bluuebunny/crossref_metadata_2025 huggingface dataset:
Combretastatin A-4 phosphate (CA4P) carboplatin and paclitaxel in patients with platinum-resistant ovarian cancer: Final phase II trial results
Authors: Zweifel M. , Jayson G. , Reed N. , Osborne R. , Hassan B. , Shreeves G. , Poupard L. , Walicke P. A. , Balkissoon J. , Chaplin D. , Rustin G.
Published: August 2020

5502

Background: CA4P is a vascular disrupting agent that in pre-clinical models can increase the efficacy of a variety of therapies. A dose escalation trial of CA4P given prior to carboplatin, paclitaxel or both showed the combination was well tolerated and responses were seen in several tumor types including 6/17 with relapsed ovarian cancer. The trial was therefore extended into a phase II trial in patients with platinum resistant ovarian cancer. Methods: Patients with ovarian cancer that had relapsed and could start trial therapy within 6 months of their last platinum chemotherapy were given CA4P 63mg/m2 18–20 hours prior to paclitaxel 175mg/m2 and carboplatin AUC 5 repeated 3 weekly. If > 2 responses were seen in first 18 patients 43 patients were to be treated to confirm response rate>19%. Results: Five of the first 18 patients responded so the study was extended and closed after 44 patients were recruited, with full data available to date on 34. Weekly blood counts have demonstrated grade 3/4 neutropenia in 11 and thrombocytopenia in only 1 patient. Other grade > 2 toxicity seen in > 1 patient was fatigue, nausea / vomiting, pain, alopecia, rapidly reversible ataxia, diarrhoea, neuropathy and was little different to what would be expected with paclitaxel and carboplatin. Hypertension is the commonest CA4P related toxicity and was easily controlled by GTN, then prophylactic amlodipine. Responses according to GCIG criteria, have been seen in 11/34 (32%) patients with an additional unconfirmed PR. Conclusions: The addition of CA4P to paclitaxel and carboplatin is well tolerated and appears to produce a higher response rate in this patient population than if the chemotherapy was given without CA4P. A planned randomised trial will hopefully confirm this.

[Table: see text]
Tau expression as a predictive marker in ovarian cancer patients (pts) treated with platinum/paclitaxel chemotherapy
Authors: Smoter M. , Grala B. , Bodnar L. , Szczylik C.
Published: August 2020

5529

Background: Ovarian cancer is the most lethal gynecologic cancer and its standard treatment consists of cytoreductive surgery followed by paclitaxel/platinum-based chemotherapy. Additional prognostic biomarkers may allow for more tailored chemotherapy and an improved outcome. Recently, microtubule associated protein tau was identified as a marker of response to paclitaxel in breast cancer. Its predictive value in ovarian cancer has not been established. We evaluated the relevance of tau expression in ovarian cancer. Methods: Tissue specimens were obtained from 74 ovarian cancer patients (stage I-IV) who underwent cytoreductive surgery followed by standard paclitaxel/platinum (cisplatin or carboplatin) chemotherapy. Tau expression was determined by immunohistochemistry using semiquantitative DAKO test. Statistical analysis included long rank test and Mann Whitney test. Results: Median age of pts was 54 years (range 31–73). 25.7% and 74.3% of the pts were classified as tau-negative and tau-positive, respectively. In the univariate analysis 2-year progression free survival in tau-negative and tau-positive groups was 75.0% and 30.6%, respectively (p = 0.0153). This relationship was confirmed in the multivariate analysis including age, disease stage, histology type, and grade (HR 2.68; 95%CI [1.13–6.37]; p = 0.0255). Among the 46 pts with measurable disease, overall response rate in tau-negative and tau-positive groups was 90.9 and 54.5%, respectively (p = 0.0299, Z = 2.17). Conclusions: Tau protein expression seems to be a strong predictor of clinical outcome in ovarian cancer pts applied paclitaxel/platinum-based chemotherapy.

No significant financial relationships to disclose.
Phase II study of intravenous (IV) bevacizumab and paclitaxel, and intraperitoneal (IP) cisplatin, followed by bevacizumab consolidation for advanced ovarian (O) or peritoneal (P) cancers
Authors: McMeekin D. D. , Lanneau G. , Curiel J. , Moore K. , Walker J. , Mannel R.
Published: August 2020

5540

Background: Excessive toxicity and difficulty in completing prescribed cycles are cited as factors behind the lack of routine acceptance of IP therapy in O/P cancer. In an effort to increase the probability of completing 6 cycles of IP therapy, we evaluated a modified IP regimen with the addition of bevacizumab to determine the proportion of patients able to receive 6 cycles successfully. Methods: An open label phase II study was conducted in patients (pts) with stage II-III O/P cancers with residual disease < 1 cm. The primary outcome measure the feasibility of delivering 6 cycles of IP therapy with a completion rate of > 80% being clinically relevant. Pts received paclitaxel 135 mg/m2 IV on day 1 followed by cisplatin 75 mg/m2 IP day 2. Bevacizumab 15 mg/kg day 1 IV was started with the second cycle. Cycles were administered every 21 days for a total of 6 cycles. Following completion of primary therapy, bevacizumab @ 15mg/kg IV was given in consolidation every 21 days for 12 cycles. Pts were assessed for toxicity and disease status. This preliminary analysis reports data from experience with 6 cycles of IP therapy. Results: 22 patients have been enrolled (21-O, 1-P) with a median age of 58 yrs. Two pts discontinued therapy due to IP port problems (following cycle 1 and 4) and per protocol, were replaced. Two pts are on active treatment (completed cycle 5). Of 20 evaluable pts, 2 pts discontinued prematurely (1 after cycle 1 due to elevated liver function tests, 1 after cycle 4 due to grade 3 neuropathy), and 1 pt received cycle 6 by IV route secondary to abdominal pain with IP infusion. The proportion of patients successfully completing 5 cycles of IP therapy was 18/20 (90%), and to date 15/18 (83%) pts have completed 6 cycles. One patient developed a DVT, one had an intra-abdominal fistula requiring surgical intervention after cycle 6. Conclusions: The addition of bevacizumab to an IP regimen for O/P cancers did not add to enhanced acute toxicity. The present regimen using 75 mg/m2 CDDP IP and no day 8 paclitaxel appears to be tolerable, with >80% of pts able to receive 6 cycles of therapy.

[Table: see text]
Intraperitoneal chemotherapy (IPC) in older women with epithelial ovarian cancer (EOC)
Authors: Tew W. P. , O'Cearbhaill R. , Zhou Q. , Thaler H. , Konner J. , Hensley M. L. , Sabbatini P. , Spriggs D. , Aghajanian C. , Lichtman S. M.
Published: August 2020

5541

Background: Over half of patients (pts) diagnosed with EOC are ≥ 65 yrs of age. GOG 172 showed a significant survival advantage with post-operative IPC in all women with newly diagnosed stage III EOC, regardless of age. Toxicity can be significant and there is limited data for pts ≥ 65 yrs. Methods: A descriptive intention-to-treat analysis of pts ≥ 65yrs treated with IPC for EOC at our center from 1994–2008. Medical records were reviewed retrospectively to detail toxicity (CTCAEv3.0), compliance and outcome. Results: 118 pts with a median age of 70 yrs (range 65–83), KPS 90% (range 70–90), and co-morbidities 2 (range 0–6) were treated with IPC: 27 pts (23%) as primary postoperative IPC (IV paclitaxel 135mg/m2 D1, IP cisplatin 75mg/m2 D2 & IP paclitaxel 60mg/m2 D8) and 91 pts (77%) as consolidation (IP cisplatin regimen, alone or combined with IV paclitaxel or with IP gemcitabine). Median no. of cycles was 3 (range 0–7) with 55% pts completed total no. planned. 18% were switched to IV treatment. 14% had treatment delays. 32% required dose reductions, 22% at cycle 1. Toxicities included: 32% had IP port complications, 42% functional decline, 43% new ≥ Gr1 neuropathy (4% Gr3), 12% Gr2 hearing impairment, 60% ≥ Gr1 nausea/vomiting (4% Gr3), 57% ≥ Gr1 diarrhea/constipation (0% Gr3), 37% ≥ Gr1 abdominal pain (2% Gr3). For evaluable pts, 78% had ≥ Gr1 electrolyte disturbance (5% Gr3–4), 71% ≥ Gr1 nephrotoxicity (5% Gr2; 1% Gr3), 20% ≥ Gr2 neutropenia (6%Gr3; 3% Gr4). Ca125 normalized in 90% (pts with elevated baseline Ca125). Kaplan-Meier estimated median PFI was 1.2yrs (95% CI: 1–1.6yrs). Conclusions: Rate of completed full IPC cycles and toxicity is similar to published data. IPC can be safely administered in pts ≥ 65yrs with adequate support and dose modifications. Older patients must be adequately represented in future prospective trials.

No significant financial relationships to disclose.
Phase I/feasibility trial of dose-dense carboplatin (C) and paclitaxel (P) in patients (pts) with ovarian cancer: A Gynecologic Oncology Group study
Authors: Tiersten A. , Sill M. , Muggia F. , Elera C. , Garcia A. , Fracasso P. , Swensen R. , Warshal D. , Mannel R. ,   Gynecologic Oncology Group
Published: August 2020

5544

Background: Dose-dense regimens improve outcome for women with breast cancer. We investigated the feasibility of dose-dense CP for women with ovarian cancer. Methods: Pts with untreated stage III/IV ovarian cancer received C AUC 5 and P 175 mg/m2 day 1, pegfilgrastim 6 mg day 2 every 2 weeks for 6 cycles. Dose-limiting toxicity (DLT) was defined as: febrile neutropenia, grade 4 neutropenia ≥7 days, grade 4 thrombocytopenia (tcp), grade 3 tcp with bleeding, dose delay >2 weeks, grade 3/4 non-hematologic toxicity (excluding fatigue, hypersensitivity, nausea/vomiting, alopecia, constipation, diarrhea or bone pain), and any treatment related death. The study utilized a 2-stage sequential design (20 pts/stage) with DLTs in 6 cycles determining regimen feasibility. Results: Between September 2006 and September 2008, 43 pts enrolled. Twenty and 17 patients were evaluable for toxicity over 6 cycles in stages 1 and 2 respectively. Six DLT's were observed for both stages. Thirty pts completed treatment and 12 did not [DLTs (6), paclitaxel hypersensitivity reactions (2), progression (1), patient choice (1), infection (1) and death unrelated to treatment (1)]. One pt remains on treatment. The 6 DLTs resulting in treatment discontinuation included grade 3 neuropathy (2), grade 4 neuropathy (1), grade 4 tcp (1), grade 4 tcp/grade 3 febrile neutropenia (1), and grade 4 SVT (1). Six other DLTs not preventing treatment completion included grade 3 infection (1), grade 3 AST/ALT elevation (1), grade 3 confusion (1), grade 3 dehydration (1), grade 3 neuropathy (1) and grade 4 tcp (1). Other toxicities resulting in treatment delays included grade 3 tcp (1), grade 3 fatigue (1) and grade 2 neuropathy (2). There were 5 P dose reductions and 4 C dose reductions. Conclusions: Seventy-two percent pts completed 6 cycles of dose-dense CP. Based on DLTs (at least 12 in 37 evaluable pts), this regimen is not feasible. Given the neuropathy and tcp, we do not recommend further investigation in a phase III trial.

No significant financial relationships to disclose.
Preliminary results of a phase II study of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube
Authors: Rose P. G. , Drake R. , Braly P. S. , Bell M. C. , Wenham R. M. , Hines J. H. , Alvarez-Secord A. , Soltes-Rak E. , Childs B. H. , Herzog T. J.
Published: August 2020

5546

Background: Objectives are to estimate efficacy and safety of a novel taxane/platinum chemotherapy doublet in combination with bevacizumab (B), as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube (FT), after initial debulking surgery. Methods: Eligibility criteria included histological confirmation of primary disease, previous debulking surgery, and normal renal, hepatic, hematological, and neurological function. Subjects were treated with 6 cycles of oxaliplatin (85 mg/m2), docetaxel (75 mg/m2) and B (15 mg/kg) Q3W, followed by maintenance B (15 mg/kg Q3W) to complete one year of therapy. The primary endpoint is progression-free survival (PFS) of pts with measurable disease at 1 year. Results: A total of 110 subjects are included in safety and 95 in efficacy analyses (55 with measurable disease). Median age was 58 years. Tumors were mostly ovary as primary site (84%), poorly differentiated (65%), serous adenocarcinoma pathology (73%) and FIGO stage IIIC (68.2%) or IV (14.6%). 61% of subjects were optimally debulked. 95 (86%) of subjects had completed the chemotherapy cycles with 87 of the 95 having started on the B-only maintenance cycles. 85 (77%) subjects have stopped study treatment [including 33 completed study treatment, 29 disease progression, 15 adverse event (AE), 8 other reasons]. The most common grade 3–4 AEs were: neutropenia (39%), leukopenia (11%), hypertension (9%), and fatigue (7%) Grade 3–4 peripheral sensory neuropathy (PSN) occurred in 2 patients (1.3%). There was one case of colonic perforation associated with B. Investigator-determined best overall confirmed response rates were: complete response 32.8%; partial response, 29.1%; stable disease 32.7%; and progressive disease (PD), 1.8%. The 1-year PFS probability is 70.1% (95% C.I., 56.8%-83.4%) in the 55 patients with measurable disease. Conclusions: This preliminary data supports feasibility of this novel regimen, with an acceptable safety profile and a low incidence of PSN and colonic perforation. Preliminary 1-year PFS is promising. The trial completed accrual to 132 patients in August 2008. Updated results will be presented.

[Table: see text]
Patterns of use of tamoxifen and aromatase inhibitors: A population-based observational study
Authors: Huiart L. , Dell'Aniello S. , Suissa S.
Published: August 2020

556

Background: Few data are available outside clinical trials on the use of aromatase inhibitors (AI) as adjuvant treatment for early breast cancer (BC). We therefore used a large population-based database to describe patterns of use of AI over time, in comparison with tamoxifen, as well as switches between these regimens. Methods: We identified 13,479 women treated for BC with tamoxifen, anastrazole, letrozole, or exemestane between 1998 and June 2008 in the UK General Practice Research Database (GPRD). Patients were followed from their first prescription for 5 years or until recurrence, death, switch to another treatment or occurrence of a major thromboembolic or uterine event. Results: Mean age at cohort entry was 62 years (SD=14.0) in the tamoxifen group (n=10,806) and 70.8 (SD = 12.4) in the AI group (n=2,673). Overall, in the first year of treatment 88.8% of patients had prescriptions covering more than 80% of the year (88.3% and 90.8% in tamoxifen and in AI group respectively). Table 1 describes prescriptions covering less than 80% of the days for each year of treatment in 3 subgroups. Among women started on AI therapy diagnosed with BC after 2006, 9.6% switched treatment. Half of them switched from one AI to another AI, the other half switched from AI to tamoxifen. Switches occurred within the first year of treatment in 76% of cases. Among women over 50 years of age who started a tamoxifen therapy after 2000, 31% of women switched to AI in the course of the study, of which 12% within the first year of treatment (11.1% and 13.7% for women diagnosed in 2000–2004 and after 2005 respectively). Conclusions: The real-life patterns of use of tamoxifen and AI therapy demonstrate high rates of adherence. However, the relatively high percentage of switchers among AI users is suggestive of an association with side-effects.

[Table: see text]

No significant financial relationships to disclose.
Ovarian cancer treatment in the New York City municipal hospital system
Authors: Boyd L. R. , Novetsky A. P. , Curtin J. P.
Published: August 2020

5569

Background: OC patients (pts) from minority groups/lower socioeconomic strata are reported to have poorer outcomes. New York City (NYC) Health and Hospitals Corporation (HHC) has 11 municipal hospitals. We evaluated surgical management of OC pts in HHC hospitals. Methods: The New York State SPARCS database of admissions was queried for OC pts in the years 2001 to 2006. Pts from HHC were compared to pts from all other NYC hospitals (other cohort). Pt demographics, procedure performed, emergent vs. scheduled admission, length of stay, and hospital charges were compared utilizing chi-square. A comorbidity index was applied to both cohorts. Surgeons were stratified by subspecialty training and OC case volume. Results: 6,010 admissions for OC were identified. 3,624 were major surgical procedures: 187 from the HHC cohort and 3,436 from the other cohort. Demographics for HHC vs other cohort, respectively: Caucasian 37 (20%) vs 2,224 (65%); African-American (AA): 64 (34%) vs 460 (13%); Asian 20 (11%) vs 181 (5%); other: 66 (35%) vs 286 (8%); unknown 0 vs. 286 (8%) (p< 0.001). Payors for the HHC vs other cohort, respectively: Medicaid 108/187 (57%) vs 279/3,437 (8%); Medicare 22/187 (12%) vs 872/3,437 (25%); private insurance 38/187 (20%) vs 2,244/3,437 (65%); self-pay 18/187 (10%) vs 40/3,437 (1%) (p < 0.001). Urgent admissions were 96/187 (51%) of HHC cohort vs 902/3,436 (26%) of other cohort (p < 0.001). There were no differences in comorbidity rating or procedures performed. Subspecialty surgeons were documented for 59/187 (32%) of HHC cohort vs 1,839/3,437 (53%) of other cohort (p < 0.001). The majority of surgeons performed less than two OC cases over the six year period, however surgeons with cases at HHC hospitals were more likely to be represented in the top 15% of total case volume (25% vs 14%, p < 0.01) due to affiliations with academic centers. Conclusions: Pts in HHC cohort were more likely to be AA, have an urgent admission and less likely to have insurance or have a gynecologic oncologist as a surgeon. However there is evidence of centralized care for some in the HHC cohort. Despite the limitations associated with using a large database, clear differences were seen in the patterns of care between municipal and all other NYC OC pts. Studies to document outcomes and further optimize care within the HHC hospital system are ongoing.

No significant financial relationships to disclose.
Detection of high-risk HPV in urine of high- and low-risk populations in India
Authors: Robbins D. , Garg D. , Li J. , Melkonyan H.
Published: August 2020

5581

Background: Infection with high-risk HPV is involved in 90%-100% of cervical cancers. HPV detection in cervical cells, used as a supporting test for Pap smear positive patients, are much more sensitive than cytology but less specific for ongoing cervical cancer. Cervical cancer is one of the most common female tumors in countries lacking a screening program such as India. In this study we investigate the feasibility of a urine-based HPV DNA test. Methods: Matching urine and cervical samples were collected from 270 high-risk subjects from STD clinics or district brothels in West Bengal, and 50 low-risk subjects with no known predisposition to disease recruited in Mumbai. The Xenomics HPV DNA test involves isolation of DNA from urine and specific PCR amplification of the HPV E1 region to detect the presence of high-risk HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Results were compared to the hc2 high-risk HPV DNA Test (QIAGEN). Discordant samples were resolved by DNA sequencing. Results: Of 320 patients, 248 samples (77.5%) were concordant between the Xenomics and hc2 assays. Of the discordant samples reactive by Xenomics but nonreactive by hc2, 31/38 (81.6%) contained high-risk HPV by DNA sequencing. 10 out of 34 (29.4%) of samples detected by hc2 but not by Xenomics were shown to contain high-risk HPV. Using DNA sequencing as the gold standard, the Xenomics test false negative and false positive rates were 10/180 (5.6%) and 7/140 (5.0%), respectively. The hc2 assay had a false negative and false positive rate of 31/184 (16.8%) and 24/136 (17.6%), respectively. Conclusions: HPV DNA can be isolated from urine samples and detected with sensitivity and specificity equal to or better than current assays based on cervical scraping.

[Table: see text]
A phase II study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer
Authors: McCormack M. , Ledermann J. A. , Hall-Craggs M. A. , Symonds R. P. , Warwick V. , Simonds H. , Fernando I. , Hackshaw A.
Published: August 2020

5586

Background: Chemoradiation (CRT) is the standard of care for locally advanced cervical cancer but survival is poor among women with large tumours, advanced stage, or positive nodes. Neoadjuvant chemotherapy (NACT) prior to CRT to down-stage tumours and lengthen the exposure to systemic treatment is designed to improve outcome. Methods: Patients (pts) with locally advanced cervical cancer received dose-dense carboplatin (AUC2) and paclitaxel (80 mg/m2) weekly, for 6 cycles, followed by CRT (external and brachytherapy) in week 7 with weekly cisplatin (40 mg/m2). The primary end-point was complete and partial response rate (RR) 12 weeks post CRT. Secondary objectives were RR for NACT at 6 weeks, toxicity and survival. The target RRs were 50% and 85% for NACT and post CRT (12-weeks) respectively. Results: Baseline characteristics were: median age at diagnosis 43 yrs (23–71); 74% squamous-, 20% adeno- and 6% adenosquamous carcinomas; FIGO stage IB2 (11%), II (50%), III (33%), IV (6%). The trial closed in Oct 08 with 46 pts. Of the first 36 pts enrolled 9 failed to complete protocol therapy (7 did not complete 6 NACT cycles, 2 did not complete the pre-specified minimum of 4 cycles of concomitant cisplatin). Using data currently available, the RR associated with NACT is 72% (95% CI 53–86%), and 81% at 12 weeks (95% CI 63–92%). Nonhaematological grade 3/4 toxicity was rare (<5%). There was grade 2 alopecia in 25% pts. Grade 3 and 4 haematological toxicity was seen in 10% and <3% of pts respectively. Updated results, including survival, will be presented for all pts. Conclusions: Dose-dense weekly NACT chemotherapy with carboplatin and paclitaxel followed by radical CRT is associated with a high response rate and is feasible. This approach merits further investigation in a phase III trial.

[Table: see text]
Utilization of Internet-based survivorship care plans by survivors of gynecologic cancers
Authors: Hill-Kayser C. E. , Vachani C. , Hampshire M. K. , Jacobs L. A. , Metz J. M.
Published: August 2020

5592

Background: Survivors of gynecologic cancers may be at risk for cancer-related late-effects, including fatigue, pain, second malignancy risk, and sexual side effects. The Institute of Medicine has recommended survivorship care plans (SCP) for all cancer survivors. Methods: A program for creation of SCP, OncoLife, is publicly accessible through OncoLink ( www.oncolink.org ), serving over 3.9 million pages/month to 385,000 unique IP addresses (August 2008). Users responding to 17 queries regarding demographics, diagnosis, and treatment receive comprehensive, individualized guidelines for future care. User data is maintained anonymously and securely, with IRB approval. Results: From May 2007-November 2008, 3,343 individuals completed OncoLife surveys. Survivors of gynecologic cancers represented 8% (n = 272; 58% ovarian, 24% endometrial, 19% cervical). Median ages at diagnosis of ovarian, endometrial, and cervical cancer were 50, 51, and 35 yrs, respectively, and median current ages 53, 55, and 47. Surgery was undergone by 98% of ovarian, 97% of endometrial, and 81% of cervical cancer survivors, and chemotherapy/ radiotherapy by 91%/12%, 51%/59%, and 67%/67%, respectively. Known genetic syndromes were reported by 13% of ovarian cancer survivors, compared to < 1% of endometrial/ cervix cancer survivors (p = 0.0006). Of all gynecologic cancer survivors, 53% reported being followed by an oncologist, 14% a primary care provider (PCP), and 27% both. Only 7% had received survivorship information previously. Conclusions: Most survivors of gynecologic malignancies have undergone multimodality treatment and may particularly benefit from SCP guidelines. Most do not receive follow-up care from both an oncologist and PCP, and few have received survivorship information. Gynecologic cancer survivors appear willing to use this tool; future iterations will focus on further individualization of guidelines, and improving access to underrepresented populations.

No significant financial relationships to disclose.
Evaluation of preoperative positron emission tomography with computed tomography (PET-CT) for detecting lymph node metastasis in gynecologic carcinoma
Authors: Murakami F. , Ogawa N. , Yamazaki A. , Sakurai S. , Ishiya T. , Katase K. , Shimizu Y. , Tanada S.
Published: August 2020

5593

Background: To evaluate the sensitivety, specificity, and accuracy of PET-CT for detecting lymph node metastasis in gynecologic carcinoma. Methods: Between May 2007 to August 2008, 36 consecutive patients (pts) with cervical carcinoma, endometrial carcinoma and epithelial ovarian carcinoma were enrolled. All pts underwent PET-CT prior to the surgery of systematic pelvic and paraaortic lymphadenectomy. For pathological metastatic lymph nodes, the size of intranodal tumor deposits (maximum diameter of metastatic foci in each lymph node) were recorded. Results: The total number of pelvic lymph nodes (PLNs) plus paraaortic lymph nodes (PANs) removed was 2426. The median number of removed lymph nodes (LNs) was 67 each pts (range: 25 to 102). The number of involvement LNs was 79 (3.5%). The sensitivity, specificity and accuracy of preoperative PET-CT to detect LN metastasis were 24%, 99.9%, and 97.5%, respectively. The sensitivity of PLNs and PANs were 39.5% and 7.3%, respectively. The sensitivity of squamous cell carcinoma (SCC) were 35.7%, that of adenocarcinoma were 8.1%. FDG-PET detected 100% of intranodal tumor deposits > or =10 mm, whereas tumor deposits smaller than 5 mm were not detected. Conclusions: The results of our study revealed 76% underdiagnosis (overlooking) in evaluation of preoperative PET-CT in LN metastasis. Particularly, tumor deposits smaller than 5 mm were not detected at all. Using PET-CT for detecting small LN metastasis in gynecologic carcinoma may be unreliable so far. However we found that PLNs are comparatively easy to be detected than PANs, and SCC are comparatively easy to be detected than adenocarcinoma. The improved usability and application of PET-CT for detecting LN metastasis in gynecologic carcinoma have to keep researching constructively.

No significant financial relationships to disclose.
Randomized phase III trial of adjuvant epicirubicin (E) followed by cyclophosphamide, methotrexate, and fluorouracil (CMF) or CMF followed by E in patients with N- or ≤ 3 N+ rapidly proliferating breast cancer (RPBC)
Authors: Amadori D. , Schittulli F. , Paradiso A. , Scarpi E. , Sismondi P. , Ravaioli A. , Rocca A. , Maltoni R. , Serra P. , Silvestrini R.
Published: August 2020

560

Background: Antimetabolites are active in proliferating cells, and the adjuvant schedule CMF is highly effective in RPBC, whereas the sequential administration of doxorubicin (D) and CMF is superior to CMF–>D, especially in indolent tumors. In a phase III study, we evaluated whether adjuvant E followed by CMF is superior to the inverse sequence in RPBC. Methods: Patients with N-, T > 1 cm or ≤ 3 N+ and any T RPBC (defined by thymidine labeling index or grade or S-phase or Ki67/MIB1) were randomized to receive E (100 mg/m2 i.v. d 1, q 21 days for 4 cycles) followed by CMF (600, 40, 600 mg/m2 i.v. d 1 and 8, q 28 days for 4 cycles) (arm A) or CMF followed by E (arm B) or CMF (600, 40, 600 mg/m2 i.v. d 1 and 8, q 28 days for 6 cycles) (arm C). Arm C was closed after the EBCTCG 2000 meta-analysis (data not shown). The main endpoint was overall survival (OS), and the study had 80% power to detect a 7% absolute increase in 5-year OS with 400 patients per arm. Results: From November 1997 to December 2004, 1066 patients were enrolled (arms A/B/C: 440/438/188): N- 53%, estrogen receptor positive 63%, grade 3, 77%. At a median follow up of 69 months, 5-year disease-free survival was 80% in both arms (A and B) (p = 0.93, logrank test), with adjusted hazard ratio (AHR) 0.99 (95% CI 0.73–1.33, Cox model), and OS was 91% in arm A and 93% in arm B (p = 0.66, logrank), with AHR 0.88 (95% CI 0.58–1.35, Cox model). Adverse events were similar, apart from a small increase in grade 4 neutropenia in arm B. Conclusions: No relevant differences in clinical outcome were observed with the 2 different sequences. Further subgroup analyses are ongoing to verify the efficacy of each sequence as a function of biomolecular and hormonal profiles.

No significant financial relationships to disclose.
Randomized, blinded, placebo-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer
Authors: Crew K. D. , Capodice J. , Greenlee H. , Brafman L. , Fuentes D. , Awad D. , Hershman D. L.
Published: August 2020

571

Background: Aromatase inhibitors (AIs) have become the standard of care for the treatment of postmenopausal, hormone-sensitive breast cancer (BC). However, patients receiving AIs may experience joint symptoms which can lead to early discontinuation of this effective therapy. We examined whether acupuncture improves AI-induced arthralgias in women with early stage BC. Methods: This study is a randomized, single-blinded trial of true vs sham acupuncture twice weekly for 6 weeks in postmenopuasal women with early stage BC and self-reported musculoskeletal pain related to adjuvant AI therapy. The active intervention included full body/auricular acupuncture and a joint-specific point prescription, whereas the sham arm involved superficial needle insertion at nonacupoint locations. Outcome measures included the Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC), and Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) obtained at baseline, 3 and 6 weeks. Lower scores reflect improvement in symptoms. Results: Of 43 women enrolled, 38 were evaluable at 6 weeks. Baseline characteristics were comparable between the groups. Median age: 57 (37–77); White/Hispanic/Black/Asian: 15/21/1/1; median body mass index (kg/m2): 29 (18–45). True acupuncture was associated with about a 50% decrease in mean BPI-SF scores, whereas no change from baseline was observed for the sham acupuncture group (see table). Similar findings were seen for the WOMAC and M-SACRAH pain, stiffness, and function scores (P<0.05). No adverse events were reported. Conclusions: Women with AI-induced arthralgias treated with acupuncture had significant improvement of joint pain and stiffness, which was not seen with sham acupuncture. Acupuncture is an effective and well-tolerated strategy for managing this common treatment-related side effect.

[Table: see text]

No significant financial relationships to disclose.
Gene expression profiling and copy number analysis to identify predictive molecular markers in breast cancer: Successful use of formalin fixed paraffin embedded tissue (FFPE)
Authors: Iddawela M. Y. , Wang Y. , Russell R. , Cowley G. , El-Sheemy M. , Eremin J. , Eremin O. , Faham M. , Earl H. M. , Caldas C.
Published: August 2020

574

Background: FFPE is a valuable and widely available resource for translational research which to date has been under-used due to technical limitations. Improvement in technology has enabled genome-wide analysis of FFPE samples. We have assessed gene expression and copy number changes in the same cohort of breast cancers to identify markers or pathways important in prediction of treatment response. Methods: FFPE tissues from patients treated with neoadjuvant adriamycin/cyclophosphamide followed by taxanes in a clinical study were used. Gene expression profiling was assessed using the cDNA mediated annealing selection and ligation assay using the cancer panel which assess 502 genes (DASL assay, Illumina). Data was analysed using BeadStudio software. Copy number changes were assessed using the Molecular inversion probe assay with the 50K SNP panel (Affymetrix, California) and analysed using Nexus software (Biodiscovery). Results: Gene expression profiling was carried out on 44 samples. 12/44 (27%) patients had a pathological complete response (pCR) following chemotherapy. Significant differential expression of genes between pCR and non-pCR cancers were shown. TNFRSF5, CTSD, BCL3, ARNT, BIRC3, TGFBR1, MLLT6, and EVI2A were over-expressed and COL18A1, FGF12, IGFBP1 and NOTCH4 which were down-regulated in cancers that have a pCR (p ≤ 0.01). Copy number changes were assessed in 33 samples and comparison of copy number changes in pCR vs. non-pCR showed gains in regions 6q22, 21q21, 4p14, 4q21, 4p14, and loss at 11q11 (p ≤ 0.01). Three regions containing microRNA coding sequences, mir130a (11q11) mir142 (17q23) and mir21 (17q23) showed significant loss among pCR tumours (p < 0.05). Conclusions: This feasibility study shows that FFPE can be used for gene expression and copy number analysis which is a useful tool for the discovery of predictive markers for treatment response in neoadjuvant treatment trials. The role of TNFRSF5, microRNA 21/130a/142, and 11q11 loss should be further investigated as predictive markers of response to chemotherapy.

[Table: see text]
Number needed to treat (NNT) to compare benefits of letrozole (LET) with adjuvant chemotherapy (CT) in patients (pts) with node-positive (N+) breast cancer (BC)
Authors: Dhillon N. , Kaura S. , Dranitsaris G. , Rugo H.
Published: August 2020

581

Background: Adjuvant CT is an accepted treatment for N+ BC. The addition of taxanes to anthracycline based adjuvant CT has been demonstrated to improve overall survival (OS) in all but one study as in table below. BIG 1–98 has reported a survival gain with the aromatase inhibitor LET compared to tamoxifen (TAM). NNT (the reciprocal of absolute benefit) is the number of pts that need to be treated with a new intervention to avoid 1 additional event over the benefit provided by standard therapy. For multiple numerical outcomes from randomized trials, NNT is an effective method to express results in a clinically meaningful way. To evaluate the degree of benefit of LET over TAM in women with early stage N+ BC in BIG 1–98, we compared the NNT for survival benefit from LET to that needed to see benefit from the addition of a taxane to anthracycline based CT based on clinical trial data in BC pts with N+ disease. Methods: 5-yr survival data were taken from the pivotal randomized controlled trial (RCT) for LET (N+ pts from BIG 1–98, TAM arm censored for crossover to LET) and from 4 RCTs of adjuvant CT trials, AC-T, FEC-D, and DAC. NNT was calculated with respect to OS at 5 yrs; outcome is presented as the NNT to save a life (see Table). Results: The NNT to save a life for adjuvant LET vs TAM is comparable to the NNT for the addition of a taxane to anthracycline based CT in women with N+ BC. Conclusions: The magnitude of survival benefit of LET over TAM in terms of NNT is comparable to that needed to see a survival benefit from paradigm- changing modern adjuvant CT regimens. F= fluorouracil, E = epirubicin, C = cyclophosphamide, D = docetaxel, T = paclitaxel, A = doxorubicin

[Table: see text]

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Effect of aprepitant (AP) on cyclophosphamide (CPA) pharmacokinetics (PK) in early breast cancer patients
Authors: Walko C. M. , Yu Y. A. , Bhushan S. , Spasojevic I. , Carey L. , Collichio F. , Armstrong D. , Dees E. C.
Published: August 2020

588

Background: AP, a moderate inhibitor of CYP3A4, is a selective neurokinin 1 receptor antagonist recommended by the ASCO guidelines for prevention of high and some moderately emetogenic chemotherapy regimens, including doxorubicin and CPA (AC). CPA is converted to the active 4-OH metabolite primarily by CYP2B6 (48–57%) and by CYP3A4 (12–18%). CYP3A4 also converts 10% of CPA to the N-dechloroethyl metabolite (DCE), which is responsible for neurotoxicity and nephrotoxicity. Because AP is utilized concurrently with CPA, this creates the potential for drug-drug interaction between AP and CPA. The objective of this study was to evaluate the effect of AP on the PK of CPA, 4-OH, and DCE in patients receiving AC. Methods: This double-blinded, placebo controlled, two-period, crossover study included breast cancer patients receiving regimens containing CPA 600 mg/m2 IV for at least two sequential cycles. Prior to each CPA cycle, patients were randomized to receive either oral AP (125 mg on d 1 prior to chemotherapy and 80 mg on d 2 and 3) or placebo for 3 d. During both cycles, patients were also pretreated with ondansetron 24 mg PO and dex 12 mg PO on d 1 and dex 8 mg PO once on d 2 and 3. Rescue anti-emetic medications were permitted. Serial plasma samples were obtained from 0 to 24 h after administration of CPA in combination with AP or placebo in each patient. CPA, 4-OH, and DCE plasma concentrations were determined using HPLC. Area under the plasma versus conc time curve (AUC) was calculated using WinNonlin. Results: 17 patients completed 2 cycles and were evaluated for PK. Geometric mean AUC data for CPA in combination with AP and placebo are summarized in the table. Conclusions: Based on geometric mean ratios ± 90% CI, concurrent administration of AP with CPA did not result in any significant changes in the 4-OH metabolite AUC, but did result in increased parent CPA and decreased DCE drug exposure levels. Based on these results, it is unlikely that aprepitant has a clinically significant effect on the efficacy of CPA.

[Table: see text]

[Table: see text]
Dose-dense (DD) cyclophosphamide, methotrexate, and fluorouracil (CMF) at 14-day intervals: A pilot study of every 14- and 10–11-day dosing intervals for women with early-stage breast cancer
Authors: Drullinsky P. , Fornier M. N. , Sugarman S. , D'Andrea G. , Troso-Sandoval T. , Seidman A. D. , Yuan J. , Patil S. , Norton L. , Hudis C.
Published: August 2020

590

Background: CMF (C 600 mg/m2, M 40 mg/m2, F 600 mg/m2) is an option for adjuvant therapy for patients with low risk early stage breast cancer. DD regimens as predicted by mathematical models of cancer growth and treatment response are superior. We previously demonstrated the safety of DD EC (epirubicin/cyclophosphamide) followed by paclitaxel at 10–11 day (d) intervals. We investigated the feasibility of administering DD adjuvant CMF every 14 d and then every 10–11 d in a 2-stage phase II trial. Methods: An initial cohort (A) was treated q 14 d with PEG-filgrastim (Neulasta) support. A second cohort (B) was treated every 10–11 d with filgrastim/Neupogen x 5 d and then, based on feasibility, modified (cohort C) to use 7 d filgrastim. The primary end point was feasibility defined as having ANC > 1.5 x 103/uL on day 1 of planned treatment for all 8 cycles with no grade 3 or higher non-hematologic toxicity. All three cohorts were tested using a Simon's two-stage optimal design with type I and type II errors set at 10%. This design would effectively discriminate between true tolerability (as protocol-defined) rates of< 60% and> 80%. Cohort A: 38 pts with early stage breast cancer were accrued from 3/2008 though 6/2008. Cohort B: 7 pts were accrued from June 2008 through August 2008. Cohort C: Is still open with 16 pts accrued from August 2008 through December 5, 2008. Results: Median age 51: range 38 to 78. Cohort A: 29/38 pts completed 8 cycles of CMF. The regimen was considered feasible. 2 other pts completed 7 cycles and were withdrawn for depression and grade 2 transaminitis. The 7 other pts completed between 1 and 6 cycles of CMF were withdrawn as follows: 3 personal, 1 (grade 3) bone pain, 2 allergy unrelated to CMF, and 1 seizure. Cohort B: 7 pts were accrued. 6 out of 7 pts could not complete 8 cycles of chemotherapy secondary to neutropenia and 1 secondary to grade 3 ALT elevation. Cohort C: Accrual has not been completed. 16 pts are currently enrolled. Conclusions: Dose dense adjuvant CMF is feasible at 14 d intervals with PEG-filgrastim support. Adjuvant CMF every 10–11 days with filgrastim given for 5 days beginning day 2 is not feasible. Accrual is ongoing for CMF at 10–11 days with filgrastim x 7 days. Updated results will be available for Cohort C.

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Neoadjuvant dose-dense sequential biweekly epirubicin and cyclophosphamide followed by docetaxel and trastuzumab for HER2+ operable breast cancer
Authors: Blakely L. , Somer B. , Keaton M. , Hermann R. , Schnell F. , Cobb P. , Johns A. , Walker M. , Schwartzberg L.
Published: August 2020

595

Background: Neoadjuvant (Neo) chemotherapy (CT) with trastuzumab (H) improves pathologic complete response (pCR) rate for HER2+ breast cancer. Dose-dense regimens improve outcome in the adjuvant setting but have not been fully evaluated as preoperative therapy. We designed this regimen to utilize full doses of active agents including docetaxel (T) and H in a novel biweekly schedule to explore efficacy and safety. Methods: Patients (pts) with biopsy proven, clinical stage IIA-IIIC, noninflammatory breast cancer were eligible. HER2+ by FISH was determined locally. CT consisted of epirubicin (E) 100 mg/m2 and cyclophosphamide (C) 600 mg/m2 Q 14 days x 4 followed by T 75 mg/m2 and H 6 mg/kg loading dose, then 4 mg/kg Q 14 days x 4, all with pegfilgrastim support. Surgery was scheduled 20–24 weeks from start after a fifth cycle of H 4mg/kg. EF was measured prior to CT, after EC, after TH and at 6, 12 and 24 months after surgery. Additional adjuvant H to complete 1 year of therapy by conventional schedule was recommended after surgery. The primary endpoint was pCR for invasive cancer in breast and lymph nodes. Results: 30 pts were enrolled at 5 centers: median age was 50.1 (range, 31–72); ethnicity African-American 14, Caucasian 14, other 2; clinical stage IIA, 14, IIB, 4, IIIA, 7, IIIB/C, 5; ER+ 18, PR+ 14; grade 3, 21 and grade 2, 8. Twenty eight pts were evaluable for pathologic response- 2 withdrew before completing treatment, 1 for toxicity. Dose delivery on schedule was >95% for all drugs. Clinical response prior to surgery was cCR 20; cPR 5; and stable 2 pts. Pathologic response: pCR 16 (57%) including 4 with residual DCIS only; 9 pPR, and 2 stable. Mean EF was 63.1 (range, 51–81) before treatment, 62.4 (49–75) after EC and 58.3 (35–74) after TH. Two pts had EF <50% during Neo, one with clinical CHF and 1 additional pt developed CHF during adjuvant single agent H. Both pts had symptomatic improvement with cessation of H. Adverse events were generally mild with 14 grade 3 AEs including 3 episodes of dyspnea and no grade 3 skin toxicity or any grade 4 toxicity noted. Conclusions: Sequential Neo dose-dense Q 14 day EC followed by Q 14 day TH yields a high pCR rate in HER2+ breast cancer with acceptable toxicity profile and no new safety signals noted.

No significant financial relationships to disclose.
Prognostic significance of HPV and p16 status in patients with oropharyngeal cancer treated on a large international phase III trial
Authors: Rischin D. , Young R. , Fisher R. , Fox S. , Le Q. , Peters L. , Choi J. , O'Sullivan B. , Giralt J. , McArthur G. ,   Tran-Tasman Radiation Oncology Group
Published: August 2020

6004

Background: Previous studies have reported that in patients with oropharyngeal cancer (OPC) the presence of human papilloma virus (HPV) is associated with an improved prognosis. We sought to determine the prognostic importance of HPV and p16 in patients with OPC treated with concurrent chemoradiation on a large international phase III trial. Methods: Patients with previously untreated Stage III or IV head and neck squamous cell cancer were randomized to receive definitive radiotherapy concurrently with either cisplatin or cisplatin plus tirapazamine. In this substudy, analyses were restricted to patients with OPC who received > 60 Gy and did not have major radiation deviations predicted to impact on tumor control. HPV 16/18 were detected by in situ hybridization and scored as detected or undetected. p16 was detected by immunohistochemistry. Nuclear and cytoplasmic staining intensity of tumor cells was scored as grade 0–3, with grade 2 and 3 called positive. Log rank and Cox regression used for survival analyses. p values were 2-sided . Results: 384 out of 861 patients had OPC and met the eligibility criteria. Slides were available for HPV assay in 195 and for p16 in 186, and for both in 173. 54/195 (28%) were HPV positive, 107/186 (58%) were p16 positive. HPV pos tumors were associated with better 2-year overall survival (OS) (94 v 77%, p = 0.007) and better failure-free survival (FFS) (86 v 75%, p = 0.035) compared to HPV neg tumors. Similarly p16 pos tumors were associated with better 2-year OS (92 v 75%, p = 0.004) and FFS (87 v 72%, p = 0.003) compared to p16 neg . After adjustment for stage, Hb and ECOG PS, HPV pos had better OS than HPV neg (HR 0.29, p = 0.018), and p16 pos had better OS than p16 neg (HR 0.39, p = 0.013). When the HPV and p16 results were combined the relative HRs for OS were: HPVpos/p16pos 0.35 (45 patients, 26% of cases), HPVpos/p16neg 0 (3pts, 2%), HPVneg/p16pos 0.73 (58pts, 33%), HPVneg/p16neg 1.79 (67 pts, 39%). Conclusions: Our results confirm the prognostic significance of tumor HPV status in oropharyngeal cancer treated with chemoradiation, but also show that p16 identifies a larger group with an improved prognosis. The HPV neg/p16 pos population has a better prognosis compared to patients with HPV neg/p16 neg tumors.

No significant financial relationships to disclose.
Phase II study of dasatinib in the treatment of head and neck squamous cell carcinoma (HNSCC)
Authors: Brooks H. D. , Glisson B. , Lu C. , Sabichi A. , Johnson F. , Ginsberg L. , Bekele B. , Papadimitrakopoulou V.
Published: August 2020

6022

Background: Dasatinib is a potent inhibitor of src-family kinases, ephA2, PDGFR, Abl, and c-kit. A single-center, open-label, phase II trial was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of dasatinib in recurrent or metastatic HNSCC. Methods: Pts with measurable disease by RECIST, who received 0 or 1 prior regimen for recurrent or metastatic HNSCC with an ECOG performance status 0–1 and tumor tissue appropriate for IHC and FISH were eligible. Dasatinib 100 mg bid was given for 28-day cycles. Primary endpoints were 12-wk progression-free survival (PFS) and objective response rate (ORR). Pts who took at least 1 dose of dasatinib and who died or left study before 12 wks were counted as progressive disease (PD). A 2 stage design, closure after accrual of 15 pts was required if PFS was 45% or less and ORR was 0. Otherwise, planned accrual was 35. Response was assessed at 4 and 12 wks. PK was studied in pts receiving dasatinib per PEG. Biomarkers relevant to Src pathway were planned in tissue and blood. Results: Fifteen pts were accrued. To date, 13 pts are evaluable for response, and 15 pts for toxicity. No grade 3/4 hematologic toxicities were noted. Grade 2–4 nonhematologic toxicities(n): pleural effusion(2), nausea/vomiting(2), dehydration(1), diarrhea(1), dyspnea(1). Toxicity led to hospitalization of 4 pts and drug discontinuation in 5 pts. ORR was 0. One pt was stable at 12 wks (PFS: 7.6%). This pt stopped drug at 15 wks due to toxicity, but also had PD. One pt died on study and cause was deemed unlikely related. Conclusions: Dosed at 100mg bid, dasatinib led to a characteristic toxicity profile in this pt population. Rates of hospitalization and discontinuation for toxicity were fairly high. Final efficacy parameters are pending evaluation of 2 pts. Evaluation of PK and tissue/blood biomarkers is ongoing.

No significant financial relationships to disclose.