bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and tolerance of androgen receptor antagonists in nonmetastatic, castration-resistant prostate cancer.
Authors: Wongsaengsak Sariya , Jahan Nusrat , Hardwicke Fred L.
Published: May 2020

e17607

Background: Metastatic castration resistant prostate cancer (mCRPC) is a fatal disease. Nonmetastatic, castration-resistant prostate cancer (nmCRPC) often predates mCRPC. Recently, three androgen receptor (AR) antagonists i.e. apalutamide, enzalutamide, and darolutamide have been approved for nmCRPC. Nonetheless, any new therapeutic approach poses new safety concerns. We conducted a systematic review and meta-analysis of the published phase 3 randomized controlled trials (RCTs) to determine the safety and tolerance of AR-antagonists in nmCRPC patients. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until November 2019. Published phase 3 RCTs using AR-antagonists in the study arm for nmCRPC were included in the analyses. We used Mantel-Haenszel (MH) method and random effects model to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) comprising 2687 patients in the AR-antagonist arm and 1417 patients in the control arm were included in the final analysis. AR-antagonists used in the study arms were following— ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy (ADT). Randomization was 2:1 in all studies. No publication bias was appreciated all three studies. The pooled RR of any-grade adverse events (AEs) is 1.08 (95% CI: 1.02 – 1.14, p = 0.01, I2 = 79%) which was statistically significant. The pooled RR of grade ≥ 3 AEs was also significant at 1.32 (95% CI: 1.19 – 1.46, p < 0.00001, I2 = 0%). The pooled RR of grade 5 event is 2.67 (95% CI: 0.79 – 9.02, p = 0.11, I2 = 70%) which was not statistically significant. The pooled RR for discontinuation of treatment regimen was also statistically significant at 1.31 (95% CI: 1.00 – 1.72, p = 0.05, I2 = 35%). Conclusions: In nmCRPC patients, AR-antagonists in combination with ADT is associated with a mild increase risk of any-grade AEs, grade ≥3 AEs, and treatment discontinuation secondary AEs. However, AR-antagonists were not associated with a significantly increased risk of death due to AEs. Careful clinical vigilance and timely intervention with appropriate supportive care are critical to prevent AEs related morbidities and prevent treatment discontinuation.
Sequential or concomitant radiotherapy treatment for patients with localized prostate cancer.
Authors: Venkitaraman Ramachandran , Harihar Lakshmi , Sabar Muhammad , Scrase Christopher D.
Published: May 2020

e17610

Background: External Beam radiotherapy is a standard treatment for patients with intermediate risk localised prostate cancer. Commonly the radiotherapy plan is delivered in two phases with adequate margins, the first phase to the prostate and seminal vesicles and the second phase to the prostate alone. The two phases can be delivered by intensity modulated radiotherapy as a sequential or concomitant treatment. We compared the toxicities and clinical outcomes of patients who received radiotherapy either as sequential or as concomitant treatment. Methods: Two hundred and twenty five consecutive patients with intermediate risk prostate cancer were included in the study. The patients who had sequential treatment received 60 Gy in 30 fractions to the prostate and seminal vesicles,, while patients who had concomitant treatment received 60 Gy in 37 fractions. All patients received 74 Gy in 37 fractions to the prostate. The Genitourinary (GU) and Gastrointestinal (GI) toxicity data and outcomes in terms of biochemical progression free survival were compared. Results: One hundred eighty patients received sequential radiotherapy, while forty five patients received concomitant radiotherapy. Acute GI toxicity was significantly less in the patients who received concomitant radiotherapy, during weeks four(p = 0.03), six(p = 0.03) and eight(p = 0.06) of treatment, compared to patients who receive sequential radiotherapy. Acute GU toxicities were similar in both groups of patients during treatment. Late GU and GI toxicity at 1 year and 2 years were similar. 3 year biochemical Progression free survival was 90 % for patients who received either sequential compared to 75 % for patients who received concomitant radiotherapy, though not statistically significant (log rank p value = 0.173). Conclusions: Concomitant radiotherapy to prostate and seminal vesicles resulted in lower acute gastrointestinal toxicity compared to sequential radiotherapy to the prostate and seminal vesicles as two phases. The genitourinary and late toxicities were similar. Biochemical progression free survival for patients who received concomitant radiotherapy treatment, could however be inferior to sequential treatment, probably due to the lower dose per fraction to the seminal vesicles and margins.
Dendritic cell vaccine as an alternative to opioid analgesia in patients with advanced cervical cancer.
Authors: Menshenina Anna P. , Kit Oleg I. , Frantsiyants Elena M. , Moiseenko Tatiana I. , Verenikina Ekaterina V. , Tumanyan Sergey V. , Dzhenkova Elena A. , Chalabova Tatiana G. , Selezneva Olga G. , Cherkasova Anna A.
Published: May 2020

e18022

Background: Locally advanced and progressive cervical cancer is always accompanied by the pain syndrome. The common analgesics include non-steroidal anti-inflammatory drugs and opioids. The purpose of the study was to assess allogeneic dendritic cell vaccine (DCV) as an alternative analgesic in patients with advanced cervical cancer. Methods: The pain syndrome dynamics was assessed in 20 patients with advanced T3-4N1M0-1 cervical cancer receiving subcutaneous paravertebral injections of allogeneic DCV in a total alternating dose of 5-10 million cells every 2 weeks. Patients received DCV for one year, with a total of 24 vaccine therapy sessions and a total dosage of 180 million dendritic cells. The pain intensity was assessed on a verbal rating scale: 0 – no pain; 1 – mild pain; 2 – moderate pain; 3 – severe pain; 4 – extremely intense pain. Results: Prior to the therapy, 15 patients (75%) had severe pain; 2 (10%) - moderate pain; 3 (15%) - extremely intense pain. After 4-6 DCV injections, the pain intensity decreased, patients refused opioid analgesics. After 10-12 DCV sessions, 19 (95%) (p < 0.05) women had no pain at all, patients denied additional pain relief with non-opioid analgesics. Unrelieved pain was registered only in one cervical cancer patient. Conclusions: DCV injections in patients with advanced cervical cancer provide pain relief thereby improving their quality of life.
Hormonal rehabilitation in patients with endothelial and cervical cancers.
Authors: Chernikova Natalia V. , Moiseenko Tatiana I. , Shikhlyarova Alla I. , Verenikina Ekaterina V. , Poryvaev Yuriy A. , Myagkova Tatiana Yu. , Kruze Polina A. , Zhenilo Oksana E. , Cherkasova Anna A. , Chalabova Tatiana G. , Kit Oleg I.
Published: May 2020

e18025

Background: Young patients with early stages of gynecological cancers often go through surgical menopause which worsens the quality of life affecting social, sexual, psycho-emotional, cognitive spheres, and causes somatic diseases rare in a young age. The purpose of the study was to evaluate the clinical effectiveness of medical and hormone replacement therapy (HRT) in patients with endothelial (EC) and cervical cancers (CC) of the reproductive age after surgical treatment. Methods: Clinical data and adaptive reactions were studied in 346 patients with stage Ia-IIa EC and CC aged 20-45 years after combination treatment. Patients were divided into 3 groups: group 1 – 192 patients, estrogen/gestagen HRT; group 2 – 112 patients, treatment with phytoestrogens; group 3 – 42 patients choosing not to have any adjuvant therapy. The Kupperman index was used to evaluate the severity of a post-castration syndrome. Results: In group 1, 158 women (82.3%) showed normal somatic and psychoemotional status and adequate cognitive functions, the Kupperman index ≤20; 34 (17.7%) patients of group 1 needed additional sedation, the Kupperman index = 30; adaptive reactions included reactions of training and adaptation. In group 2, 112 patients (100%) demonstrated moderate hormonal imbalance signs: vegetative and emotional disorders, decreased libido, manifestations of the metabolic syndrome, the Kupperman index = 30-35; adaptive reactions included reactions of training and stress. All patients of group 3 (n = 42) developed metabolic disorders shortly after surgical castration, with social, sexual and psycho-emotional disadaptation, the Kupperman index = 35 (reactions of stress). Conclusions: Combination HRT after surgical castration contributes to full adaptation in the social, sexual, psycho-emotional spheres of life in patients of the reproductive age, restoring the quality of life without affecting the prognosis.
Patient-reported outcomes (PRO) in the GARNET trial in patients (pts) with advanced or recurrent dMMR/MSI-H endometrial cancer (EC) treated with dostarlimab.
Authors: Kristeleit Rebecca Sophie , Mathews Cara Amanda , Redondo Andres , Huang Joice , Eliason Laurie , Im Ellie , Brown Jubilee
Published: May 2020

e18032

Background: PRO enable direct measurement of the experiences of patients with cancer. Anti-programmed death 1 (PD-1) therapies have shown favorable PRO in lung cancer but a data gap remains in EC. Dostarlimab is an investigational anti-PD-1 monoclonal antibody which has shown promising activity in GARNET in advanced mismatch repair deficient (dMMR) EC pts (with an ORR of 42.9% and a disease control rate of 58.6%), and a low incidence of symptomatic grade ≥3 treatment-related adverse events (anemia [2·9%], colitis [1·9%], and diarrhea [1·9%]). Here, we report on PRO measures collected from pts with dMMR/microsattelite instability high (MSI-H) EC in the single-arm GARNET trial. Methods: Pts with dMMR/MSI-H EC confirmed by local tests, with recurrent or advanced disease that progressed on a platinum regimen were enrolled. Pts received 500 mg Q3W of dostarlimab for 4 cycles, then 1000 mg Q6W until disease progression or discontinuation. PRO assessment was an exploratory endpoint and was measured by the EORTC Quality of Life Questionnaire (QLQ-C30), a validated instrument used to evaluate quality of life, functioning, disease symptoms, and treatment-related side effects. PRO were collected at each dose administration, end of treatment, and follow-up. A mixed-model for repeated measures was used to assess change from baseline, accounting for time and baseline ECOG scores. The threshold to determine clinically meaningful group-level change was ±10 points. Results: PRO data were available for 43 pts. Compliance rates were high at 98%. Relative to baseline, pts reported meaningful improvements in pain, insomnia, and social and emotional functioning over the trial duration. Appetite, nausea, vomiting, constipation, diarrhea, and physical and role functioning were stable over the trial duration. Quality of life and global health status were also maintained. Conclusions: PRO from 43 pts enrolled in the GARNET trial show that disease- and treatment-related symptoms and quality of life are improved or maintained while receiving treatment. These data, along with with the efficacy and safety profile of dostarlimab, strongly support the use of dostarlimab in dMMR/MSI-H advanced EC. Clinical trial information: NCT02715284.
Outcomes among women with brain metastases from gynecologic (gyn) malignancies.
Authors: Cagino Kristen , Kahn Ryan , Chan Susie , Thomas Charlene , Christos Paul J. , Pannullo Susan , Ashmalla Hani , Holcomb Kevin , Frey Melissa Kristen , Chapman-Davis Eloise
Published: May 2020

e18034

Background: Brain metastasis secondary to gyn malignancy is rare and associated with poor prognosis, with limited available data and no definitive management guidelines. We aimed to identify factors and treatments associated with improved overall survival (OS). Methods: Patients were identified retrospectively with brain metastases from gyn malignancies between 2004-2019. Descriptive statistics were used to describe the cohort of patients using N (%) and median [IQR] for categorical and continuous variables, respectively. Univariate cox proportional hazards regression was performed to evaluate the effect of different prognostic factors on OS. Results: 32 patients presented with brain metastasis from gyn primaries (ovarian/primary peritoneal n = 14, cervical n = 7, uterine n = 11). Median age of initial cancer diagnosis was 62 (54-59). At initial diagnosis 83% of patients were Stage III/IV and underwent surgical management (56%), chemotherapy (100%), or pelvic radiation (31%). The median time from cancer diagnosis to brain metastasis was 18mos. 66% presented with multiple; 34% with isolated brain metastases. The most common presenting symptoms were extremity weakness/numbness (78%), seizures (34%), and headaches (28%). Surgical resection was most often combined with stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT) (Table 1). Median survival from date of brain metastases was longer in patients treated by SRS alone compared to WBRT alone (95 vs 11 mos). Treatment with SRS + Surgery compared to SRS or WBRT alone revealed a trend toward improved OS (p = .06; p = .07). Increased time from initial cancer diagnosis to brain metastasis was associated with improved OS, with one-month increase in time associated with a 7% reduction in risk of death (p = 0.01). Initial cancer treatment, Stage, histology, and number of brain lesions did not affect OS. Conclusions: Patients with brain metastasis secondary to gyn malignancies with the longest OS had the greatest lag time between initial cancer diagnosis and brain metastasis diagnosis. Treatment with multimodal therapy with radiation and surgical resection was associated with the longest OS. [Table: see text]
Real-world treatment patterns of maintenance therapy in platinum-sensitive recurrent epithelial ovarian cancer: Are some patients missing out?
Authors: Moss Haley , Secord Angeles Alvarez , Perhanidis Jessica , Hawkes Carol
Published: May 2020

e18042

Background: The clinical utility of maintenance therapy (MT) for patients with platinum-sensitive recurrent ovarian cancer (PSROC) has been validated in several clinical trials. We assessed real world treatment patterns using a US nationwide electronic health record database. Methods: A retrospective study of patients with PSROC between March 2017 and July 2019 was conducted using the Flatiron Health database. This longitudinal, demographically and geographically diverse de-identified database covers > 2.2 million oncology patients in > 280 cancer clinics. Patients were excluded if second or third line (2L or 3L) platinum-based chemotherapy (PBT) regimens included less than four or more than eight cycles of platinum. Information regarding somatic or germline BRCA mutations and homologous recombination deficiency (HRD) were obtained. Results: 2292 patients with PSROC were identified (had 2L or 3L treatment); 1214 of these received PBT at recurrence; 610 completed the PBT for recurrence on or after March 2017; 351 received 4–8 cycles of PBT; 225 patients had ≥2 months of active surveillance or were receiving MT of PARPi or bevacizumab (B) and were included in this analysis. 183 patients (80%) had BRCA testing and 14 patients (6%) had HRD testing. 46 (20%) had a germline or somatic BRCA mutations (t BRCA), 134 (59%) had a wildtype wt BRCA gene, and 48 (21%) were unknown. Of patients with tBRCA, 63% received a PARP inhibitor (PARPi), 17% received B, 20% received active surveillance. Of patients with wt BRCA, 40% received a PARPi, 24% received B, and 37% received active surveillance. Olaparib was the most commonly used PARPi among tBRCA patients (26%), while niraparib was most commonly used among wt BRCA patients (21%). MT was more common in younger patients, those with a better performance status and with a BRCA mutation. MT use trend increased by 21% during the study period. As PARPi use increased, the use of active surveillance as a post-platinum regimen decreased during the later time periods (Table). Conclusions: In this real world population, the majority of patients with PSROC are receiving maintenance therapy. While genetic testing is improving, universal testing of all patients with ovarian cancer remains the goal. The results provide insight into the shifting treatment patterns for patients with ovarian cancer. [Table: see text]
CRS + HIPEC in stage IIIc epithelial ovarian cancer and comparison of oncological outcome only with CRS and IV chemotherapy and CRS + IP chemotherapy.
Authors: Somashekhar S.P. , C. Rohit Kumar , Rajgopal Ashwin K. , Yethadka Ramya , Zaveri Shabber , Ahuja Vijay , Rauthan Amit , Patil Poonam
Published: May 2020

e18054

Background: Our study aims to describe role of CRS & HIPEC in stage IIIC epithelial ovarian malignancy & compare the oncological outcome (DFS & OS) of extensive CRS+ HIPEC in comparison with CRS & IV chemotherapy & CRS + IP chemotherapy. Methods: Patients diagnosed of stage IIIc EOC underwent extensive CRS + HIPEC. All data prospectively entered in the HIPEC registry was analysed. Outcome of CRS & IV group (n = 50), CRS + IP group (n = 60) operated around same period was compared with the CRS & HIPEC group. Results: Out of 135 patients, upfront, interval and secondary cytoreduction plus HIPEC was done in 29.6%, 44.4% & 25.9% & mean PCI was 14.1, 9.6 & 13.0 respectively. Multi-visceral resection, diaphragmatic resection & bowel resection was required in 12.7%, 50% & 41.8% respectively. Overall G3- G5 morbidity was seen in 25.4% with major being electrolyte imbalance 16.3%, hematological 12.7% & surgical 11.8%. Mean ICU & hospital stay 1.5 & 11 days respectively. Overall 30 day mortality was 4.5%. With a median follow up of 42 months DFS was 30, 33 & 16 months and OS was 70%, 67% & 51% at 4 year for upfront, interval and the recurrent settings respectively. Detailed description presented in Table. Most of the recurrences in CRS & IV group were in peritoneum whereas the other two groups had lesser peritoneal & systemic recurrence. Conclusions: Optimal cytoreduction & some form of IP therapy is needed to improve outcomes. CRS+ HIPEC is feasible in all groups of ovarian cancer with acceptable morbidity & mortality. However the role of single HIPEC in comparison to 6 cycles of IP chemotherapy needs to be evaluated with a well-designed multi-institutional randomised study. [Table: see text]
Sex cord stromal and germ cell ovarian cancer: Is there a racial disparity?
Authors: Reyes Fatima , Guerra Rosa , Liao Cheng-I , Argueta Chris , Mann Amandeep Kaur , Abel Mary Kathryn , Kapp Daniel Stuart , Chan John K.
Published: May 2020

e18056

Background: We proposed to determine the incidence and presentation of sex cord stromal and germ cell ovarian cancers in various racial groups. Methods: Data was obtained from the United States Cancer Statistics (USCS) and National Cancer Database (NCDB) databases between 2004 and 2016. Chi-squared tests were used for statistical analyses. Results: Of 8,917 women, 48.2% were diagnosed with sex cord stromal ovarian cancer, and 52.5% had germ cell ovarian cancer. White, Black, and Asian individuals comprised 72.5%, 19.8%, and 4.16% of the population, respectively. Of the sex cord stromal tumors, 84.1% were granulosa cell, 7.9% sertoli leydig, 1.8% steroid cell, and 6.2% "other" tumors. Of the germ cell tumors, 23.3% were immature teratoma, 19.6% dysgerminoma, 10.3% yolk sac, 8.3% mixed germ cell tumor, 0.1% embryonal carcinoma, and 38.3% "other" germ cell tumor histologies. Using the UCSC database, the age-adjusted incidence of sex cord stromal was 0.50 per 100,000 for Blacks compared to 0.23 for Whites and 0.14 for Asians. The incidence for germ cell tumors was 0.40 per 100,000 in Whites, 0.46 in Blacks, and 0.44 in Asians. Using NCDB data, the proportion of sex cord stromal tumor was 5.6% in Blacks compared to 1.5% in Whites and 1.55% in Asians, and the most common histology of sex cord stromal tumors was granulosa cell tumors in every racial group. The proportion of germ cell tumors was also higher in Blacks at 4.4% compared to 2.0% in Whites and 3.9% in Asians. Of germ cell tumors, the most common histology was dysgerminoma for Whites at 22.3% and immature teratoma in Blacks and Asians at 28.0% and 26.9%, respectively. Conclusions: Our data suggest that Black women are more likely to be diagnosed with sex cord stromal tumors compared to White and Asian women. Black and Asian women also had more germ cell cancer than White women.
Surface-modified nanoparticle transport evaluated in a multistage model of ovarian cancer.
Authors: Winter Stephen , Miller Hunter , Frieboes Hermann , Steinbach-Rankins Jill
Published: May 2020

e18057

Background: A novel multi-stage model composed of ovarian cancer (SKOV-3) and fibroblast (MRC-5) cells was developed to provide a physiologically relevant in vitro platform to assess nanoparticle (NP) transport and aid in the development of more targeted clinical therapies. This multicellular ovarian tumor spheroid model is customized to the stages of ovarian cancer progression. The model leverages knowledge of these distinct stages in vivo to simulate their respective microenvironment, and thus provide a more accurate platform for evaluation of nanoparticle transport and drug delivery into ovarian tumor tissue. We hypothesized that alterations to the tumor microenvironment (TME) along with inclusion of a peptide-based scaffold (Puramatrix, PMX) to represent the site of metastasis, would lead to enhanced cell growth, migration and altered NP transport, which may be more indicative of the challenging transport conditions encountered in clinical ovarian cancer. Methods: In order to validate the in vitro model, tumor spheroid growth and invasion were evaluated while exposed to stromal cell activation and tissue hypoxia. MRC-5 activation was achieved via the TGF-ß1 mediated pathway, while tissue hypoxia was induced via incubation at 5% oxygen. PEG and MPG surface-modified NP transport was assessed in both stages of the model via confocal microscopy. Results: Consistent with in vivo observations in the ascites and site of distal metastasis, spheroids exposed to an activated stromal microenvironment were denser, more contractile and more invasive than their unactivated counterparts (p < 0.05). Additionally, hypoxic conditions, like those observed in the low pH environment of the ascites, resulted in negative spheroid radial growth over 5 days, compared to an increase for those cultured in normoxic conditions (p < 0.005). MPG-modified NPs exhibited superior tissue penetration relative to PEG-modified NPs in the ascites stage of the model (p < 0.05). Alternatively, PEG NPs enhanced penetration relative to MPG NPs when evaluated under metastatic conditions. In this case, NP transport was attenuated regardless of surface modification, due to the PMX-induced ECM reorganization. Conclusions: A novel multi-stage model, representative of ovarian cancer, was developed to evaluate NP transport in tumor tissue. We evaluated critical conditions in the microenvironment of ascites and metastasis and how these conditions may affect nanotherapy. Future studies will evaluate NP treatments by encapsulating a chemotherapeutic and measuring IC-50 values.
Use of clinical classification software to differentiate good versus poor prognostic patients with ovarian cancer: A SEER-Medicare database analysis from the viera study.
Authors: Adeboyeje Gboyega , Desai Kaushal , Iqbal Shahed , He Jinghua , Monberg Matthew J.
Published: May 2020

e18069

Background: Historically, recurrence in ovarian cancer (OC) following first-line (1L) chemotherapy (CT) occurs in up to 80% of patients within 2 years. The Clinical Classification Software (CCS) systematically classifies thousands of ICD-9 codes into a smaller number of clinically meaningful categories. We sought to use CCS and other routinely collected variables to differentiate the clinical and demographic profiles of patients with good prognosis (GP) versus poor prognosis (PP) in the United States (US). Methods: This was a retrospective cohort study of newly diagnosed (FIGO stage II - IV), treatment-naïve patients, ≥ 66 years, who received 4-10 cycles of platinum-based 1L CT between Jan 2009 - Dec 2015 using the SEER-Medicare database, a nationally representative cancer registry. Patient were assumed to have progressed to a subsequent line of therapy following a gap between consecutive CT cycles ≥ 63 days. Patients were classified as GP if alive ≥4 years with no further treatment following 1L CT; PP was defined as receipt of ≥2L CT within 12 months of initial 1L CT. Demographic and prognostic characteristics were assessed during a 6-month baseline period prior to initiation of 1L CT. We assessed clinically meaningful differences in baseline characteristics with absolute standardized differences (ASD) using a threshold of 0.1 (indicating negligible difference between two cohorts). Results: There were a total of 2,262 patients (mean age: 74.6 ±6.2 years) including 251 GP (11%) and 209 PP (9%) patients (table below). PP patients were significantly more likely to be older than 70 years, and present at stage IV, liver disease and ascites, and anemia at diagnosis. PP patients were also less likely to have primary debulking surgery. Conclusions: Approximately one tenth of OC patients received no further treatment 4 years after the initial treatment with contemporary standard of care. GP may be differentiated from PP on the basis of commonly used clinical characteristics such as stage and also specific comorbidities such as liver disease and ascites. [Table: see text]
Comparison of poly(ADP-ribose) polymerase inhibitors (PARPi's) as maintenance therapy for platinum-sensitive ovarian cancer: Systematic review and network meta-analysis.
Authors: Stemmer Amos , Tsoref Dalia , Stemmer Salomon M.
Published: May 2020

e18070

Background: Over the past decade, 3 PARPi's (olaparib, niraparib and rucaparib) have been approved by the FDA as maintenance therapy for recurrent ovarian cancer. However, thus far, no trial compared the 3 approved PARPi's in the overall population, in patients with BRCA mutations (BRCAm), or in those with wild-type BRCA (BRCAwt). Methods: We performed a systematic review and identified relevant literature from Embase, Pubmed and Cochrane Library. To be included in the analysis, studies had to be phase 2 or 3 randomized controlled trials (RCT) of platinum-sensitive recurrent or newly diagnosed ovarian cancer, randomized to placebo or PARPi as maintenance therapy and where complete or partial response was documented. A frequentist network meta-analysis was used for indirect comparisons between the different PARPi's to assess superiority in terms of progression free survival (PFS), overall survival (OS), and adverse events. Results: Overall, 6 RCTs involving 2,770 patients, were included in the network meta-analysis. Results from the indirect comparisons revealed no statistically significant differences between the 3 different PARPi's with respect to OS. PFS results demonstrated a nonsignificant trend supporting superiority for niraparib in all patients as well as in BRCAm patients (Table). Only 2 studies reported OS results for niraparib and none reported OS results for rucaparib. Niraparib showed a statistically significant increased risk for all grade thrombocytopenia and neutropenia. Conclusions: Our analysis demonstrates no statistically significant differences between the 3 PARPi’s in any of the analyzed groups, and a trend supporting PFS superiority for niraparib in all patients and in BRCAm patients, while having greater risk for thrombocytopenia and neutropenia. Additional OS results are pending from current studies, and would be useful for elucidating the relative roles of the different PARPi's in platinum-sensitive ovarian cancer. [Table: see text]
Efficacy of platinum-based chemotherapy in platinum-resistant ovarian cancer: A systematic review with pooled analysis of outcomes.
Authors: Rumyantsev Alexey , Tyulyandina Alexandra , Fedyanin Mikhail , Pokataev Ilya , Glazkova Elena , Nikulin Vladislav , Tjulandin Sergei
Published: May 2020

e18076

Background: Current management of recurrent ovarian cancer (OC) is based on the amount of time between the completion of penultimate platinum-based treatment and the detection of relapse. Patients with platinum-free interval (PFI) < 6 mo. are considered to be platinum-resistant (PROC) and to have low response rate (RR) probability to platinum-based chemotherapy. Methods: We searched PubMed database for all prospective and retrospective full-text articles and abstracts on the treatment of patients with PROC for all years between 01/01/2000 and 01/06/2019 in English language. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) tool was used to ensure transparent reporting of the results. Study inclusion criteria were: 1) morphologically confirmed epithelial ovarian cancer; 2) standard definition of PROC as a disease that recurred within 6 months after completion of platinum-based chemotherapy; 3) treatment with platinum- or non-platinum chemotherapy with agents that are routinely used for OC; 4) no concomitant therapy with targeted or investigational agents; 5) clearly defined RR for patients with PROC and criteria used for response assessment. Pooled analysis of outcomes and multiple linear regression analysis was conducted to assess the impact of platinum salts on probability of response. Results: We identified 7156 articles and screened them for title and abstract. After the review process we selected 197 studies for further analysis. Of them, 52 (n = 1320) and 145 (n = 6937) trials assessed efficacy of platinum- and non-platinum based chemotherapy respectively. Among patients treated with platinum-based and non-platinum chemotherapy RR was 36.04% (95% CI 33.45-38.63) and 14.85% (95% CI 14.01-15.68) respectively. Pooled median progression-free survival was 5.8 mo. and 3.75 mo. respectively. In multiple linear regression model administration of platinum-based chemotherapy was the strongest predictor of objective response with B value 0.503 (p < 0.001). Among platinum agents cisplatin (RR 39.9%: 95% CI 35.8-44.0%) and carboplatin (RR 42.3%; 95% CI 37.0-47.6%) were associated with better rates of objective response compared to oxaliplatin (RR 28.1%; 95% CI 23.9-32.3). Conclusions: This systematic review shows that patients with 'platinum-resistant' ovarian carcinoma may derive significant benefit from reintroduction of platinum agents and their value should be evaluated in further randomized trials.
Effect of bevacizumab in first-line chemotherapy on progression-free survival in advanced ovarian clear cell carcinoma.
Authors: Tate Shinichi , Nishikimi Kyoko , Matsuoka Ayumu , Shozu Makio
Published: May 2020

e18086

Background: Advanced ovarian clear cell carcinoma (ACCC, stage III/IV disease) is a rare tumor characterized by chemoresistance. To evaluate the efficacy of bevacizumab (Bev) for ACCC, we investigated the survival outcome of first-line treatment before and after the approval of Bev for ovarian cancer treatment in November 2013 in Japan. Methods: We recruited 28 consecutive patients diagnosed with ACCC at our institution between 2007 and 2018. We performed cytoreductive surgery and administered paclitaxel-carboplatin chemotherapy (paclitaxel: 80 mg/m2 + carboplatin area under the curve 2.0–3.0 mg/mL/min, weekly without break) as first-line chemotherapy. Bev (15 mg/kg/3 weeks) was also administered after its approval. We compared progression-free survival (PFS) between Bev+ group (n = 18) and Bev- group (n = 10) using the Kaplan–Meier method and a Cox regression model. Results: Patients characteristics were similar between the Bev- and Bev+ groups. The median age was 54 years and 53 in the Bev- and Bev+ groups (p = 0.810), respectively. Three (30%) and 4 (22%) patients in the Bev- and Bev+ groups had stage IV disease (p = 0.674), respectively. The performance status (PS) was ≥2 in 1(10%) and 5 (28%) patients in the Bev- and Bev+ groups (p = 0.375), respectively. Peritoneal cancer index was 5.5 and 5.5 in the in Bev- and Bev+ groups (p = 0.727), respectively. Primary debulking surgery was performed in 10 (100%) and 11 (61%) patients in the Bev- and in Bev+ groups, respectively. Surgical complexity score was 9 and 9 in the Bev- and in Bev+ groups (p = 0.700), respectively. Completeness of resection was higher in the Bev- group (9/10, 90%) than in the Bev+ group (15/18, 83%) (p = 0.044). Eleven (61%) patients in the Bev+ group received ≥21 cycles of Bev. The median PFS increases from 12.0 months before Bev approval to 29.8 months after Bev approval (Wilcoxon test, p = 0.026). Multivariate analysis revealed that Bev use (p = 0.005) and PS < 2 (p = 0.035) were independent prognostic factors for PFS; however, completeness of resection was not a prognostic factor (p = 0.052). Conclusions: Bev in first-line chemotherapy improves the survival outcome of ACCC. [Table: see text]
Development of a personalized ex vivo drug screening test for patients with ovarian cancer.
Authors: Brückner Luzi , Reinshagen Annika , Aktas Bahriye , Bechmann Ingo , Nel Ivonne , Kallendrusch Sonja
Published: May 2020

e18090

Background: The standard therapy of patients with ovarian cancer consists of primary surgery followed by chemotherapy. Initial response rates are very high, but recurrence occurs in 85% of the cases. Personalized ex vivo analyses of various anti-tumor compounds in a standardized tissue slice culture system (1) might be a very promising approach for individualized therapeutic decisions. In comparison to cell culture, tumor slice cultures maintain the direct tumor microenvironment which plays a role in resistance mechanisms and thus therapy response. Methods: Patient derived tumor cultures (1) are grown under standardized conditions and are analyzed semi-automated. Patient’s tumor samples were collected during surgery, cut into standardized slices and were cultivated in triplicates for 2, 4, 7 and 14 days and treated with standard therapy for 7 days. A baseline control was prepared at day 0. The cultured tissue is PFA-fixated and paraffin embedded. Hematoxylin eosin staining was performed for microscopic evaluation of morphologic structures. Subsequently, immunohistochemical staining against CD3 was applied to examine the immune setting of the tumor and its environment. Results: Ovarian tumor tissues remained their morphological properties over a period of 14 days. Parameters like cellular formation, proliferation and heterogeneity were adequately represented in the cultures.. Staining against CD3 revealed T-cells in ovarian tumor tissue slices up to 14 days ex vivo and individual response to treatment was observable. Conclusions: Correlation to clinical data is ongoing to analyze the tissue culture model of ovarian cancer for clinical usage. Different approaches, concerning mutational burden, immunological signature and histology are considered for decision of response and non-response.
Prognostic significance of hormone receptor (ER/PR) status in endometrial carcinoma in black women: Implications with lymph node metastasis.
Authors: Shah Manan , Jain Sanjay R , Oprea Gabriela , Shafi Saba
Published: May 2020

e18099

Background: Histological examination of tumor tissues is necessary for deciding if endometrial surgery should include lymph node sampling. Studies have demonstrated that loss of estrogen and progesterone receptors (ER/ PR) independently predicts lymph node metastasis and poor prognosis. African American females in comparison to their Caucasian counterparts are diagnosed at a later stage, with higher grade, poorer prognostic histological types and worse outcomes. Our study aimed to investigate if the correlation between hormone receptor status and lymph node metastasis holds true in African American females which could aid in treatment strategies. Methods: We reviewed African American females (n = 70) diagnosed with Endometrial Cancer at our institution from 2015-2018 including endometrioid/non-endometrioid histology, FIGO stage I-IV, grade 1-3 for ER/PR receptors and presence or absence of pelvic lymph nodes based on preoperative endometrial curettage and post-surgical pathology specimens. Statistical analyses were performed using Fisher’s Exact test exploring associations between categorical variables (ER/PR and Lymph nodes Metastasis). All statistical tests were two-sided and considered significant if P value < 0.05. Results: The mean age of our sample was 61 ± 13 years. Mean BMI was 36±10kg/m2. Majority of our patients were postmenopausal (59 out of 70, 84%). FIGO Stage 1 and 2 constituted 72% (50 out of 70). Endometrioid histology constituted 39 out of 70 (55%) cases and non-endometrioid histology which includes serous, mixed and carcinosarcomas constituted 45% of the cases. Loss of estrogen receptor(ER-) was observed in 19 of 70 patients (27%) and loss of progesterone receptor(PR-) was seen in 22 patients (31%) which was significantly associated with lymph node metastasis (p value < 0.05).On subgroup analyses significant association was observed between PR+ and absence of lymph node metastasis in cases of endometrioid cancer (p value < 0.05) . Nevertheless, there was no statistical significant association (P value .10) between ER receptors and lymph node metastasis in patients with endometrioid cancer. In non-endometrioid histology both ER- and PR- were found to have statistical significant lymph node involvement. Conclusions: Loss of ER and PR receptors independently predicts lymph node metastasis in endometrial cancers in African American females.
Treatment and outcome of patients with uterine carcinosarcoma: Data from developing world.
Authors: Gulia Seema , Srikanth Anne , Adsul Dr Ketaki , Mahantshetty Umesh , Ghosh Jaya , Maheshwari Amita , Rath Sushmita , TS Shylasree , Chopra Supriya , Menon Santosh , Deodhar Kedar , Rekhi Bharat , Popat Palak , Gupta Sudeep
Published: May 2020

e18102

Background: To evaluate the clinicopathological factors, outcome and prognostics factors of uterine carcinosarcoma. Methods: All patients of uterine carcinosarcoma treated between January 2013 and December 2018 were identified and their clinical, laboratory and imaging details were retrieved from electronic medical record. Details of the treatment received, toxicity profile and outcome were recorded and analyzed. Patients (including stage I) were considered for four cycles of chemotherapy (Paclitaxel +Carboplatin) followed by radiation (EBRT to pelvis with vaginal brachytherapy). Survival analysis was done using the Kaplan–Meier method and compared between treatment groups using the Log-rank test. Results: Of 81 cases, 48 % presented with early stage disease (FIGOI-II) and 52 % with late stage (FIGO III-IV) disease. Median age was 58 years (30-80 years). Most women (83%) were postmenopausal and 80% of them presented with postmenopausal bleeding. Six patients developed carcinosarcoma on adjuvant tamoxifen (given for breast cancer) after a median drug intake of 8 years. In early stage, 10% patients received only surgical treatment; 46% received both chemotherapy (CT) and radiation therapy (RT) while 33 % received RT alone. In advanced stage, 31% received only CT, 14 % received only RT and 33% received both CT and RT after surgery. About 8% of patients had myelosuppression(grade I/II), 10 % had peripheral neuropathy (grade I/II) and 11% had electrolyte imbalance. At a median follow up of 2 years (1- 80 months), median DFS and OS in early stage group was 28.5 months and 31.0 months while in advanced stage group it was 13.0 months and 15.0 months respectively. Distant metastasis (omentum, peritoneum and lung being the common site) were seen in 30% of patients while local relapse was seen in 5 % cases. On univariate analysis stage of disease and receipt of adjuvant therapy were the factors found to be significantly associated with improved OS (p < 0.001) and adjuvant RT alone was associated with improved DFS (p < 0.023). Conclusions: Adjuvant treatment (chemotherapy and or radiation therapy) is associated with improved overall survival in uterine carcinosarcoma, irrespective of stage at presentation.
The humanistic burden reported by first-line (1L) head and neck cancer patients diagnosed with recurrent/metastatic squamous cell carcinoma (R/M SCCHN) in europe: A real-world study.
Authors: Singh Prianka , Bennett Bryan , Bailey Tom , Taylor-Stokes Gavin , Rajkovic Ivana , Postema Roelien , Curtis Sharon , Curtis Chris
Published: May 2020

e18514

Background: R/M SCCHN is associated with substantial humanistic burden and limited tolerable treatment options that are able to preserve heath-related quality of life (HRQoL). Real world evidence is lacking to characterize and quantify burden in these patients by geographic region and treatment. Methods: A cross-sectional study was conducted in France, Germany, Italy, Spain and the UK from Jan to May 2019. Physicians (n = 184) recruited patients to complete a survey assessing the impact of their SCCHN and completed medical charts for corresponding patients. Patient burden and HRQoL was captured through the patient survey, which included the Functional Assessment of Cancer Therapy Head and Neck Cancer (FACT H&N) (range: 0-148; sub scores physical/social/functional: 0-28, emotional 0-24). Higher scores for instruments indicate better HRQoL. Patients were identified as 1L platinum eligible according to clinical characteristics and treatments captured in the medical charts. Results: Physicians recruited 577 (99 UK, 114 France, 117 Germany, 117 Spain, and 130 Italy) 1L platinum eligible patients of mean age 62.8 years, most were male (72%) and had ECOG score 0-1 (79%) or 2 (21%). Over half (52%) received the EXTREME regimen, 9% received a separate cetuximab-based regimen. Patients experienced a high symptom burden, most commonly fatigue (43%), weight loss (40%), pain (35%), and difficulty swallowing (32%). Dry mouth and persistent sore throat were reported by 19% patients. Most patients reported at least some problems with performing usual activities (62%), at least moderate pain/discomfort (79%), and at least moderate anxiety/depression (71%). Patients had a diminished HRQoL in every FACT-H&N domain: total score, 73.2; physical, 15.0; social, 16.5; emotional, 11.7; functional well-being, 10.7. Conclusions: In Europe, patients treated for 1L R/M SCCHN experience considerable humanistic burden and diminished HRQoL. These data suggest an unmet need in this patient population for novel treatments that are able to maintain or even improve HRQoL.
Exploration of associations between adverse drug reactions and clinical outcomes in anlotinib treatment against medullary thyroid carcinoma (MTC): A subgroup analysis based on the ALTER01031 trial.
Authors: Chi Yihebali , Gao Ming , Tang Pingzhang , Zheng Xiangqian , Xu Zhengang , Li Dapeng , Chen Xiaohong , Ge Minghua , Zhang Yuan , Guo Zhuming , Wang Jun , Chen Jie , Zhang Jiewu , Cheng Ying , Li Zhendong , Liu Hui , Qin Jianwu , Zhu Jingqiang , Cheng Ruochuan
Published: May 2020

e18518

Background: Anlotinib demonstrated favorable efficacy in a randomized, placebo-controlled phase 2b trial (ALTER01031, NCT02586350) for MTC which was published in 2019 ASCO annual meeting. Similar with other anti-angiogenesis drugs, hand-foot syndrome (HFS), hypertension and proteinuria were the major adverse drug reactions (ADRs) observed in this trial. We explored the association between common ADRs and the clinical outcomes with anlotinib in this subanalysis. Methods: Patients in the anlotinib group of ALTER01031 were divided into different groups according to the development of ADRs including HFS, hypertension or proteinuria. Kaplan-Meier method was used to estimate median PFS (mPFS) for patients in different groups. The mPFS for patients with or without dose reduction were also evaluated. Results: A total of 62 patients received anlotinib in ALTER 01031. HFS of any grade was observed in 39 patients with a mPFS of 28.5 months, which was longer than in those without HFS (14.0 months, P = 0.079). The hazard ratio for progression was 0.540 (95% CI 0.252, 1.158) although statistical difference was not reached. Similarly, more survival benefit was also observed in 29 and 38 patients who experienced hypertension and proteinuria, with mPFS of 28.5 months and 22.4 months respectively. While the mPFS for patients without corresponding ADRs were only 17.0 months (HR = 0.648 [95% CI 0.320, 1.314], P = 0.237) and 14.0 months (HR = 0.738 [95% CI 0.331, 1.65], P = 0.421). Median PFS had not been reached in 20 patients with dose reduction while was recorded as 17.0 months in those without (HR = 0.707 [95% CI 0.335, 1.496], P = 0.392). Conclusions: This analysis indicated a trend of greater PFS benefit for MTC patients treated with anlotinib who experienced HFS, hypertension or proteinuria although no statistical differences were observed. A possible positive association was also observed between dose reductions and better clinical outcomes. Clinical trial information: NCT02586350.
Peripheral immunological response to treatment with checkpoint inhibitor in recurrent/metastatic nasopharyngeal carcinoma.
Authors: Kwong Dora Lai Wan , Kam Ngar-Woon , Luk Ho-Yin , Hung Tae Yang Desmond , Yim Man Kim , Lee Victor Ho-Fun
Published: May 2020

e18519

Background: A better understanding of peripheral cellular phenotypes in association with checkpoint inhibitors (CPI) responsiveness in recurrent/metastatic NPC could profoundly impact our knowledge of NPC immunopathology. Methods: Blood were collected from 11 patients with recurrent/metastatic NPC who received CPI (pembrolizumab) after failing second-line chemotherapy. Response to pembrolizumab was assessed by imaging and EBV DNA. Patients who achieved CR/PR were considered responsive and those with SD/PD were considered non-responsive. Four patients in the responsive group also had baseline blood before pembrolizumab. PBMC were freshly isolated and stored until analysis. For surface staining, cells were rested overnight at 37°C before resuspended in BD Brilliant stain with 2.5ng/µl Fc block for 15mins. Cells were then co-stained: 7-AAD, CD19-BV510, CD3-Alexa Fluo 700, CD4-BV510, CD279(PD-1)-BB515, CD197(CCR7)-BV421, CD45RO-APC, CD45RA-Pe-Cy5, CD8-APC-H7, CD27-PE, CD95-PE-Cy7, incubated on ice for 30mins. Samples were washed and acquired on NovoCyte Quanteon. Immune phenotypes were correlated with clinical response. Results: We found that: 1) %CD3 was upregulated in responsive group; 2) CD4/CD8 ratio did not directly stratify drug responsiveness; 3) frequency of PD1-expressing CD8+ T cells was significantly reduced in responsive group; 4) lower frequency of CCR7+PD1+CD8+ T cells in responsive group, suggesting that these may be highly differentiated and have the ability to move into peripheral sites in response to inflammatory chemokines; 5) frequency of naïve and TEMRA CD8+ T cells, but not Tscm was upregulated in responsive group; 6) finally, an interesting finding of sustained CD19+ subsets was observed in non-responsive group. Conclusions: Our results suggest that peripheral blood analysis may provide valuable insights into NPC patients’ responses to PD-1-targeted therapies. [Table: see text]