrolled into g BRCAmut or non-g BRCAmut cohorts based on BRCA mutation test results and randomized 2:1 to receive N 300 mg qd or P until progression of disease or death (PD). Tumors were tested for homologous recombination deficiency (HRD). Estimated probability of PD in each cohort at 12, 18 and 24 months post randomization, representing ~18, 24 and 30 months post chemotherapy initiation, was determined; the difference between PFS2 and PFS (PFS2-PFS) was evaluated in all randomized pts. Results: 203 pts were randomized in the g BRCAmut cohort. Of 350 pts randomized in the non-g BRCAmut cohort, 162 had HRD+ and 134 HRD− tumors. Estimated probability (product-limit method) of PFS at 12, 18 and 24 months was greater in the niraparib arm than in the placebo arm in each cohort and subgroup at each time interval. Probabilities (95% CI) at 24 months for niraparib vs control were 0.42 (0.30, 0.55) vs 0.16 (0.07, 0.28) (gBRCAmut) and 0.27 (0.19, 0.35) vs 0.12 (0.06, 0.21) (non-gBRCAmut). PFS2-PFS was similar in the 2 treatment arms in the combined cohorts (HR 1.02, 95% CI 0.765, 1.349). Conclusions: Niraparib provided long term benefit in pts with recurrent OC irrespective of g BRCAmut or HRD status, and no decrement in the benefit of subsequent therapy was observed. Clinical trial information: NCT01847274.
Management of platinum-sensitive recurrent ovarian cancer (PSROC) in the era of biologics: Can ASCO’s net health benefits (NHB) inform our decisions?
Authors: Foote Jonathan , Havrilesky Laura Jean , Jewell Elizabeth Lin , Gamble Charlotte , Ehrisman Jessie , Broadwater Gloria , Coleman Robert L. , Cohn David E. , Secord Angeles Alvarez
Published: September 2018

5544

Background: The ASCO value framework allows assessment of novel cancer therapies based on NHB. We assessed novel biologic therapies in the management of PSROC. Methods: ASCO’s revised value framework NHBs were constructed for key therapies based on randomized clinical trials for PSROC. BRCA-germline and HRD status were included. Additionally, patient-centered NHB calculations were weighted based on results from a prospective patient preferences study (n=54) and compared to ASCO-based NHB. Results: ASCO-centered NHB calculations were: platinum + taxane-based chemotherapy (ICON4) = 35; carboplatin + liposomal doxorubicin (CALYPSO) = 22; platinum-based chemotherapy + bevacizumab (OCEANS = 35; GOG 213 = 26). NHB scores based on germline-BRCA alterations were maintenance niraparib (NOVA) = 50 and maintenance olaparib (Study 19) = 62; wild-type BRCA, maintenance niraparib = 36 and maintenance olaparib = 33; and HRD-positive status, maintenance niraparib = 42. Patients valued clinical benefit as the most important component of NHB. Patients valued OS as the most important component of clinical benefit, followed by response rate (RR), then PFS. Patient-weighted NHB were significantly lower than ASCO-weighted scores (mean NHB 37.8 versus 23.5; p=0.009) due to decreased preference for PFS compared to other clinical benefit measures (Table). Conclusions: NHB scores for treatment of PSROC were highest in women with germline-BRCA and HRD tumor alterations who were treated with maintenance PARPi. Our data suggest that a patient-centered NHBs can be used to inform treatment decisions. [Table: see text]
Randomized surgical multicenter trial to evaluate the usefulness of lymphoscintigraphy (LSG) prior to sentinel node biopsy (SLNB) in early breast cancer: SenSzi (GBG80) trial.
Authors: Kummel Sherko , Holtschmidt Johannes , Gerber Bernd , Von der Assen Albert , Heil Joerg , Thill Marc , Krug David , Schem Christian , Denkert Carsten , Lubitz Juliane , Blohmer Jens Uwe , Hötzeld Michael , Seither Fenja , Nekljudova Valentina , Schwidde Ilka , Uhrhan Klara , Von Minckwitz Gunter , Rezai Mahdi , Loibl Sibylle , Kuehn Thorsten
Published: September 2018

555

Background: It is not clear whether SLNB performed with LSG is necessary to reliably detect sentinel lymph nodes (SLN) in breast cancer. The omission of LSG might offer an accelerated preoperative workflow, cost reduction, and the opportunity for developing innovative, safe detection strategies. Methods: Patients with cN0 early breast cancer or extensive/high grade DCIS received standard radiolabeled colloid LSG and SLNB. Patients were randomized 1:1 to either conducting SLNB with the performing surgeon knowing the preoperative LSG pictures and results or without knowledge of the LSG results. Since the false negative rate (FNR) of SLNB correlates with the number of harvested SLN, our primary endpoint was the average number of histologically detected SLN per patient in both treatment arms in a non-inferiority design. An average number of 2.7 SLN with a standard deviation of 1.8 was assumed. LSG of all patients were collected postoperatively for central review. Results: Between May 2014 and October 2015 n = 1198 patients were randomized in 23 participating breast centers. Baseline characteristics were well-balanced between the treatment arms. Modified intention-to-treat analysis (n = 1163) confirmed the omission of LSG. The average number of histologically detected SLN was 2.207 with LSG and 2.258 without. The range for the one-sided 95% CI for the difference between the arms was (-0.18, +infinity), i.e. above the pre-specified non-inferiority margin of -0.27. Secondary endpoints were analyzed to rule out differences in reliable detection of nodal metastases. Rates of nodal positive disease as identified by SLNB (Odds ratio (OR) 1.005, 95%CI (0.759, 1.33), p = 0.972) and rates of completion axillary dissection (OR 0.984, 95% CI (0.567, 1.71), p = 0.954) in the two treatment arms and in specific subgroups showed no statistically significant differences. Conclusions: Our results support the hypothesis that SLNB is equally effective irrespective of the knowledge of preoperative LSG results. We therefore suggest performing SLNB without LSG to accelerate the preoperative workflow, reduce costs, and improve the comfort for the patients. Clinical trial information: NCT02481128.
Should MMMT of the endometrium/ovary be treated with anthracycline instead of taxane based chemotherapy?
Authors: Heinzelmann-Schwarz Viola A. , Russell Kenneth , Omar Siti , Schoetzau Andreas , Hoeck Kerstin , Vetter Marcus , Fink Daniel A. , Friedlander Michael , Hacker Neville F.
Published: September 2018

5563

Background: Carcinosarcomas of endometrial (MMMT-E) and ovarian (MMMT-O) origin are rare biphasic tumors, associated with poor prognosis and thought to be epithelial in origin. In view of this, there has been a shift towards carboplatin and paclitaxel rather than anthracycline based chemotherapy regimens which were used when they were treated as “sarcomas”. The purpose of this large retrospective study is to determine whether this change in chemotherapy is associated with better outcomes. Methods: Firstly, clinicopathological features of patients with all stages of MMMT-E (n=103) and -O (n=17) were compared to patients with adenocarcinoma of the endometrium (n=172) and ovary (n=189) in a case-controlled study. Clinicopathological characteristics, FIGO stage, first-line regimens and patient outcomes were analyzed. Secondly, primary tumor specimens of high grade serous ovarian cancers (HGSOC, n=1290) and MMMT-O (n=450) from an independent cohort were analyzed using immunohistochemistry and next generation sequencing to predict response to chemotherapeutic agents. Results: MMMT have a poor prognosis, however, there was a plateau in survival of MMMT-E after 2.5 years in patients with FIGO stage I/II disease, with no recurrence/cancer deaths observed beyond this. There was a statistically significant worse relapse-free survival in patients with MMMT-E treated with carboplatin and paclitaxel compared to carboplatin and anthracyclines (p=0.0011). In the second independent prospective cohort comparing HGSOC versus MMMT-O, both were driven predominantly by p53 mutations. MMMT-O expressed statistically more commonly PI3KCA and KRAS (p=0.015 and 0.018), respectively. Of particular interest, both HGSOC and MMMT-O showed a higher percentage of probability of responding to a combination of carboplatin/anthracyclins (71.2 vs. 73.9%) than carboplatin/taxanes (58.4 vs 39.4%). Conclusions: Patients with MMMT-E and stage I/II have an excellent prognosis if there is no recurrence by 2.5 years. Platinum/anthracyclines regimens appear to be associated with a better outcome than platinum/taxane in MMMT-E and MMMT-O. This could be tested in an international prospective randomized controlled trial.
Predictors of stopping chemotherapy early and short survival in patients with potentially platinum sensitive (PPS) recurrent ovarian cancer (ROC) who have had ≥3 lines of prior chemotherapy: The GCIG symptom benefit study (SBS).
Authors: Roncolato Felicia , Joly Florence , O'Connell Rachel , Lanceley Anne , Heitz Florian , Buizen Luke , Okamoto Aikou , Aotani Eriko , Salutari Vanda , Donnellan Paul P. , Oza Amit M. , Avall-Lundqvist Elisabeth , Berek Jonathan S. , Hilpert Felix , Feeney Amanda , Roemer-Becuwe Celia , Stockler Martin R. , King Madeleine Trudy , Friedlander Michael ,   GCIG Symptom Benefit Study Group
Published: September 2018

5575

Background: PPS ROC is defined by a platinum free interval > 6 months. Women starting ≥3 lines of chemotherapy for PPS ROC are however a heterogeneous group with variable response to chemotherapy and OS. We sought to identify baseline characteristics (health related quality of life [HRQL] and clinical features) that were associated with stopping chemotherapy early and shorter OS to improve patient selection for palliative chemotherapy. Methods: 378 women with PPS ROC starting ≥3 lines chemotherapy enrolled in GCIG SBS. HRQL was assessed with EORTC QLQ-C30/QLQ-OV28. Associations with stopping chemotherapy early (by 8 weeks) were assessed with logistic regression. Associations with OS were assessed with Cox proportional hazards regression. Variables significant in univariable analysis (p < 0.05) were included as candidates for multivariable analyses using backward elimination to select those independently significant at p < 0.05. Results: Median age was 64 years. The line of chemotherapy was third in 40%, fourth in 29%, and ≥ fifth in 31%. Chemotherapy was stopped early in 45/378 (12%) and their median OS was 3.4 months. Poor physical function (PF) and global health status (GHS) at baseline were significant univariable predictors of stopping chemotherapy early (p < 0.008); PF remained significant in a multivariable model adjusting for clinical factors (haemoglobin [Hb], ascites, abdominal cramps, neutrophil: lymphocyte≥5, platelets, log CA125); p = 0.03. Median OS in the whole group was 16.6 months. PF, role function, GHS and abdominal/GI symptoms were significant univariable predictors of OS (p < 0.001); PF and GHS remained significant predictors of OS in multivariable models including Hb, ascites, neutrophil: lymphocyte≥5, platelets, log CA125, ECOG and BMI (p < 0.007). Conclusions: In women with PPS ROC ≥3 lines chemotherapy, baseline PF and GHS are independent significant predictors of stopping chemotherapy early and short OS. HRQOL is easily measured, prognostic and may improve clinical trial stratification, patient-doctor communication and support clinical decision making. Clinical trial information: 12607000603415.
Open label phase II clinical trial of orteronel (TAK-700) in metastatic or advanced non-resectable granulosa cell ovarian tumors: The Greko II study.
Authors: García-Donas Jesús , Garrigos Laia , Lainez Nuria , Santaballa Ana , Redondo Andres , Cueva Juan Fernando , Rubio M Jesus , Prieto Mario , Lopez-Guerrero Jose Antonio , Garcia-Casado Zaida , Grande Enrique , Guerra Alia Eva , Bover Isabel , Hernando Polo Susana , Sanchez-escribano Ricardo , Hurtado Alicia , Navarro Paloma , Rodriguez-Moreno Juan Francisco ,   GETHI (Spanish Group for Orphan and Unfrequent Tumors)
Published: September 2018

5577

Background: Granulosa-cell tumors (GCT) of the ovary are a rare entity characterized by presenting a punctual mutation at the FOXL2 gene 402C→G (C134W). Such mutation leads to a disregulation and overstimulation of the steroidogenic pathway and, ultimately, hormone overproduction. A prior trial by our group (GREKO I trial-GETHI 2011-03; NCT01584297) showed promising activity of ketoconazole, a CYP17 inhibitor used to control steroidogenesis in several conditions. Thus, we aimed to assess the activity of Orteronel (TAK700), a selective inhibitor of 17, 20-lyase, in GCT. Methods: An open-label phase II single arm clinical trial was designed for women with metastatic or locally advanced non-resectable GCT who harbored the somatic mutation FOXL2 402C→G (C134W) and who had not received prior treatment with any CYP17 inhibitor. Treatment consisted on Orteronel 300mg BID, given orally, continuously in a 28-day treatment cycle. The primary objective was clinical benefit rate; secondary objectives were response rate, progression free and overall survival, assessment of the impact of Orteronel in reducing hormonal overproduction and toxicity. Sample size calculation was based on a two stage Simon´s design. A power of 80% was set to differentiate between a 5% and a 25% clinical benefit rate. 20% of losses had been assumed thus 20 patients were scheduled to be enrolled. Results: Since 30/06/2014 to 11/01/2017 10 patients have been included in 9 participating institutions members of Spanish Group for Research in Orphan and Unfrequent Tumors (GETHI). Due to a low recrutiment rate the study was terminated early. Median PFS was 3 months 95%CI (0-12) with 3 patients achieving disease stabilization longer than 12 months. 2 patients remain on treatment after 16 and 14 months. Clinical benefit rate (CR + PR + SD) was 50%, 95%CI (19%-81%). Seven patients have progressed and 2 have died. Only 6 suspected unresected adverse reactions (SUSARs) have been communicated so far (chest pain, fever, febrile neutropenia, eosinophila, neutropenia and anemia). Conclusions: Orteronel achieved a significant clinical benefit in advanced GCT with an favorable toxicity profile. Clinical trial information: NCT02101684.
Activity of lurbinectedin (PM01183) as single agent and in combination in patients with endometrial cancer.
Authors: Forster Martin David , Moreno Victor , Boni Valentina , Guerra Eva , Poveda Andres , Kristeleit Rebecca , Kahatt Carmen Maria , Lardelli Pilar , Lopez Vilarino Jose Antonio , Cuevas Nazly M , Soto-Matos Arturo , Calvo Emiliano
Published: September 2018

5586

Background: Lurbinectedin (L) is a new anticancer drug that blocks trans-activated transcription, induces DNA double-strand breaks and modulates the tumor microenvironment. Advanced endometrial cancer (EC) is an unmet medical need. Methods: Activity in EC patients was reviewed in 3 trials: a phase IB study of lurbinectedin combined with doxorubicin (L+DOX), a phase I study of PM combined with paclitaxel (L+TAX) and a phase II single-agent basket trial (L). Baseline characteristics, safety and efficacy were analyzed. Results: 97 patients were evaluated: 34 (2 cohorts) with L+DOX, 11 with L+TAX and 52 with L. Median age was similar in the 3 studies. Endometrioid was the most frequent histology. Median (range) of prior chemotherapy lines for advanced disease was: L+DOX, 1(0-2); L+TAX, 2(1-3); L, 1(0-2). Responses were observed in the 3 studies (see table). Main adverse event was myelosuppression (grade 3-4 neutropenia/thrombocytopenia/febrile neutropenia: L+DOX Cohort A, 94%/26%/40%; L+DOX Cohort B, 79%/10%/16%; L+TAX, 54%/0%/0%; L, 33%/6%/6%). Non-hematological toxicity was mostly grade 1-2: fatigue, nausea and vomiting, and transaminase increase. Conclusions: Lurbinectedin is active as single agent and in combination in patients with advanced EC, with remarkable activity in terms of response rate, duration of response and PFS when combined with doxorubicin. Safety was acceptable in L+DOX Cohort B, L+TAX and L, and myelosuppression was well managed. Clinical trial information: NCT01970540. [Table: see text]
Association of delayed adjuvant therapy and overall survival in early stage endometrial cancer.
Authors: Luo Leo , Shi Weiji , Zhang Zhigang , Tsai C. Jillian
Published: September 2018

5590

Background: The primary treatment for early stage endometrial cancer includes definitive surgical staging procedure followed by adjuvant therapy in women with high risk of recurrence. The optimal interval time between surgery and adjuvant therapy is unclear. Methods: 349,404 patients with primary uterine carcinoma diagnosed from 2004 and 2012 were extracted from National Cancer Database (NCDB). Study population was limited to patients with FIGO 2009 stage I and II endometrial cancer with endometroid, mucinous, clear cell, or serous histology. Adjuvant therapy included radiation therapy, chemotherapy, or a combination. A binary variable of interval time between surgery and adjuvant therapy (“early” vs. “delayed”) was created by using the median time as a cutoff. Analysis of relationship between the interval time and overall survival was performed. Results: Final analysis included 118,373 early stage endometrial cancer patients who had definitive surgical treatment. Median age was 61 (interquartile range 55-69). 87,189 patients (74%) had stage IA disease, 21,573 (18%) patients had stage IB disease, and 9,611 (8%) patients had stage II disease. 28,824 (24%) patients received adjuvant therapy after surgery. The median time from surgery to adjuvant therapy was 1.6 months (interquartile range 1.3-2.2 months). Of the patients that received adjuvant therapy, 48% received intra-vaginal brachytherapy alone, 31% received pelvic external beam radiation, and 7% received a combination of chemotherapy and brachytherapy. There was a significant difference in overall survival in patients who received adjuvant therapy within 1.6 months from surgery and 1.6 months after surgery (Log-rank test, p = 0.04). Patients with advanced age, African-American or Hispanic race, and uninsured status or government-sponsored insurance were associated with delayed treatments. Conclusions: In this large retrospective review of early stage endometrial cancer patients, delayed time between surgery and adjuvant therapy is associated with worse overall survival. Further analysis will be performed to determine an optimal timing between surgery and adjuvant therapy.
Evaluation of systemic and local immune responses in patients with endometrial cancer.
Authors: Ore Martin , Romero Ignacio , Garcia-Casado Zaida , Zorrero Cristina , Illueca Carmen , Lopez-Guerrero Jose Antonio , Poveda Andres
Published: September 2018

5594

Background: Several studies suggest that systemic immune response (SIR) and local immune response (LIR) have independent roles in multiple types of cancer. In endometrial cancer (EC), the correlation between SIR and LIR and its prognostic value remains unclear. Methods: A total of 146 EC patients (stage I-IV) who had undergone surgery from 2009 to 2015, were identified from a prospective institutional database. Lymphocyte/monocyte ratio (LMR) to represent SIR was calculated from preoperative blood samples. The presence of intratumoral and peritumoral infiltrating lymphocytes (TILs) on hematoxylin and eosin-stained slides was considered as a surrogate of LIR. LMR and TILs were correlated to pathological findings and survival outcomes (overall survival: OS, disease free survival: DFS). Results: A LMR cutoff value of 4.4 for survival was determined based on receiver operating characteristic (ROC) curve analysis. LMR high was significantly associated with endometrioid histology (p=0.03), lower grade (G1-2; p=0.003), < 50% myometrial invasion (p=0.01) and I-II stage (p=0.02). TILs were correlated with MSI-high (p<0.005), but not with LMR (p=0.3). Low LMR was associated with worse 5-year OS rates (64.5% vs 93.9%; p<0.01) and presence of TILs with better 5-years OS rates (72% vs 27%; p=0.04). On multivariate analysis (table 1) LMR, histology, stage and grade remained independent prognostic factors for OS (p=0.01). Using the combination of LMR and TILs, four groups with decreasing 5-years OS rates were identified: LMR-high/TILs+ (100%) > LMR-high/no-TILs (87%) > LMR-low/TILs+ (71%) > LMR-low/no-TILs (61%). Conclusions: In our series of resected EC patients, SIR (defined by LMR) constituted an independent prognostic factor for OS and LIR for DFS. We did not find any correlation between SIR and LIR, but the combination of both higher SIR and LIR showed better OS. [Table: see text]
Axillary management in early breast cancer: Surgeon attitudes in a population-based study.
Authors: Morrow Monica , Katz Steven J. , Jagsi Reshma
Published: September 2018

561

Background: The ACOSOG Z0011 trial established the safety of omitting axillary dissection (ALND) for patients with 1‒2 sentinel node (SN) metastases having breast-conserving therapy (BCT) to reduce treatment-related morbidity. Little is known about surgeon uptake of this practice. Methods: Women with stage I and II breast cancer diagnosed between 7/13‒8/15 (n=3729) reported to the Los Angeles and Georgia SEER registries were surveyed about 2 months after diagnosis. All attending surgeons identified by the patients (n=489) were sent a questionnaire and 77% (n=377) responded. Pathology reports for SN positive patients are under review. Results: Mean surgeon age was 54 years, 25% were female, and median years in practice was 21. 49% and 63% endorsed ALND for Z0011 eligible patients with 1 or 2 SN macrometastases, respectively. Surgeons were classified as low (n=92), selective (n=178), or high (n=91) users of ALND based on responses to case scenarios with SN involvement ranging from isolated tumor cells in 1 SN (12% would do ALND) to macrometastasis in 3 SNs (92% would do ALND). 93% of high-use surgeons would perform ALND for any SN macrometastasis vs 40% of selective surgeons and 1% of low-use surgeons (p<.001). High-use surgeons were older, male, saw fewer breast cancer patients, and were less likely to discuss cases in tumor board (Table). High-ALND users were substantially less likely to endorse BCT margins of no ink on tumor (40%) than selective (63%) or low users (83%; p<.001). Conclusions: Wide variation exists in acceptance of Z011 results with one-quarter of surgeons endorsing routine ALND. Surgeons favoring ALND also endorse wider margins for BCT, suggesting an overall more aggressive surgical approach. Lower breast volume and lack of tumor board participation identify surgeons who should be targeted for educational interventions. [Table: see text]
Evaluation of simplified lymphatic microsurgical preventing healing approach (SLYMPHA) for the prevention of breast cancer-related clinical lymphedema after axillary lymph node dissection.
Authors: Ozmen Tolga , Lazaro Mesa , Zhou Yan , Vinyard Alicia , Avisar Eli
Published: September 2018

563

Background: Lymphedema (LE) is a serious complication of axillary lymph node dissection (ALND) with an incidence rate of 16%. Lymphatic Microsurgical Preventing Healing Approach (LYMPHA) has been proposed as an effective adjunct to ALND for the prevention of LE. This procedure however requires microsurgical techniques. The aim of this study was to assess the efficiency of Simplified-LYMPHA (SLYMPHA) in preventing LE in a prospective cohort of patients. Methods: All patients, undergoing ALND with or without SLYMPHA between January 2014 and December 2016 were included in the study. SLYMPHA is a slightly modified and simplified version of LYMPHA. It is performed by the operating surgeon performing the ALND. One or more lymphatic channels identified by reverse arm mapping are inserted using a sleeve technique into the cut end of a neighboring vein. During follow-up visits, tape-measuring limb circumference method was used to detect clinical LE. Demographic, clinical, surgical and pathologic factors were recorded. The incidence of clinical LE was compared between ALND with and without SLYMPHA. Univariate and multivariate analysis were used to assess the role of other factors in the appearance of clinical LE. Results: 406 patients were included in the study. SLYMPHA procedure was attempted in 81 patients and was completed successfully in 90% of patients. Early complication rates were similar between patients who underwent SLYMPHA and who did not (4% vs. 4.13%; p = 0.948). Median follow-up time was 15±13.73 [1-32] months. Patients, who underwent SLYMPHA, had a significantly lower rate of clinical LE both in univariate and multivariate analysis (3% vs 19%; p = 0.001; OR 0.12 [0.03-0.5]). Excising > 22 lymph nodes and a co-diagnosis of diabetes were also correlated with higher clinical LE rates on univariate analysis, but only excising > 22 lymph nodes remained to be significant on multivariate analysis. Conclusions: SLYMPHA is a safe and relatively simple method, which decreases incidence of clinical LE dramatically. It should be considered as an adjunct procedure to ALND for all patients during initial surgery.
Trends in rates of modified radical mastectomies and bilateral mastectomies in unilateral breast cancer.
Authors: Bulbul Ajaz , Braik Tareq , Rashad Sadaf , Mino Emilio Araujo , Bautista Adrianna , Khorsand-Sahbaie Masoud , Tripathy Debu ,   Kymera Physicians
Published: September 2018

569

Background: Women with unilateral breast cancer (BC) without genetic predisposition have a low risk for local and contralateral recurrence with breast conservation surgery (BCS) and adjuvant treatment. We aimed to study the pattern of surgical care across centers in rural New Mexico and its correlation to clinical outcomes. Methods: We retrospectively evaluated 533 patients with Stage 1-3 BC diagnosed between January 1989 to October 2015. Clinical Outcomes with BCS, sentinel lymph node dissection (SLND), simple mastectomy (SM), modified radical mastectomy (MRM) and Bilateral Mastectomy (BM) were studied. Descriptive statistics were performed to describe the proportion of surgery types. Predictors of clinical outcomes were evaluated by multivariate logistic regression. Results: Out of 533 patients, 510 (82%) had early stage (0-3) resectable BC. Among these, 48% (246/510) had either MRM (209/510) or BM (37/510). MRM was performed in 3% of stage 0 (6/209), 23% (49/209) stage I, 46%(97/209) of stage II and 27% (57/209) of Stage III patients. Overall, the rate of SLND was 42% among Early stage Breast cancer. Of 41 patients treated with bilateral mastectomy, 10 were positive for BRCA mutation, 6 for family history and 3 for contralateral disease. Median age of BM was 53 +12 y. The local recurrence rate was 8.8% (45/510), and metastatic recurrence rate was 15.5% (79/510). Lymphedema rate was 9.2% (47/510). Using MRM as reference, the Odds Ratio (OR) for lymphedema after BM and BCT were 2.15 (95% CI, 0.84-5.50) and 0.58 (0.28-1.22), respectively. With 9.6 years of median follow up, the predictive probabilities of lymphedema after BCT, SM, MRM and BM were 1%, 4%, 9% and 18%. The OR for local recurrence in women with BCT were 1.46 (95th C/I: 0.72-2.95), SM 0.27 (0.03-2.13), BM 2.06 (95th C/I:0.70-6.06). Conclusions: Less BCT and more aggressive procedures are being performed, and the latter is associated with more lymphedema. No significant differences were noted in local recurrences. Presence of a genetic mutation was not the sole indicator of BM’s in our patient population. There is a need for evidence-based shared decision-making and surgical management of breast cancer, especially in a rural community setting.
Effect of neoadjuvant chemotherapy regimen choice in patients with breast cancer with pathologic complete response.
Authors: Weiss Anna , Bashour Sami , Hsu Limin , Hess Kenneth R. , Thompson Alastair Mark , Ibrahim Nuhad K.
Published: September 2018

570

Background: Breast cancer patients with a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) have improved survival. We hypothesize there is no difference in post-surgical recurrence free survival (RFS) between regimens used if pCR has been achieved. Methods: Breast cancer patients treated with NACT (using various regimens) between 1996 and 2011 who achieved pCR were examined, using a prospectively maintained electronic database. RFS was estimated by Kaplan-Meier method, differences between groups assessed using log-rank test. Cox proportional hazards regression analysis adjusted for age, menopausal status, stage, grade, tumor subtype, and adjuvant treatments. Results: 721 patients were identified: 40.4% Stage IIA, 21.2% IIB, 10.8% IIIA, 9.2% IIIB, 18.3% IIIC. 21.8% were hormone receptor positive (HR), 43.3% HER2 amplified, 32.7% triple negative. 50.9% of patients were treated with adriamycin-based chemotherapy plus taxane (adriamycin+taxane), 7.8% without taxane (adriamycin-taxane), 31.5% HER2 targeted therapy, and 9.8% provider choice. Median follow up was 7.4 years. There was no significant difference in RFS by treatment group (table 1). Adjusted RFS hazard ratios comparing each treatment to adriamycin+taxane were 1.25 (95% confidence interval 0.47-3.35) adriamycin-taxane, 0.90 (CI 0.37-2.20) HER2 targeted, and 1.28 (CI 0.55-2.98) provider choice. Conclusions: These data suggest that post-surgical RFS among patients with pCR is not significantly influenced by the type of NACT. Meta-analysis of randomized trial data should be explored to evaluate these findings. If RFS of pCR patients is not affected by regimen, this could allow flexibility in treatment choice and length. [Table: see text]
Improving pathological response in locally advanced triple negative breast cancer: Comparison between CbD and AC-T regimens.
Authors: Enriquez Daniel , Poma Nieto Nathaly , Fuentes Hugo Alejandro , Guerra Henry , Ruiz Mendoza Rossana Esther , Gomez Henry Leonidas
Published: September 2018

585

Background: Pathological complete response (pCR) is a well-known surrogate for DFS and OS in triple negative breast cancer (TNBC). New approaches are being tested to increase pCR rate. We compared the standard of care (AC-T) vs Carboplatin/Docetaxel (CbD) for locally-advanced TNBC. Our objective is to determine whether CbD will increase the pCR rate, with PFS and OS as secondary objectives. Methods: A single arm phase II prospective trial with historical controls. 61 stage II-III TNBC patients were included between 2013-2014 at Instituto Nacional de Enfermedades Neoplasicas (Peru). 27 patients received Carboplatin 6AUC + Docetaxel 75mg/m2 q21d for 6cy, and 34pts, Adriamycin 60mg/m2 + Cyclophosphamide 600mg/m2 q21d for 4cy followed by weekly paclitaxel 80mg/m2 for 12 weeks. The Miller and Payne method was used to evaluate pathological response after definitive surgery. Results: Median age was 47 years, most patients were premenopausal (55.7%), median tumor size was 61 mm (T3=32.8%, T4=50.8%) and most patients had LN+ve (77%). There was a significantly greater tumor size in the CbD arm (mean 72.8 vs 52.2mm, p=0.007), no toxicity differences were noted. Only pCR was independently associated with OS/PFS on multivariate analysis. pCR was achieved in 37% (n=10) and 23.5% (n=8) in the CbD and AC-T groups, respectively (p=0.44). Partial pathological response was achieved in 37% (n=10) and 38.2% (n=13) patients in AC-T and CbD respectively. No characteristics were associated to pCR on logistic regression. At 2-year follow-up, all patients with pCR were alive and without recurrence, while patients with partial response achieved a 2-year PFS of 75% and, 2-year OS of 83.5%. The non-respondent group had the worse outcomes (2-year PFS: 32.7%, 2-year OS: 58.7%). The CbD group had a better 2-year PFS and OS (73.1% and 84%, respectively) than the AC-T group (59.3% and 71%, respectively), however no-statistical difference was found. Conclusions: CbD is an effective and promising neoadjuvant chemotherapy regimen for TNBC. Despite a larger mean tumor size in the CbD group, a non-significant trend towards higher pCR rate and longer PFS and OS was observed and warrants further exploration.