bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential chemoradiation versus radiation alone or concurrent chemoradiation in adjuvant treatment after radical hysterectomy for stage IB1-IIA2 cervical cancer (STARS Study): A randomized, controlled, open-label, phase III trial.
Authors: Huang He , Feng Yanling , Wan Ting , Zhang Yanna , Cao Xinping , Huang Yongwen , Xiong Ying , Huang Xin , Zheng Min , Li Yanfang , Li Jundong , Chen Guandi , Li Hu , Chen Yile , Ma Liguo , Yang Hongying , Li Li , Yao Shuzhong , Liu Qing , Liu Jihong
Published: May 2020

6007

Background: There are limited data from previous studies regarding whether the addition of chemotherapy to adjuvant radiation after radical surgery improves outcomes among patients with early-stage cervical cancer and adverse pathological factors. Methods: This was a prospective randomized trial including patients with FIGO 2009 stage IB1-IIA2 cervical cancer and squamous-cell, adenocarcinoma, or adenosquamous carcinoma with at least one adverse factor after radical hysterectomy. Patients were randomized 1:1:1 to receive adjuvant radiation alone, concurrent chemoradiation with weekly cisplatin (30-40 mg/m2), or sequential chemoradiation with cisplatin (60-75 mg/m2) plus paclitaxel (135-175 mg/m2) in 21 day cycles, given 2 cycles before and 2 cycles after radiotherapy respectively. The primary outcome was the rate of disease-free survival at 3 years. Results: A total of 1,048 patients were included in the study (350, radiation alone; 345, concurrent chemoradiation; and 353, sequential chemoradiation). Overall, the median follow-up was 56 months and the median age of patients was 48 years. Most patients (75%) had stage IB1 or IIA1 disease. The three groups were similar with respect to histologic subtypes, the rate of lymphovascular invasion, parametrial, surgical margin and deep stromal involvement, tumor grade, rate of use of minimally invasive surgery, and neoadjuvant chemotherapy, except for lymph-node involvement that was lowest in radiation alone arm. In the intention-to-treat population, sequential chemoradiation was associated with a higher rate of disease-free survival than radiation alone (3-year rate, 90·0% vs. 82·0%; HR 0·52; 95% CI, 0·35 to 0·76) and concurrent chemoradiation (90·0% vs. 85·0%; HR 0·65; 95% CI, 0·44 to 0·96), differences remained after adjustment for lymph-node involvement. Sequential chemoradiation was also associated with a higher rate of overall survival than radiation alone (5-year rate, 92·0% vs. 88·0%; HR for death from cancer, 0·58; 95% CI, 0·35 to 0·95). However, neither disease-free survival nor cancer death risk was different between patients treated with concurrent chemoradiation or radiation alone. Conclusions: In this trial, sequential chemoradiation, rather than concurrent chemoradiation, resulted in a higher disease-free survival and lower risk of cancer death than radiation alone among women with early-stage cervical cancer after radical surgery. Clinical trial information: NCT00806117.
Olaparib treatment in patients (pts) with platinum-sensitive relapsed (PSR) ovarian cancer (OC) by BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: Phase II LIGHT study.
Authors: Cadoo Karen Anne , Simpkins Fiona , Mathews Cara Amanda , Kabil Nashwa , Bennett James , Aghajanian Carol
Published: May 2020

6013

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

6015

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

6019

Background: In GOG 49, factors associated with a 3-year, 30% recurrence risk in squamous cell carcinoma of the cervix (SCC) after surgery alone were defined. These "intermediate" risk factors [tumor size (TS), depth of tumor invasion (DOI), and lymphvascular space invasion (LVSI)] were then studied in GOG 92, which demonstrated the utility of treating patients (pts) with ≥2 intermediate risk factors with adjuvant radiation (RT), Sedlis Criteria. However, pts with < 30% recurrence risk were not eligible and few pts with adenocarcinoma (AC) were included. Our study purpose was 1) to evaluate recurrence risk factors for AC vs SCC, and 2) to define contemporary nomograms for adjuvant treatment in pts with both histologies. Methods: We performed an ancillary analysis of GOG 49, 92, and 141, and included Stage I pts who received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were created separately for AC and SCC to evaluate independent risk factors for recurrence. Model accuracy was tested with ROC curves. Prognostic nomograms were generated for 2-year recurrence risk for AC and SCC. Results: We identified 715 with SCC and 105 pts with AC; 142 with SCC (19.9%) and 18 with AC 17.1%) recurred. For SCC, factors associated independently with recurrence were: LVSI [HR 1.58 (CI 1.12-2.22)], DOI [middle 1/3, HR 4.31 (CI 1.81-10.26); deep 1/3, HR 7.05 (CI 2.99-16.64)] and TS [≥4cm HR 2.67 (CI 1.67-4.29)]. In contrast, for AC, only TS ≥4cm was independently associated with recurrence [HR 4.69 (CI 1.25-17.63)]. At 3 years, ROC curves for these models predicted recurrence with 76% and 75% accuracy for SCC and AC, respectively. Utilizing a nomogram generated from these models, for SCC, DOI had the greatest impact on recurrence, with mid 1/3 conferring an 18% risk and deep 1/3 a 32% risk, while LVSI and TS increased risk by 4-10%, respectively. In contrast, for AC, TS alone had the greatest impact on recurrence risk with TS 2-4cm conferring a 20% risk over 3 years and TS ≥4cm, a 28% risk. Conclusions: Our nomogram differs from the Sedlis Criteria in demonstrating that single, as well as a combination of risk factors predict substantial 3-year recurrence rates in Stage I cervical cancer. Furthermore, these factors differ by AC and SCC subtypes, suggesting that distinct, histology-specific nomograms may have greater utility in identifying pts who will most benefit from adjuvant therapy.
Camrelizumab plus apatinib in patients with advanced cervical cancer: A multicenter, open-label, single-arm, phase II trial.
Authors: Lan Chunyan , Huang Xin , Shen Jing-Xian , Wang Yin , Xiong Ying , Li Jundong , Cao Xinping , Deng Yanhong , He Mian , Zou Guorong , Wang Xiaodi
Published: May 2020

6021

Background: Camrelizumab is a fully humanized, monoclonal antibody against PD-1. We aimed to assess the efficacy and safety of camrelizumab plus apatinib, a tyrosine kinase inhibitor targeting VEGFR2, in patients with advanced cervical cancer. Methods: In this open-label, single-arm, phase 2 study done at four centres in China, eligible patients were aged 18–70 years, had an ECOG performance status of 0 or 1, progressed after at least one line of systemic chemotherapy for metastatic, recurrent or persistent cervical cancer, and had measurable disease. Patients received camrelizumab 200 mg every 2 weeks and apatinib 250 mg once daily. Treatment continued until disease progression, unacceptable toxicity, and withdrawal of consent. The primary endpoint was the objective response rate (ORR) assessed by RECIST version 1.1. An optimal Simon two-stage design was employed to test the null hypothesis of a 17% ORR versus 35% alternative (1-sided alpha 0.10, 80% power), if > 3 responses out of the first 16 patients were observed, then the study would continue to enroll a total of 44 patients. Results: Between Jan 21st, 2019, and Aug 1st, 2019, 45 patients were enrolled and received study treatment (safety population). The median age was 51 (range, 33–67) years. Median previous treatment lines were 2 (range, 1–4). As of Jan 22, 2020, median follow-up was 9.2 months (range, 2.4–12.2). 25 (59.5%; 95%: CI 44.7–74.4) of 42 patients who had at least one post-baseline tumor assessment (efficacy evaluable population) achieved an objective response, including two (4.8%) complete response, and 23 (54.8%) partial response. Median duration of response was not reached. The disease control rate was 88.1% (37/42). Median progression-free survival (PFS) was 7.6 months (95% CI: 5.8–not reached). 31 (68.9%) patients had grade ≥ 3 treatment-related adverse events (TRAEs). Grade ≥ 3 TRAEs occurring in ≥ 5% of patients were hypertension (24.4%), anemia (20.0%), fatigue (15.6%), γ-glutamyltransferase increased (13.3%), neutropenia (6.7%), and thrombocytopenia (6.7%). In post-hoc analyses, objective response was noted in 20 (69%) of 29 patients with PD-L1-positive tumors, and in 5 (50.0%) of 10 patients with PD-L1-negative tumors (Chi-square test, P = 0.281). PFS was longer in patients with PD-L1-positive tumors than patients with PD-L1-negative tumors (median PFS: 9.6 versus 5.3 months; log-rank test, P = 0.017). Conclusions: Camrelizumab plus apatinib showed promising antitumor activity and tolerable toxicities in patients with advanced cervical cancer. Clinical trial information: NCT03816553.
Phase II trial of guadecitabine priming and pembrolizumab in platinum resistant recurrent ovarian cancer.
Authors: Matei Daniela , Pant Alok , Moroney John William , Fleming Gini F. , Tanner Edward , Swetzig Wendy M , Xu Jiahui , Cardenas Horacio , Kandpal Manoj , Gavrilescu Andreea , Chen Siqi , Kocherginsky Masha , Davuluri Ramana V , Zhang Bin
Published: May 2020

6025

Background: Platinum resistant ovarian cancer (PROC) remains a disease of high need. Immune checkpoint inhibitors (ICI) have modest activity. We hypothesized that priming with a hypomethylating agent (HMA) guadecitabine (G) will improve the anti-tumor activity of ICI in PROC by enhancing tumor cell recognition by CD8+ T cells. Methods: This open-label phase II study used a Simon’s two-stage design. Eligible patients (pts) had recurrent PROC; ECOG PS of 0-1; normal end organ function; and measurable disease. Up to 5 prior cytotoxic regimens were allowed. Treatment consisted of G 30mg/m2 sq D1-4 and pembrolizumab (P) 200mg iv D5. Each cycle was 21 days. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS), clinical benefit rate (CBR), and toxicity assessment. Translational endpoints were LINE1 methylation in PBMCs, global tumor methylation, and immune endpoints. Tumor biopsies were obtained at baseline and after 2 cycles. If 2 patients experienced clinical benefit in stage I [n = 16], enrollment proceeded to stage II. The null hypothesis was rejected for ≥ 6 responses in 35 evaluable patients. Results: 48 pts were enrolled, 43 were treated, and 33 were evaluable for response. Histology was serous (35), endometrioid (2), clear cell (3) and other (3). Median age was 63 (range 40-88) and median number of prior regimens was 4 [range 1-8]. Two PRs were recorded in the first stage, allowing second stage of enrollment. Overall, there were 2 PRs (RR = 6.6%) and 16 pts had stable disease (SD) [48%]. The clinical benefit rate (PR + SD > 3 months) was 27%. One patient continued treatment for > 2 yrs. Grade 3-4 related toxicities were neutropenia [20], lymphopenia, (9), anemia (2), neutropenic fever (1), rash (1), and others (8). There were 13 grade 3-4 SAEs and 4 grade 5 SAEs, assessed as being unrelated to treatment. LINE1 was hypomethylated in PBMCs D5 vs. D1 (n = 21, p = 0.001). Epic arrays measured global tumor methylation, with 39579 CpG sites (0.05%) being differentially methylated (C2D5 vs. C1D1, n = 11, paired t-test; p < 0.01). Main pathways affected included endosomal transport, K+ transport, cathecolamine secretion, etc. PDL1 staining in archival tissue showed tumor staining > 0 in 16 of 35 and tumor/stroma interface staining > 0 in 20 of 35 specimens. Antigen-specific cytotoxic T cell activity was increased in CD8+ cells from ascites (C2D5 vs. C1D1). Conclusions: G+P has modest anti-tumor activity in patients with PROC, but some patients experienced prolonged disease stabilization. Biomarkers of response are being investigated. Clinical trial information: NCT02901899.
Histopathologic validation of the sentinel node technique in early-stage cervical cancer patients.
Authors: Mathevet Patrice , Guani Benedetta , Ciobanu Andrea , Mery Lamarche Eliane , Boutitie Florent , Balaya Vincent , Lecuru Fabrice
Published: May 2020

6028

Background: Sentinel lymph node biopsy (SLN) could be an alternative to systematic lymphadenectomy in early cervical cancer. SLN is less morbid and had shown a high sensitivity for metastasis detection. However, sensitivity of the SLN technique could be over evaluated because SLN are examined with ultrastaging and non sentinel nodes are only examined with routine techniques. The aim of this study was to validate the negative predictive value (NPV) of the SLN technique, with ultrastaging of SLN and non sentinel nodes (NSLN). Methods: We used the SENTICOL 1 study data, published in 2011. All nodes, SLN and NSLN have been secondarily subjected to ultrastaging. The ultrastaging consisted in sectioning every 200 µm and immunohistochemistry. A central reviewing of the positive slides and 10% of the negative slides was undertaken. Results: One hundred thirty-nine patients were included. SLNs were detected in 136 (97.8%) of the 139 patients. SLNs were found bilaterally in 104 (76.5%) of the 136 patients. 2056 NSLNs were identified (median = 13 NSLNs per patient [range 1-54]). Of 136 patients with SLNs detection, 23 had positive SLNs, after serial sectioning and IHC. NSLNs were metastatic in 8 patients. However, in case of bilateral SLN detection, the FN rate was 1/99 (1%) with detection of ITC in one NSLN from 99 bilateral negative SLNs. The NPV was 99% (0,99 [IC 95% = 0,97-1,00]). Conclusions: The pelvic SLN technic is a safe and trustfully technic to determine the nodal status in patients with early-stage cervical cancer. In case of optimal mapping with bilateral detection, NPV is 99% (IC 95% = 0,97-1,00).
Prexasertib, a cell cycle checkpoint kinase 1 inhibitor, in BRCA mutant recurrent high-grade serous ovarian cancer (HGSOC): A proof-of-concept single arm phase II study.
Authors: Lampert Erika Joelle , An Daniel , McCoy Ann , Kohn Elise C. , Annunziata Christina M. , Trewhitt Kathryn , Zimmer Alexandra Dos Santos , Lipkowitz Stanley , Lee Jung-min
Published: May 2020

6038

Background: Preclinical data suggest cell cycle checkpoint inhibition induces greater cell death in BRCA mutant HGSOC by causing replication stress and dysregulation of DNA damage responses. We hypothesized that prexasertib, a cell cycle checkpoint kinase 1 (CHK1) inhibitor, would be active in BRCA mutated HGSOC patients. Methods: We conducted a single center, two-stage phase II study of prexasertib (105mg/m2 IV every 2 weeks) in HGSOC patients with known germline or somatic BRCA mutations. The primary endpoint was RECIST response rate (RR). Progression-free survival (PFS) and safety (CTCAE v4) were secondary endpoints. Baseline research biopsies and blood samples were collected for exploratory biomarker endpoints. Results: Between February 2015 and July 2019, 22 heavily pretreated (median 5 prior systemic therapies [1-12]) women with BRCA mutant HGSOC (median age 58.7 [44-74.8]) received at least one dose of prexasertib. 13 (59%) patients were secondary platinum-resistant (median 8 [3-12] prior therapies) and 9 (41%) maintained platinum-sensitivity (median 4 [1-5] prior therapies). All but one received prior PARP inhibitor (PARPi) either in combination (10 [48%]) or as monotherapy (11 [52%]), with a median 5 month [mo; 1-29] PARPi-free interval prior to study entry. There was one complete response (41+mo, platinum-sensitive, no prior PARPi) and one partial response (9+mo, platinum-sensitive, 13.5mo PARPi-free interval) yielding an 11% RR (2/18 evaluable). No response was seen in platinum-resistant patients with prior PARPi. Median duration on study treatment was 4mo [1-9] among 21 patients with prior PARPi and 4mo [1.5-9] among 17 evaluable patients with prior PARPi. Common (>10%) grade 3/4 adverse events were neutropenia (82%), leukopenia (64%), and thrombocytopenia (14%); only one patient had grade 3 febrile neutropenia. 16 of 18 (89%) patients with grade 3/4 neutropenia received prophylactic growth factors for subsequent treatments. Conclusions: Prexasertib is tolerable and has modest activity in heavily pretreated BRCA mutant HGSOC patients. Further evaluation of predictive biomarkers for exceptional responders is ongoing. Clinical trial information: NCT02203513.
Quality of life, vascular endothelial growth factor inhibition, and survival outcomes with combination oral metronomic therapy in platinum refractory epithelial ovarian carcinoma: Results from a randomized study.
Authors: Sharma Aparna , Khurana Sachin , Malik Prabhat Singh , Singh Mayank , Mathur Sandeep , Kumar Sunesh , Sreenivas Vishnu kumar , Kumar Lalit
Published: May 2020

6048

Background: Patients with recurrent and refractory epithelial ovarian cancer (EOC) have dismal outcomes. We evaluated a combination of oral metronomic therapy in platinum refractory EOC vis-à-vis angiogenic marker expression and its impact on patient reported outcomes. Methods: Between October 2017 and September 2019, 75 patients were randomized to receive etoposide (VP-16) (50 mg daily for 14 days) cyclophosphamide (50 mg daily for 28 days) (Arm A, n = 38) or etoposide (VP-16) (50 mg daily for 14 days) cyclophosphamide (50 mg daily for 28 days) and pazopanib (400 mg daily 28 days) every 28 days (Arm B, n = 37). Eligibility criteria included histopathological diagnosis of EOC, platinum refractory disease and ECOG performance status 0-2. Primary endpoint was serological progression free survival (PFS) as defined by Rustin criteria. Quality of Life (QoL) (evaluated using the EORTC QLQC30 and OV 28 questionnaires) and serum vascular endothelial growth factor (VEGF) were ascertained at baseline and after 3rd and 6th cycle. Intention to treat analysis was done. Results: Baseline characteristics were well matched in 2 arms. At a median follow up 14.4 months (95% CI 13.2-15.7), the median serological PFS is better for patients in Arm B 5.1 months (95%CI 3.13-10.33) compared to 3.4 months (95%CI 3-6.53) in arm A ( P= 0.045). Median overall survival (OS) is not reached in arm B versus 11.2 months (95%CI 5.66-NR) in arm A (P= 0.032). Disease progression was seen in 42.1% (n = 16) in Arm A versus 40.5 %(n = 15) in arm B ( P= 0.40). Sixteen patients are maintaining response. Mucositis (29.7% n = 11) and fatigue (13.5%, n = 5) were more in the pazopanib-containing arm ( P= 0.36). Serum VEGF demonstrated significant decline with subsequent cycles of therapy {median values (range): Arm A, baseline; 466.0 pg/mL(123.9-1930) vs. 6 cycles; 92.05pg/ mL(42.34-279.5) P< 0.0001; Arm B, baseline; 382.0 pg/mL(49.44-2054.0) vs 6 cycles; 119.7 pg/mL(18.20-367.5) P= 0.013} without any difference between the two arms ( P= 0.18). QoL symptom scales in both QLQC 30 and OV 28 questionnaires indicated small but significant improvement in pazopanib arm ( P= 0.02) without differences in global (p = 0.96) and physical functioning scales. ( P= 0.68). Conclusions: Addition of pazopanib to etoposide and cyclophosphamide resulted in improvement in serological PFS and OS with a well-tolerated toxicity profile and modest improvement in QoL.Serum VEGF expression requires validation in a larger cohort. Clinical trial information: CTRI/2017/10/010219.
Pharmacokinetics and safety following a single oral dose of niraparib in patients with moderate hepatic impairment.
Authors: Akce Mehmet , El-Khoueiry Anthony B. , Piha-Paul Sarina Anne , Bacque Emeline , Pan Peng , Zhang Zhi-Yi , Ewesuedo Reginald , Gupta Divya , Milton Ashley , Judson Patricia , O'Bryant Cindy L.
Published: May 2020

6054

Background: Niraparib is approved for the maintenance treatment of adult patients (pts) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, or with similar cancers but advanced, associated with homologous recombination deficiency (HRD) and have been treated with ³3 prior chemotherapy regimens. Niraparib is extensively metabolized in the liver and eliminated via both hepatobiliary and renal routes. Objectives of this study included characterization of niraparib pharmacokinetics (PK) and safety in pts with normal hepatic function vs. pts with moderate hepatic impairment. Methods: This phase I, open-label, parallel-group, single-dose study enrolled pts with advanced solid tumors into 2 groups: normal hepatic function and moderately impaired hepatic function, defined as bilirubin >1.5 to 3 times the upper limit of normal and any aspartate aminotransferase elevation. Pts received a single 300-mg dose and underwent PK sampling for 7 days. Exposure parameters included maximum concentration (Cmax), area under the concentration-time curve calculated to last measured concentration (AUClast), and extrapolated to infinity (AUCinf). PK parameters were determined using a non-compartmental analysis in WinNonlin. Results: Seventeen pts were enrolled; 9 with normal hepatic function and 8 with hepatic impairment. Niraparib Cmax was 7% lower in pts with moderate hepatic impairment compared with pts with normal hepatic function (Table). Overall exposure was increased in pts with moderate hepatic impairment, with niraparib AUClast and AUCinf increased 45% and 60%, respectively. Safety data during the PK phase of the study is consistent with the known profile for niraparib. Conclusions: Pts with moderate hepatic impairment experienced increased niraparib exposure which did not noticeably alter the toxicity profile in this population. Clinical trial information: NCT03359850. [Table: see text]
Risk stratified multidisciplinary ambulatory management of malignant bowel obstruction (MAMBO) program for women with gynecological cancers: Preliminary results from a prospective single-center study.
Authors: Liu Shiru Lucy , Lee Yeh Chen , Jivraj Nazlin , Bowering Valerie , Wang Lisa , Bhat Gita , Madariaga Ainhoa , Kasherman Lawrence , Nathwani Kashish , Tesfu Azieb , Lee Sarah , Ferguson Sarah E. , Croke Jennifer M. , O'Brien Catherine , Lau Jenny , Chawla Tanya , Schlomovitz Eran , Oza Amit M. , Lheureux Stephanie
Published: May 2020

6062

Background: Malignant Bowel Obstruction (MBO) is one of the most common and devastating complications in women with gynecological cancer (GC). There is currently no consensus guideline to improve patient (pt) care in this setting. MAMBO (NCT03260647) is an ongoing prospective study evaluating the clinical implementation of a novel management algorithm for multidisciplinary management of MBO in GC pts. We report preliminary patient outcomes. Methods: All GC pts at Princess Margaret Cancer Centre with a confirmed diagnosis of or are at risk of MBO are eligible for enrollment. Participants follow a low fiber diet titrated by severity of symptom and their monthly weight and albumin levels are recorded, along with standardized patient-reported outcome measures (PROMs) at different time points. For pts who develop MBO, inpatient and ambulatory management algorithms are applied using a multidisciplinary and interprofessional care model consisting of nurses, surgeons, oncologists, radiologists, nutritionists, total parenteral nutrition team, social work, and palliative care. Decisions regarding most optimal management strategies are made by this team with regular MAMBO rounds. A retrospective analysis of pts hospitalized with MBO between 2012 and 2017 was performed in order to have a historical comparison for outcome and survival analysis using Kaplan Meier methods. Results: Since August 2017, 70 pts have been enrolled in MAMBO. Most had high-grade serous ovarian carcinoma (75%), of whom 68% are platinum-resistant. So far, 36 (51%) developed MBO, 6 of whom had multiple sequential episodes. Mean number of days in hospital with MBO was 10 days (median 7, range 0-45), compared to 18 days (median 9, range 0-134) for historical control (p = 0.009). There was no significant loss in weight 6 months from MBO diagnosis but a significant reduction in albumin level by 2.75 g/L after 3 months (p = 0.005). PROMs suggest fatigue and general lack of wellbeing were the symptoms with highest distress. Most patients (78%) received chemotherapy following MBO and most received weekly paclitaxel (36%). Median time from first MBO to death was 219 days (95% CI: 101-not reached) for all-comers in MAMBO and 174 days (95% CI: 98-363) for MBO requiring hospitalization, compared to 108 days (95% CI: 79-160) for historical controls (p = 0.007 and p = 0.062, respectively). Conclusions: Patient care and outcomes from MBO seem to be improved in GC pts enrolled in MAMBO compared to historical controls. Clinical trial information: NCT03260647.
Juvenile granulosa cell tumor: An interim report from the international ovarian and testicular stromal tumor (OTST) registry.
Authors: Harris Anne , Nelson Alexander , Watson David , Mallinger Paige , Langford Miranda , Stering Allen , Turk Farheen , Billmire Deborah F. , Schneider Dominik T. , Frazier A. Lindsay , Dehner Louis P , Hill Ashley , Messinger Yoav H. , Schultz Kris Ann P
Published: May 2020

6064

Background: Juvenile granulosa cell tumors (JGCT) are rare sex cord-stromal tumors which occur primarily in children and adolescents. Methods: All individuals or proxy caregivers provided informed consent/assent for participation in the International OTST Registry. Clinical data was collected. When available, pathology was centrally reviewed. Staging was evaluated using the International Federation of Gynecology and Obstetrics (FIGO) classification. Kaplan-Meier survival analyses and exact permutation tests were performed. Results: Forty-two individuals with ovarian JGCT were enrolled. Median age at diagnosis was 9 years (range 0-27). Most individuals had Stage I disease (Stage Ia=16; Stage Ib=1; Stage Ic=16). Seven individuals presented with higher stage (Stage II=2; Stage III=5). Stage was unknown for 2 individuals. Three-year overall survival (OS) was 88% (CI 77%, 100%) and event-free survival (EFS) was 69% (CI 54%, 88%). At median follow-up time of 25 months (range 0-416), 9 patients (Stage Ia=1, Stage Ic=5, Stage III=3) had recurrent disease. Use of post-operative adjuvant chemotherapy varied by stage and timing of rupture. Of those with Stage Ic JGCT, 2/7 with preoperative rupture and 3/9 with intraoperative rupture recurred. Among individuals with recurrence, median time to recurrence was 11.5 months (range 3-19). Four of 9 individuals with recurrence survived (no evidence of disease n=2; alive with disease n=2). All individuals who died presented with extrapelvic recurrence. Median time from recurrence to death was 10 months (range 2-53). In individuals with recurrence, advanced stage at diagnosis (HR 5.1; p-value 0.087) and recurrence outside the tumor bed (HR Infinity; p-value 0.048) were associated with inferior OS. Three-year OS for individuals with recurrence was 57% (CI 30%, 100%). Conclusions: Low stage JGCT is associated with a favorable prognosis, however, recurrence is associated with lower survival rate. Within this series, recurrences presented within 2 years of diagnosis. Novel strategies are needed to address recurrent and extrapelvic disease.
Financial toxicity and patient-reported outcomes over time: A longitudinal study of women with recurrent ovarian cancer.
Authors: Meyer Larissa , Schneider Amy , Chen Tsun Hsuan , Wang Xin Shelley , Sun Charlotte C.
Published: May 2020

6079

Background: The chronic nature of treatment for ovarian cancer (OC) can place women at increased risk of financial toxicity (FT) from ongoing direct and indirect costs coupled with potential loss of income. We explored FT and its association with anxiety, depression, and quality of life over time in women with recurrent OC. Methods: Women with recurrent OC enrolled in a longitudinal study were given the following validated instruments at baseline and every 3 months: FACIT Comprehensive Score for Financial Toxicity (COST), GAD-7 (anxiety), CES-D (depression) and FACT-Ovary. Mixed models were performed on longitudinal data over 12 months of follow-up. Multivariable analysis of demographic data was performed. Results: 225 patients were divided into low FT (top 2 terciles, n = 152) and high FT (bottom tercile, n = 73,) by baseline COST scores. The median age was 59 (range 22.9-78.9). There were no significant differences between the groups in regards to marital status, number of people in household or education level. There were significant differences between the low and high financial toxicity groups in terms of median age (low FT = 61 yrs vs. high FT = 54 yrs, p < 0.0001); race (5.4% black in low FT vs. 15.1% in high FT, p = 0.04), number of children < 18 years in the home ((p = 0.02), employment status p( < 0.0001) and annual income p( < 0.0001). On multivariable analysis, only income and age remained significantly associated with FT. The mean baseline COST score in the low FT group was 34 vs. 16 in the high FT group. Interestingly, pts with low baseline FT had significant worsening of FT over the 12 month time period while those with high FT had slight improvement over time. Consistently, the high FT group had higher scores on screening measures for anxiety and depression, as well as lower overall quality of life which persisted over time. Conclusions: Financial toxicity is a measurable and clinically relevant patient reported outcome. The cohort of women with high FT demonstrated higher mean scores on screening measures for depression and anxiety as well as persistently lower quality of life. Targeted interventions to decrease financial toxicity may provide more global improvements in mental health and quality of life.
Preoperative chemotherapy for advanced endometrial cancer-registry analysis of outcomes.
Authors: Salamekh Samer , Yan Jingsheng , Zhu Hong , Albuquerque Kevin V.
Published: May 2020

6088

Background: Hysterectomy followed by risk-adjusted adjuvant treatment is the standard of care for staging and treatment of locally advanced endometrial cancer. Up-front surgery is difficult in some locally advanced cases with extensive local invasion since negative margins may not be achievable. Pre-operative systemic treatment may be used to shrink the tumor and facilitate resection, echoing the experience from ovarian cancer. There is limited data for this paradigm in endometrial cancer. Methods: The National Cancer Database (NCDB) was queried for cases with FIGO stage III/IV endometrial cancer (serous, clear cell, or endometrial histology) who underwent surgery and had known chemotherapy/radiation sequencing. Those who received pre-operative chemotherapy +/- post-operative chemotherapy (PreCT) were compared to those who received post-operative chemotherapy alone (PostCT). PreCT cases were considered to be initially borderline resectable or unresectable. Downstaging was determined by comparing clinical and pathologic T-stage. Univariable (UV) and multivariable (MV) analyses were performed, with statistically significant values reported. Results: 12,310 cases in PostCT and 1,059 cases in PreCT were included in the analysis. Pre-CT cases were more likely to have higher AJCC T-stage, clinically positive nodes, serous histology, higher grade, and positive surgical margins (28% compared to 16%). Overall survival (OS) was lower for PreCT compared to PostCT (HR = 2.18 UV; HR = 1.87 MV). 20% of patients who received PreCT were down-staged compared to 2% in PostCT group. Patients who were downstaged with PreCT were more likely to achieve negative margins (OR 0.36 UV) and had improved OS compared to those whose stage did not change (HR = 0.61 UV; HR = 0.37 MV). Positive margins portended worse OS for both PreCT (HR = 1.93 UV) and PostCT (HR = 2.63 UV). Negative margins in PreCT had improved OS compared to positive margins in PostCT (HR = 1.2 UV; 2.67 MV). Post-operative radiation benefited both PreCT (HR = 0.45 UV; HR = 0.34 MV) and PostCT groups (HR = 0.48 UV; HR 0.64 MV). Conclusions: Preoperative chemotherapy increased the number of patients who were downstaged and those who were downstaged were more likely to achieve a negative margin. Patients who achieved negative margins in PreCT had improved OS compared to those with positive margins in PostCT. Adjuvant radiation further improved OS in both cohorts. Pre-operative chemotherapy can be considered for patients with unresectable/borderline resectable locally advanced endometrial cancer.
Equivalence randomized trial comparing treatment based on sentinel node biopsy versus neck dissection in operable T1-T2N0 oral and oropharyngeal cancer.
Authors: Garrel Renaud , Perriard Françoise , Favier Valentin , Richard Fanny , Daures Jean Pierre , De Boutray Marie
Published: May 2020

6501

Background: Although sentinel node (SN) biopsy is known to be accurate in operable oral and oropharyngeal cT1-T2N0 squamous cell carcinomas (OC), the oncological equivalence of a treatment based on SN compared to that based on neck dissection (ND) has to be evaluated. Methods: A prospective multicenter randomized medico economic study included patients with OC operated of primary tumor and systematic neck dissection in ND-arm (standard treatment) versus patients operated of primary tumor and SN biopsy only if negative or ND if SN biopsy positive (SN-arm, experimental treatment). Primary endpoint was neck-relapse-free survival at 2 years and 5 years. Hypothesis of equivalence was tested with a delta of 10%. Functional outcomes were assessed by comparing the length of the hospital stay, the number of physiotherapy prescriptions and dysfunctions in neck and shoulder scales during the 2 post-operative years. Results: Out of 307 included patients in 10 hospital centers, 279 evaluable cases showed a neck-relapse-free survival at 2 years and 5 years respectively of 89,6% (95%CI: 0.827; 0.938) and 89,6 %, (95%CI: 0.827; 0.938) in the ND-arm (14 neck relapses out of 139 patients) and of 90,7% (95%CI: 0.842; 0.946) and 89,4% (95%CI: 0.823; 0.938) in the SN-arm (13 neck relapses out of 140 patients). The survival difference between the two arms was less than the 10% expected interval, confirming the equivalence with p = 0.008. The median length of hospital stay was 7 days (ext. 3-30) in SN-arm and 8 days (ext. 2-94) in ND-arm (Wilcoxon’s test, p = 0.001). The other functional outcomes were statistically worse in the ND-arm at the 2nd, 4th and 6th postoperative months. There was no more difference at 12 months and later. Conclusions: This study demonstrated the oncological equivalence of the SN approach compared to the ND approach in a multicenter study with a lower morbidity and care consumption in the SN approach during the 6 first post-operative months. Treatment based on sentinel node biopsy is established as a standard of care in OC. Clinical trial information: NCT02855723 .
Atezolizumab combinations with targeted therapy for anaplastic thyroid carcinoma (ATC).
Authors: Cabanillas Maria E. , Dadu Ramona , Ferrarotto Renata , Liu Suyu , Fellman Bryan M. , Gross Neil D. , Gule-Monroe Maria , Lu Charles , Grosu Horiana , Williams Michelle D. , Duose Dzifa Yawa , Mallampati Saradhi , Dervin Shannon , Mckenna Edward Francis , Wang Rui Jennifer , Zafereo Mark , Busaidy Naifa Lamki
Published: May 2020

6514

Background: ATC is a rare/aggressive cancer with dismal outcome. Dabrafenib/trametinib is approved for BRAF-mutated ATC but pts eventually develop resistance. There are no approved drugs for pts with BRAF-wild type ATC. Better treatments (tx) are needed. Methods: ATC pts with PS < 3 enrolled on a prospective trial at a single center, and tx was assigned by driver mutation: BRAF (cohort 1), RAS, NF1, or NF2 (cohort 2), or none of these (cohort 3). Cohort 4 with paclitaxel was exploratory for pts who did not qualify for 1-3. All pts received atezolizumab (A) IV + targeted therapy. Cohort 1 had run-in with vemurafenib (V) 960mg BID/cobimetinib (C) 60mg QD po for 28 days, followed by A 840mg Q2 weeks, at which time V dose was decreased to 720mg BID. Cohort 2: A + C (same doses as cohort 1); cohort 3: A 1200 mg Q3 weeks + bevacizumab 15 mg/kg q3 weeks. Pts unable to swallow used alternative drug preparation (ADP; crushed vemurafenib, suspension cobimetinib). Primary objective is to determine whether the tx in cohorts 1-3 leads to improved overall survival (OS). The trial was designed to enroll 36 pts but we are reporting early due to positive findings. Response rate (RR) was measured by RECISTv1.1. Median OS was estimated by Kaplan-Meier method. cfDNA and biopsy were obtained at baseline, course 2 and progression. Pts were allowed to undergo surgery and radiation while on trial. Results: From August 2017-January 2020, 34 ATC pts were enrolled in cohorts 1-3 and 9 in cohort 4. Cohort 3 closed early for futility. 3 pts had ADP. Median follow-up time was 7.51 mos (range: 0.43 – 27.37). Median OS in cohorts 1-3 was 18.23 mos (CI 10.45-NE) and 1-year OS was 67% (95%CI: 45%, 82%). See table. Response rate (RR) in cohort 1 was 71%: CR 1/17 (6%), PR 11/17 (65%), SD 4/17 (23%), 1 never restaged; in cohort 2 RR was 7%: PR 1/14 (7%), SD 7/14 (50%), PD 4/14 (29%), 2 died early. 8 (24% of cohort 1-3) pts had complete tumor resection after tx with VCA (n = 7) or CA (n = 1); all but 1 of these pts are alive. AEs as expected. cfDNA data will be reported at meeting. Conclusions: Atezolizumab + vemurafenib/cobimetinib for BRAF-mutated or + cobimetinib for NF1/2 or RAS-mutated ATC is effective, as evidenced by the long OS in these pts (13 mos > historical control). A significant number of patients, particularly in cohort 1, were able to undergo complete tumor resection due to a favorable response to tx. Clinical trial information: NCT03181100 . [Table: see text]
A multicenter phase II trial of the combination cisplatin/ docetaxel/durvalumab/tremelimumab as single-cycle induction treatment in locally advanced HNSCC (CheckRad-CD8 trial).
Authors: Hecht Markus , Gostian Antoniu-Oreste , Eckstein Markus , Rutzner Sandra , von der Grün Jens , Illmer Thomas , Hautmann Matthias G. , Brunner Thomas , Laban Simon , Klautke Gunther , Tamaskovics Balint , Hinke Axel , Frey Benjamin , Semrau Sabine , Hartmann Arndt , Roedel Claus , Budach Wilfried , Gaipl Udo S , Iro Heinrich , Fietkau Rainer
Published: May 2020

6519

Background: PD-1/PD-L1 inhibitors are efficient in head and neck squamous cell cancer (HNSCC). Combination with anti-CTLA4 agents may enhance anti-tumor activity compared to anti-PD-1/PD-L1 monotherapy in different tumor types. In the CheckRad-CD8 trial the typical induction treatment consisting of Cisplatin/Docetaxel was combined with Durvalumab/Tremelimumab. Patients with pathological complete response (pCR) in the re-biopsy after induction treatment or at least 20% increase of intratumoral CD8 density in the re-biopsy compared to baseline entered radioimmunotherapy with concomitant Durvalumab/Tremelimumab. Methods: In this prospective multicenter phase II trial, patients with HNSCC stage III-IVB received a single cycle of Cisplatin 30mg/m² d1-3, Docetaxel 75mg/m² d1, Durvalumab 1500mg fix dose d5 and Tremelimumab 75mg fix dose d5. Objectives of this interim analysis were to quantify the effect of the induction treatment on intratumoral CD8 density and the pCR rate and to generate safety data. Results: Between Sep 2018 and Dec 2019, 57 patients were enrolled. Median age was 59 years, 22 patients (37%) were current smokers, 27 patients (47%) had oropharyngeal tumors (52% p16 positive). The median pre-treatment intratumoral CD8 density was 335 CD8+ cells/mm². After induction treatment 27 patients (47%) had a pCR in the re-biopsy and further 25 patients (44%) had a relevant increase of intratumoral CD8+ cells (median increase by factor 3.0). Response according to RECIST criteria was CR in 1 (2%), PR in 19 (33%) and SD in 20 patients (35%) (17 patients not evaluable). Adverse events (AE) grade 3-4 appeared in 39 patients (68%) and mainly consisted of leucopenia (43%) and infections (28%). 6 patients (11%) developed grade 3-4 immune-related AEs. In multivariable analysis the intratumoral CD8 density was the only independently significant predictor of pCR (odds ratio 1.0013 per cell/mm², 95%-CI 1.00023-1.0023, p=0.017). 42 patients (74%) continued with Durvalumab/ Tremelimumab concomitant to radiotherapy. Conclusions: Single cycle induction treatment with Cisplatin/Docetaxel/Durvalumab/Tremelimumab is feasible and achieves a high pCR rate. CD8 density may have a predictive role for further treatment planning in locally advanced HNSCC. Clinical trial information: NCT03426657 .
Association of autoimmunity with survival in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs).
Authors: Economopoulou Panagiota , Gavrielatou Niki , Papaxoinis George , Kotsantis Ioannis , Pantazopoulos Anastasios , Anastasiou Maria , Kavourakis George , Gkolfinopoulos Stavros , Psyrri Amanda
Published: May 2020

6537

Background: ICIs are associated with immune-related adverse events (irAEs) that occur as a consequence of enhanced immune response due to T-cell activation. The objective of this observational cohort study was to investigate the association between irAEs and disease outcome in pts with R/M HNSCC. Methods: 110 pts treated with ICIs were reviewed. Overall survival (OS) was calculated from the date of initiation of ICI to the date of death. To overcome guarantee-time bias, we calculated post-irAEs survival from the date of first irAE presentation in patients who developed irAEs or from the date of ICI initiation in pts without irAEs. Results: Primary site was the oral cavity (N = 51), oropharynx (N = 20), larynx (N = 29), hypopharynx (N = 1), paranasal sinuses (N = 5) and nasopharynx (N = 4). 41 (37.3%) had metastatic and 69 (62.7%) recurrent disease. 32 pts (29.1%) developed irAEs, with more common thyroiditis (N = 15, 13.6%). Of 100 pts with evaluable disease, 14 (14%) responded. 6/31 (19.4%) with irAEs vs. 8/69 (11.6%) without irAEs responded to ICI (p = 0.354). After a median follow-up of 16.4 months, 69 pts died. Median OS was 10 mo (95%CI, 6.7-13.4), 10 mo (95%CI, 5.6-14.5) for pts with recurrent and 10 mo (95%CI, 7.7-12.3) for pts with metastatic HNSCC (p = 0.966). Median OS was 17.9 mo (95%CI, 7.9-27.9) for pts with irAEs and 6.6 mo (95%CI, 3.3-9.9) for pts without irAEs (p = 0.001). Median post-irAEs survival was 16.3 (95%CI, 7.1-25.5) for pts with irAEs vs. 6.6 mo (95%CI, 3.3-9.9) for pts without irAEs (p = 0.020). Responders to ICI did not differ in median post-irAEs survival irrespective of whether they developed irAEs (p = 0.561), while among non-responders, those who developed irAEs had significantly longer median post-irAEs survival compared to those who did not (10 vs. 6 mo, respectively, p = 0.044). Multiviariate Cox proportional hazard models showed that independent favorable prognostic factors for post-irAEs survival were the development of irAEs (HR 0.54, 95%CI 0.30-0.97, p = 0.039) and response to ICI (HR 0.16, 95%CI 0.05-0.50, p = 0.002). Conclusions: The development of irAEs is a strong predictor of improved survival in patients with advanced HNSCC treated with ICIs.