bluuebunny/crossref_metadata_2025 huggingface dataset:
Second-line pemetrexed (P) for the treatment of hormone refractory prostate cancer (HRPC): A Hoosier Oncology Group phase II study—Preliminary analysis
Authors: Hahn N. M. , Whalen C. , Sweeney C. J.
Published: March 2020

4644

Background: We evaluated the efficacy and toxicity of pemetrexed in men with HRPC who had progressed on one prior taxane chemotherapy regimen. Methods: Patients with HRPC received P 500 mg/m2 IV d1 q21d cycle with B12 and folate supplementation until progression or dose-limiting toxicity. The primary outcome measure was PSA response rate (PSAr) defined as a > 50% decline from baseline PSA that was confirmed at least four weeks later. Pts were required to have documented PSA progression prior. If no metastatic disease, a PSA > 20 ng/dL was required. A two-stage Simon phase II design with early stopping rules is being utilized with a PSA response rate of 20% deemed to be clinically relevant. Results: Patient characteristics: To date, 21 of the planned 42 patients have been treated with a median age of 67 years (53–79), median baseline PSA 97.8 (0.7–754.3), and median Karnofsky performance status of 90 (70–100). Treatment Cycles: A total of 83 treatment cycles have been administered with a median of 3 cycles per patient (0–12). Toxicity: 6 of 21 (28.6%) patients experienced a total of 17 grade 3 events. Treatment related grade 3 events included thrombocytopenia (1), anemia (2), mucositis (1), rash (1), and fatigue (1). 3 of 21 (14.3%) patients experienced a total of 8 grade 4 events. Treatment related grade 4 events included neutropenia (2), thrombocytopenia (3), anemia (1), and neutropenic fever (1). Response: Best response observed included 4 PSAr (19.0%, 95% CI 2.2–35.8%), 8 stable disease (SD) (38.1%, 95% CI 17.3–58.8%) and 9 progressive disease (PD) (42.9%, 95% CI 21.7–64.1%). PSAr were maintained at 5, 12+, 5+, and 3+ weeks with sustained SD seen at 15, 12, 15, 21+, 18+, and 12+ weeks. Survival data is immature at this time. Conclusion: This preliminary analysis reveals that pemetrexed has met criteria to move into the second stage of the study and has an acceptable toxicity profile in this patient population.

[Table: see text]
The prognostic value of percent positive biopsies in intermediate to high risk prostate cancer treated with brachytherapy and supplemental beam radiotherapy
Authors: Nurani R. D. , Wallner K. E. , Merrick G. S. , Orio P. , Virgin J. , True L.
Published: March 2020

4645

Background: Percent biopsy core positivity (%BCP) has been correlated with tumor volume, extraprostatic disease and biochemical progression free survival (bPFS) in surgical series. In an external beam series, it can predict time to progression in a subset of patients. Methods: The percentage of biopsy cores involved with cancer was determined from original pathology reports of 566 patients with clinical stage T1c-T2a, Gleason grade 7–10 and/or PSA 10–20 CaP. These patients had previously been treated on a prospective study that randomized between 20 or 44 Gy of supplemental beam radiation therapy followed by Pd-103 brachytherapy. bPFS was defined as having a serum PSA ≤0.5 ng/ml at last follow-up. Patients were censored at last follow-up if their serum PSA was still decreasing. Results: 5 year bPFS was 79% for the entire group of 566 patients and 84% for the sub-group of 333 patients with %BCP quantified. On Cox regression analysis, biological variables analyzed included PSA, PSA < or ≥ 10, Gleason score, Gleason score < or ≥8, %BCP divided into two different grouping schemes (<34, 34 through 50 and ≥50) and < or ≥50. Treatment related variables analyzed included V100, V100 < or ≥90%, D 90, D 90 < or ≥80%, supplemental beam dose of 20 or 40 Gy. On univariate analysis, significant factors were limited to: %BCP < vs. ≥50 (p = 0.004), %BCP <34 Vs. ≥50% (p = 0.006), PSA, PSA < or ≥10, Gleason score, V100 < or ≥90%, D 90. On multivariate analysis, %BCP was the only significant determinant (p = 0.006) irregardless of which stratification scheme was utilized. For %BCP ≥50%, the hazard ratio for biochemical failure was 3.6 (95% confidence interval 1.4 to 8.8). On Kaplan-Meier analysis, 5 year bPFS was 90% and 79% for patients with <50% and ≥50% cores involved respectively (p = 0.002). Conclusions: With implementation of implant techniques that uniformly meet optimal dosimetric criteria in patients felt to be at intermediate to high risk of failure based on Gleason and PSA, the percent of biopsy cores positive with malignancy emerges as the single most important factor in predicting biochemical failure. There is a statistically significant reduction in bPFS in patients with ≥50% of their core needle biopsies involved with malignancy.

No significant financial relationships to disclose.
Phase I trial results of PCK3145 in patients (pts) with castrate metastatic prostate cancer (PC)—The US experience
Authors: Slovin S. F. , Daigneault L. , Dulude H. , Panchal C. , Richardson J. , Curley T. , Delacruz A. , Fleisher M. , Morris M. , Scher H.
Published: March 2020

4650

Background: PCK3145 is a synthetic 15-mer peptide derived from the natural sequence of amino acids of Prostate Secretory Protein (PSCP94), a predominant protein found in seminal fluid. Its expression in PC is down-regulated in pts with metastatic disease and is believed to be a signal transduction inhibitor via multiple pathways in carcinogenesis. Recent data from a phase IIa trial in Great Britain demonstrated safety and suggested reduction in MMP-9 levels, an enzyme involved in angiogenesis, tumor invasion and metastasis. A phase I trial was performed to assess dosing and dosing schedule, pharmacokinetics, safety and impact on MMP-9 levels in pts with castrate metastatic PC who have failed multiple therapies including hormones and chemotherapy. Methods: Two cohorts of 10 pts received either 7.5 mg/m2 twice weekly or 15 mg/m2 weekly, respectively. Pts were treated for 4 weeks followed by a 2 week non-treatment period. Pts could receive addtional two-month cycles if PSAs and scans remained stable. MMP-9 levels, PSA, pharmacokinetics and imaging assessments were done at screening, and at weeks 2, 4 and 6. Results: Ten pts have been enrolled at each dose level. No adverse events were observed, however, declines in MMP-9 levels occurred in most pts by week #3 posttreatment. MMP-9 levels rose when drug was discontinued. Six pts were taken off study due to disease progression whereas 5 pts were discontinued due to rising PSAs. One pt at the 7.5 mg/m2 biweekly dosing schedule received 4 additional cycles with stable PSAs and scans with a PSA doubling time which increased from 4 months pretreatment to 8 months posttreatment. Conclusions: PCK3145 was well-tolerated without toxicity. While early, the weekly dosing schedule appears to result in greater declines in MMP-9 levels and will likely be used in a forthcoming phase II trial in chemotherapy naive pts.

[Table: see text]
A phase I study of ABT-751 in combination with docetaxel in patients with metastatic hormone-refractory prostate cancer
Authors: Michels J. E. , Ellard S. , Le L. , Murray N. , Guns E. , Hagey A. , Chi K. N.
Published: March 2020

4651

Background: ABT-751 (A) is a novel oral sulfonamide anti-microtubule agent with broad-spectrum preclinical activity including paclitaxel-resistant tumors and additive effect with docetaxel (D). Dose-limiting toxicities (DLTs) with ABT-751 include peripheral neuropathy, ileus, and fatigue. The recommended phase II single-agent dose for a 21/28-day schedule is 200 mg/day. Methods: Patients (pts) with hormone-refractory prostate cancer (HRPC), ECOG performance status ≤ 2, and adequate organ function were eligible. D was administered intravenously on day 1 and A was administered orally once daily on days 1–14 of a 21-day cycle for a maximum of 10 cycles. Starting dose was 60 mg/m2 D and 100 mg A; escalated in 4 dose levels (DLs) to 75 mg/m2 D and 200 mg A. Pts received 10 mg oral prednisone daily. Plasma for PK analyses was obtained. Results: 18 pts have been enrolled (3 pts/DL1, 3 pts/DL2, 6 pts/DL3, 6 pts/DL4), 17 pts are currently evaluable: median age 66 years, median PSA 250 μg/L, metastatic sites to bone and/or lymph nodes (17), visceral (2), prior chemotherapy 5 pts. The median number of treatment cycles was 6 (range 2–10). 2 pts experienced DLT (1 febrile neutropenia/DL 3 and 1 diarrhea/grade 4 neutropenia at DL4); these dose levels were expanded to 6 pts with no further DLT. Hematologic toxicities include febrile neutropenia (2 pts), grade 3/4 neutropenia (7 pts). Additional non-hematologic toxicities were grade 1/2 beside 1 episode of grade 3 diarrhea and lethargy each. AUC and Cmax for A were similar to single-agent data. AUC and Cmax for D appeared independent of ABT-751 dosing. PSA decline of ≥50% occurred in 10/16 evaluable pts (63%), ≥30% in 14/16 pts (89%) and <30% in 2/16 pts as best response thus far. Best response per RECIST in 12 pts with measurable disease was partial response in 4 pts (33%) and stable disease in 8 pts (67%). Conclusions: The combination of ABT-751 and docetaxel is well tolerated at the tested doses. PK results suggest no significant PK interaction. Early findings indicate encouraging clinical activity of the combination treatment. Extended accrual to the recommended phase II dose is ongoing to further define activity and toxicity.

No significant financial relationships to disclose.
Randomized study of docetaxel (D) and dexamethasone (DX) with low or high dose estramustine (E) for patients with advanced hormone-refractory prostate cancer (HRPC)
Authors: Nelius T. , Klatte T. , Reiher F. , Filleur S. , Yap R. , Allhoff E. P.
Published: March 2020

4653

Background: D-based chemotherapy is a burgeoning option for men with advanced HRPC. Alone or in combination with E, D has been shown to improve median survival. In this study we tested the combination of D with two different doses of E in patients (pts) with HRPC to improve response rates and to lower side effects. Methods: 72 metastatic HRPC pts were randomly assigned to receive D (70 mg/m2 IV, d2, q3w) and E (3 × 280 mg/d PO starting 1 day prior to D, for 5 consecutive days) for arm A or E (3 x 140 mg/d PO starting 1 day prior to D, for 3 consecutive days) for arm B. Premedication with oral DX at a total daily dose of 16 mg, in divided doses two times a day was administered in arm A on day 1 to 5 and in arm B on day 1 to 3. Initially, 6 cycles were administered and repeated after significant PSA rise. Pts were monitored for PSA response, time to progression (TTP), survival and toxicity. Results: PSA declines of ≥75%, ≥50% and ≤50% were 36.8%, 55.3% and 44.7% in arm A and 38.2%, 67.6% and 32.4% in arm B, respectively (P = .442). TTP in Arm A and Arm B were 11 months (95% CI, 7–14) versus 14 months (95% CI, 8–19), P = .6911) and overall survival 21 months (95% CI, 6–35) versus 22 months (95% CI, 18–27), respectively, (P = .4149). The primary treatment-related side effects observed in arm A and arm B were granulocytopenia (34% and 29%, P = .663) and thrombotic complications caused by E (four pts (11%) and one pt (3%), respectively, P = .206). Associated baseline factors with overall survival in univariate analysis were ECOG performance status (P < .001), hemoglobin level (P < .001), bone pain (P < .001), and PSA (P < .097) and in multivariate analysis ECOG performance status (95% CI, 2.9–13.9) and bone pain (95% CI, 3.2–20.1), (P < .001). Conclusions: In this randomized phase II study the combination of D and E had substantial activity in HRPC. We did not find a statistically significant difference of higher dose of E in combination with D compared to a lower dose of E and D regarding PSA response, TTP and survival. However, there was a tendency of higher toxicity in the high dose E group. These treatment-related toxicities were mainly hematologic and manageable. The results of this study support the assertion that estramustine is not necessary in docetaxel-based treatment regimens.

No significant financial relationships to disclose.
A multicenter, randomized, phase III study comparing paclitaxel/carboplatin (PC) versus topotecan/paclitaxel/carboplatin (TPC) in patients with stage III (residual tumor > 1 cm after primary surgery) and IV ovarian cancer (OC)
Authors: Scarfone G. , Scambia G. , Raspagliesi F. , Mangili G. , Danese S. , Presti M. , Petruzzelli F. , Costa B. , Bolis G.
Published: March 2020

5003

Background: Despite treatment with standard first-line PC, survival rates of patients with OC is disappointing, especially in patients suboptimally debulked. In this phase III, open-label, randomised, parallel-arm study topotecan, a non cross-resistant topoisomerase I inhibitor was added to the standard platinum-taxane doublet in order to improve survival and progression-free interval compared to PC alone. Methods: 326 ITT patients with FIGO stage III (residual tumor > 1 cm) and IV OC were randomly allocated to receive either carboplatin AUC 5 and paclitaxel 175 mg/sqm d1q21 (arm A; 170 pts) or topotecan 1 mg/sqm dd1–3q21 + carboplatin AUC 5 and paclitaxel 175 mg/sqm d3q21 (arm B, 156 pts) for 6 cycles. Primary endpoint was the 3-year survival rate with 350 patients originally planned to show an increase in 3-year survival from 20 in arm A to 35% in arm B with 80% power and alfa = 0.05. Results: 81.8% and 77.6% of patients in arm A and B respectively completed the 6 cycles planned. The 2 arms were well balanced for demography, tumor staging and histology except for an excess of serous histotype in the arm B (68.2% vs 75%). Best overall response was CR/PR in 51.5%/33.7% (ORR 85.2%) in arm A and 57.8%/36.3% (ORR 92.5%) in arm B (p = 0.586 with χ2 test, NS). Median time to progression (TTP) was 70.4 and 71.8 weeks in arm A and B respectively (p = 0.5058 with Wilcoxon test, NS). Most common G3/4 hematological toxicity was neutropenia (7.1% and 13.2% of courses and 23.5% and 39.7% of pts in arm A and B) and most common non-hematological toxicities were alopecia (78.2% and 72.4% in arm A and B) and nausea/vomiting (43.5% and 50.5% in arm A and B). 13.9% and 15.5% of courses were delayed and 2.1%/2.4% and 7.2%/6.2% of carboplatin/paclitaxel doses reduced for toxicity in arm A and B respectively. 9.4% and 23.3% of courses required transfusions in arm A and B respectively. Conclusions: The addition of topotecan to standard PC primary chemotherapy does not increase RR and TTP in stage III (residual tumor > 1 cm) or IV OC compared to PC alone. The TPC regimen was well tolerated with a minority of patients experiencing G3/4 hematological toxicity. Study funded by GlaxoSmithKline.

No significant financial relationships to disclose.
Phase III randomized trial of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy (RH) versus RH for bulky stage I/II cervical cancer (JCOG 0102)
Authors: Katsumata N. , Yoshikawa H. , Hirakawa T. , Saito T. , Kuzuya K. , Fujii T. , Hiura M. , Tsunematsu R. , Fukuda H. , Kamura T.
Published: March 2020

5013

Background: NAC may represent an alternative to conventional RH for locally advanced cervical cancer. We compared NAC followed by RH with RH for bulky stage I/II cervical cancer. Methods: Patients (pts) with stage IB2, IIA (> 4 cm), or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7mg day 1–5, vincristine 0.7mg/m2 day 5, mitomycin 7mg/m2 day 5 and cisplatin 14 mg/m2 day 1–5,) q21 days, 2 to 4 cycles followed by radical hysterectomy (NAC arm) or undergo RH (RH arm). Pts with positive surgical margins, metastatic nodes, infiltration to parametrium, and/or deep myometrial invasion received postoperative irradiation. Eligibility included preserved organ function, aged 20–70, and Performance Status 0 or 1. Primary endpoint was overall survival (OS) to be compared by log-rank test. Assuming 100 eligible pts in each arm, the study had 80% power to detect a 15% increase in 5-year survival at 0.05 one-sided alpha. Results: 134 pts (67 NAC, 67 RH) were randomized between 12/01 and 08/05. The first planned interim analysis was performed in July 2005 using data from 108 pts registered as of 11/04. Data and Safety Monitoring Committee recommended to terminate the study because overall survival in NAC arm was inferior to that in RH arm (HR 2.11, multiplicity adjusted 99% CI 0.34 to 13.2) and the predictive probability of significant superiority using Spiegelhalter’s method of NAC arm was extremely low (6.4%). No increase of operability and no decrease of surgery-related morbidity were observed in NAC arm. Response Rate of NAC was 61% (33 of 54) using RECIST criteria. One-year progression-free survival and overall survival, updated as of 05/05, were 69.9% and 91.8% (95% CI 84.1–99.6) in NAC arm and 78.6% and 95.4% (95% CI 89.1–100) in RH arm respectively. Conclusions: Neoadjuvant chemotherapy with BOMP regimen followed by radical hysterectomy did not demonstrate clinical benefit, and conventional radical hysterectomy still remains to be a standard treatment option for bulky stage I/II cervical cancer.

[Table: see text]
Angiogenesis pathway gene polymorphisms associated with clinical outcome in recurrent ovarian cancer treated with low dose cyclophosphamide and bevacizumab: A California Consortium Trial
Authors: Schultheis A. M. , Yang D. , Garcia A. A. , Morgan R. , Gandara D. , Scudder S. , Oza A. , Hirte H. , Fleming G. , Roman L. , Lenz H.
Published: March 2020

5017

Background: Despite advances in chemotherapy, ovarian cancer remains a major cause of cancer mortality worldwide. It has therefore become essential to identify novel therapeutic targets, such as angiogenesis which is a complex process regulated by the delicate balance between various local proangiogenic and antiangiogenic proteins. Bevacizumab, a monoclonal antibody binding to VEGF, has shown significant activity in colon, breast, lung and ovarian cancer. There are no established molecular markers to predict response or time to tumor progression for Bevacizumab based chemotherapy. The key enzymes of the VEGF pathway are: Vascular Endothelial Growth Factor (VEGF), VEGF Receptor (VEGFR), Hypoxia Inducible Factor1 (HIF α and β-subunit), Neuropilin1 (NRP), Interleukin-8 (IL-8), Adrenomedullin (AM) and Leptin. Methods: Seventy patients with refractory ovarian cancer were enrolled in a Phase II clinical trial and treated with Cyclophoshamide 50 mg po/Bevacizumab 10 mg/kg IV every 14 days. From 52 patients blood samples were available for gDNA extraction and PCR-RFLP assays. Results: 13 patients had a PR (25%) and 39 were non responders. 31 pts had progressed. Median follow-up of 8.3 months with a median progression-free survival of 6.6 months. Patients who were homozygous A/A or heterozygous A/T genotype at the −251 locus in the IL-8 gene had a lower response rate than those who were T/T (P = 0.047 Fisher’s exact test). Patients with Vegf936 C/C had a median TTP of 6.5 months, pts with any T (T/T, C/T) had a median TTP of 17.2 months. Pts carrying both AM 3’end alleles <14 CA repeats had 3.4 months median TTP, patients with at least one allele >14 showed a median TTP of 6.6 months; for both alleles >14 patients showed 8.7 months of median TPP (P = 0.0006 Log-rank test) Conclusions: Our data suggest for the first time, that IL-8 may be a potential molecular predictor of response to Bevacizumab based chemotherapy. We also demonstrate that both VEGF 936 and the AM 3’ dinucleotide repeat polymorphisms are potential molecular markers for time to tumor progression. A larger prospective study is needed to validate and confirm our preliminary findings. This study was supported by NCI grant NO1 CM 17101.

[Table: see text]
Bevacizumab (B) plus erlotinib (E) for patients (pts) with recurrent ovarian (OC) and fallopian tube (FT) cancer: Preliminary results of a multi-center phase II trial
Authors: Friberg G. , Oza A. M. , Morgan R. J. , Vokes E. E. , Gandara D. R. , Fleming G. F.
Published: March 2020

5018

Background: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are commonly over-expressed in OC and correlate with poor prognosis. The anti-VEGF antibody B and the EGFR tyrosine kinase inhibitor E have each demonstrated activity in OC. Dual inhibition with BE may overcome mechanisms of resistance encountered with either agent alone. Methods: We are conducting a 2-stage phase II trial of BE in pts with recurrent OC, primary peritoneal, and FT cancer. Eligible pts had ≤ 2 prior chemo regimens for recurrent or refractory disease; no prior VEGF or EGFR inhibitors; ECOG performance status (PS) 0–2; measurable disease; normal organ function; no proteinuria (<1000 mg/24 hours). B 15 mg/kg was given IV on day 1 every 21 days and daily E 150 mg PO was given continuously. CT scans were obtained every 9 weeks. 2 responses are required in the first stage to justify accrual into a second stage. Results: 13 pts enrolled at 3 centers from 7/05 to 10/05. Median age: 56 (range 45–70). PS (N with 0/1/2): 6/4/3. Primary site (N): OC 11, FT 2. Primary platinum response (N): refractory 4, resistant (<12 mo PFS) 2, sensitive (≥12 mo) 7. Total prior chemo regimens (N with 1/2/3): 1/8/4. 55 cycles of BE have been delivered (median 4, range 1–8). 12 pts are evaluable for response (1 too early). There has been 1 major response (8%). 8 patients (67%) had stable disease (SD). 1 pt with SD met 75% CA-125 response criteria. 8 pts remain on study. Median PFS has not been reached (median f/u 2.2 months). Attributable toxicities (N with grade 1/2/3/4): rash 4/7/0/0, diarrhea 6/1/2/0, stomatitis 3/1/0/0, myalgias 4/0/0/0, proteinuria 3/0/0/0, bilirubin 0/2/0/0. There were 2 bowel perforations (grade 3/4): both had 2 prior regimens, peritoneal implants >1 cm, 3 doses of B (last was 10 and 42 days prior), and small bowel obstructions in the preceding 28 days. Conclusions: The first stage of accrual is complete and further enrollment is on hold pending continued efficacy evaluation. There appeared to be an increased rate of bowel perforation, and identification of potential risk factors for this event would be critical for further development of this combination. Updated results will be presented. Supported by NCI Grant N01-CM-17102.

[Table: see text]
Phase II study of carboplatin, paclitaxel and bevacizumab as first line chemotherapy and consolidation for advanced müllerian tumors
Authors: Penson R. T. , Cannistra S. A. , Seiden M. V. , Krasner C. N. , Matulonis U. A. , Horowitz N. S. , Berlin S. , Dizon D. S. , Lee H. , Campos S. M.
Published: March 2020

5020

Background: Vascular endothelial growth factor (VEGF) is a major promoter of tumor angiogenesis. Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes VEGF and is active in several tumor types, including epithelial ovarian cancer. Methods: We are conducting a phase II trial of carboplatin, paclitaxel and bevacizumab (CPB) in newly diagnosed patients with chemotherapy naïve, stage ≥ IC, epithelial ovarian, fallopian, primary peritoneal, or uterine papillary serous (UPSC) tumors. Patients receive carboplatin AUC of 5 IV, paclitaxel 175 mg/m2 IV, and bevacizumab 15 mg/kg IV for 6–8 cycles on a 21-day cycle. Bevacizumab is omitted in the first cycle, and continued for one year’s consolidation. Principle endpoints include response rate and progression free survival. Results: Since 3/05, 35 patients have been enrolled. Of the 30 evaluable patients, 24 have ovarian, 4 peritoneal, 1 fallopian tube cancer, and 1 UPSC (1 stage IIB, 22 stage III, and 7 stage IV), and median age is 57 (range 18–77). 133 cycles of chemotherapy have been administered with acceptable toxicity. Grade IV neutropenia has been seen in 3 cycles with 1 episode of febrile neutropenia. Grade I, II, and III HTN was observed in 1, 3, and 4 cycles, and grade I (42% hematuria 45% epistaxis) and II bleeding observed in 36 and 1 cycle(s), respectively. There has been 1 nasal perforation, 2 delayed wound healing, and no bowel perforation. 1 woman withdrew consent (for PMH diverticulitis), and 3 women have been removed for toxicity (1 autonomic neurotoxicity, 1 HTN, and 1 PE). To date, 13 patients have completed the chemotherapy phase of treatment, and only one patient has come off study for progression on consolidation bevacizumab. Conclusion: First line CBP is a highly active regimen that has been well tolerated thus far. Updated toxicity and response data will be available in the spring of 2006.

[Table: see text]
A novel multiple biomarker assay for the detection of ovarian carcinoma
Authors: Moore R. G. , Brown A. K. , Miller C. M. , Badgwell D. , Lu Z. , Verch T. , Lu K. H. , Allard J. W. , Granai C. O. , Bast R.
Published: March 2020

5023

Background: Studies show that ovarian cancer patients operated on by gyn oncologists are more often adequately staged and debulked than those operated on by non-gyn oncologists. Many benign gynecologic conditions will elevate the CA125 tumor marker decreasing its specificity. An accurate test is needed to help triage patients with a pelvic mass to centers with expertise in treating ovarian cancer. This project examined several novel tumor markers to develop a multiple biomarker assay to predict the risk of ovarian cancer in patients with an ovarian cyst or pelvic mass. Methods: Data from two separate IRB approved prospective trials from two institutions were collected. After obtaining informed consent, serum samples were obtained preoperatively from women undergoing surgery for an adnexal mass and analyzed for levels of CA125, SMRP, HE4 and CA72–4. All pathology results were compared to the tumor markers. Sensitivities at set specificities of 90, 95 and 98% were determined using logistic regression for each marker individually and all combinations of 2, 3, & 4 markers. Results: 448 samples were analyzed. There were 267 benign cases and 181 ovarian cancers (27 stage I, 20 stage II, 115 stage III and 19 stage IV). Median values for HE4, SMRP, CA125 and CA72–4 all differed significantly between benign masses and cancer (p < 0.001). In the differentiation of benign masses and stage I malignancies, the addition of HE4 to CA125 increased the sensitivity by 22.2% at a specificity of 90%. The combination of HE4 and CA125 for all stages was superior to HE4 or CA125 alone (p ≤ 0.003). Conclusions: The improvement in sensitivity shown by the addition of HE4 to CA125 suggests that this biomarker combination can be used to provide an accurate risk assessment for the presence of ovarian cancer in patients with an ovarian cyst or mass. This multiple biomarker assay is now undergoing validation in a multicenter prospective study.

[Table: see text]

[Table: see text]
Tumor-specific correlation of tumor-type M2 pyruvate kinase (Tu M2-PK) in patients with cervical carcinoma
Authors: Kuemmel S. , Jeschke S. , Landt S. , Korlach S. , Schmid P. , Sehouli J. , Blohmer J. , Ulm K. , Lichtenegger W. , Thomas A.
Published: March 2020

5044

Background: Pyruvate kinase is a key enzyme in glycosis. Proliferating cells express the tetrameric isoenzyme pyruvate kinase type M2 (M2-PK), which decomposes to the dimeric form during tumor development (Tu M2-PK). This suggests that Tu M2-PK can be used as a tumor marker. The goal of the present study was to investigate the diagnostic value of Tu M2-PK in patients with cervix carcinoma and in patients with preinvasive lesions (CIN I-III). Methods: Plasma samples were investigated from a total of 116 patients using the quantitative sandwich enzyme immunoassay for Tu M2-PK (ScheBo, Tech GmbH). The patients were divided up into 3 groups depending on the severity of their condition: Group 1 (n = 43): CIN I-III; Group2 (n = 49): cervix carcinoma FIGO stage I-IV; Group3 (n = 24): relapse of cervical cancer. Results: The differentiation into three groups depending on the severity of the condition gave significant results, with the group of patients with relapsed cervix carcinoma having the highest concentration of Tu M2-PK (p < 0.001) (mean rank: Group 1 - 33.67, Group 2 - 62.48, Group 3 - 94.85 U/ml). In addition, there was a significant differentiation with respect to the FIGO stage, with increasing concentration for increasing stages (p < 0.001). In contrast with this there was no significant differentiation in patients with preinvasive lesions (p < 0.99). In the evaluation of the correlation with prognosis factors of cervix carcinoma (lymph-node status: N(+), N(−); lymphangioinvasion: L1;L0; angioinvasion: V1, V0 and grading G1–3) there were significantly higher values with positive lymph nodes (N+) (p < 0.0001). No significant differences were determined in the analysis of different tumor sub-types (squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma) (p = 0.076). Conclusions: These are first results which indicate that Tu M2-PK can be used as a marker to differentiate between malignant and premalignant lesions for patients with cervical cancer. In addition, the concentration correlates with the stage of the disease.

No significant financial relationships to disclose.
Herpes simplex virus 2 (HSV-2) is not a co-factor of human papillomavirus (HPV) in adenocarcinoma of the uterine cervix (AUC)
Authors: Zereu M. , Zettler C. G. , Zelmanowicz A. M. , Canto M. E. , Cambruzzi E.
Published: March 2020

5048

Background: Cervical cancer is an important public health problem worldwide. Following skin and breast carcinoma, cervical cancer is the third most common cancer among Brazilian women, ranking first in some developing countries. AUC occurs in 15–20% of primary cervical neoplasias. Although some etiologic factors for squamous cell carcinoma are well defined, and its relationship with sexually transmitted disease as HPV is established, we still don’t know about the causative factors of most of AUC. The objective of this abstract is to determine the presence of HSV-2 DNA in AUC specimens, and its correlation with HPV infection. Methods: From 1995 to 2003, 229 cases of AUC were diagnosed in a hospital from Brazil. Data was collected retrospectively from medical records. The local ethical committee approved the study. Paraffin embedded tissue was selected and DNA extraction was performed. Samples were first screened for betaglobin DNA sequences. To detect HSV-2 DNA using polymerase chain reaction, a pair of primers that bracket 391 base pair segment of DNA polymerase gene was used as described by Madhavan et al. (2003). The sequences are an upstream primer HSV-5’-ATG GTG AAC ATC GAC ATG TAC GG-3’ and one type specific downstream primer HSV-2–5’- CCT CCT TGT CGA GGC CCC GAA AC-3’ (Invitrogen Custom Primers, Sao Paulo, Brazil). The reaction conditions contained 1microlitre sample DNA. The thermal profile consisted of denaturation 94° for 2” followed by 40 cycles with 45’ of denaturation (94°), annealing (60°) and extension (72°). Analysis with agarose gel electrophoresis with ethidium bromide staining was performed. HSV-2 positive sample was used as control. Results: In our series, patient’s mean age was 53.2 years (from 21 to 94), most of them were multiparous (60.6%) and 42% never used any kind of anticontraception method. In 79.4% of specimes DNA of HPV was identified (51% HPV 18 and 34% HPV 16). All samples were negative for DNA of HVS-2. Conclusion: Although some epidemiologic studies reported an interaction between HPV and HSV-2 in increasing cervical cancer risk, in our series HSV-2 is not found integrated to human genome of adenocarcinoma of the uterine cervix and does not seems to be a co-factor of HPV on the etiology of this cancer subtype.

No significant financial relationships to disclose.
A large-scale multi-center independent validation study of a panel of seven biomarkers for the detection of ovarian cancer
Authors: Zhang Z. , Bast R. C. , Vergote I. , Høgdall C. , Ueland F. R. , Van der Zee A. , Wang Z. , Yip C. , Chan D. W. , Fung E. T.
Published: March 2020

5057

Background: Previously we discovered seven serum biomarkers: ITIH4, transthyretin, ApoA1, CTAPIII, hepcidin, transferrin, and SAA, for the detection of ovarian cancer. They are fragments, cleavages, or PTMs of circulating proteins that are difficult to measure by conventional immunoassays. Using optimzed mass spectrometry assays, we evaluated these biomarkers in a large-scale multi-center study. Methods: A total of 607 serum samples from five sites were analyzed using SELDI TOF-MS protocols optimized for the seven biomarkers. They included 234 women with benign gynecologic diseases, and 373 patients with invasive epithelial ovarian cancer (101 early stage, 231 late stage, and 40 stage unknown). Among them, 165 benigns and 228 cancers had a CA125 available at time of analysis. The median and quartiles of CA125 for benign, early stage, and late or unknown stage were 26/11/57 IU, 80/22/434 IU, and 234/40/1114 IU, respectively. The biomarkers were assessed individually using the Mann-Whitney U Test. A linear composite index was derived in an unsupervised fashion using data from one site and then calculated for the remaining data using the fixed formula. ROC curve analyses were performed on data from individual sites and all sites combined. Results: All seven biomarkers individually demonstrated statistically significant differentiating power, and the majority had p-value<0.00001. AUCs of the composite index in ROC analyses for the six sites were 0.602, 0.566, 0.821, 0.813, and 0.592 in detecting cancer at all stages from benign. On the combined data, the differences in AUC between the index and CA125 were not statistically significant for the detection of cancer at all stages (AUC=0.706 vs. 0.725) or early stages only (AUC=0.534 vs. 0.653). However, the index did better at the high-sensitivity range. At a fixed sensitivity of 86%, the specificity of the index was 34% (77/226) compared to CA125 at 26% (42/163). For early stage cases, at a fixed sensitivity of 84%, the specificity of the index was 24% (55/226) compared to CA125 at 14%% (22/163). Conclusions: We validated seven previously discovered biomarkers, individually and in combination. Prospective studies and assay development are under way to further characterize their clinical utility.

[Table: see text]
Advanced ovarian carcinoma: Which place for neoadjuvant chemotherapy?
Authors: Bousquet G. , Narducci F. , Lesoin A. , Taieb S. , Fournier C. , Querleu D. , Leblanc E.
Published: March 2020

5071

Background: Most patients with ovarian carcinoma are diagnosed at an advanced stage. The ability to surgically resect tumor to microscopic residual disease remains a major prognostic factor. The use of a preoperative chemotherapy for patients with bulky disease is still debated. The objective of this study was to evaluate this therapeutic sequence. Methods: We retrospectively collected data from 207 stage III ovarian cancer patients between January 1998 and August 2004. 127 patients were considered as poor surgical candidates and received neoadjuvant chemotherapy. After 3 courses of a platinum-based chemotherapy, 51 patients who showed a good response by CA125 and CT scan underwent an interval debulking surgery (Group A). For the 43 patients with a partial response or stable disease, 3 other cycles of the same protocol were administered, followed by a secondary surgery (Group B). The remaining 33 patients progressed and had no surgery (GroupC). Results: Optimal tumor debulking (residuum <1 mm) was achieved in 90% and 81% of group A and B patients respectively. Node involvement was not different between the two groups (62%). After a median follow-up of 20.8 months, 98 patients had relapsed and 54 had died. Median OS was 42 months, 37.2 months and 14.4 months for group A, B and C respectively. Three-year OS was 76.7% for group A vs. 50.9% for group B (p = 0.11). Two-year disease free survival was not statistically different for groups A and B (17.3% and 18.5%). In the combined A and B sub-group, univariate analysis for OS showed non-optimal staging according to EORTC criteria (p = 0.005), post-surgical residuum (p = 0.02) and lack of lymphadenectomy (p = 0.01) as adverse prognostic factors. On multivariate analysis, only non-optimal staging remained significant. Conclusions: Neoadjuvant chemotherapy is feasible. We believe the difference in overall survival between groups A and B was likely due to a higher chemosensitivity for group A. Our results support the importance of an optimal surgical staging and the possible therapeutic role of routine lymphadenectomy.

No significant financial relationships to disclose.
Phase I safety and immunogenicity study of NY-ESO-1b peptide and Montanide ISA-51 vaccination of patients with ovarian cancer (OC) in high risk first remission
Authors: Magid Diefenbach C. S. , Sabbatini P. , Aghajanian C. , Spriggs D. , Lee H. , Pezzulli S. , Jungbluth A. A. , Old L. J. , Gnjatic S. , Dupont J.
Published: March 2020

5078

Background: The Cancer Testis (CT) antigen NY-ESO-1 is expressed in over 60% of advanced OC. NY-ESO-1 demonstrates strong immunogenicity and expression is restricted to gonadal tissues, making it an appealing immunologic target. Patients with high risk OC (suboptimal debulking, incomplete CA125 response at 3 cycles, or positive second look surgery) have a high recurrence rate, with median time to progression (TTP) of 10–12mos. Strategies to prolong remission are needed. Methods: After primary surgery and platinum based chemotherapy high risk HLA-A*0201 OC patients in first clinical remission received HLA-restricted NY-ESO-1b peptide (100 μg) and Montanide adjuvant (0.5mL) every 3 weeks for a total of 5 vaccinations. NY-ESO1 tumor expression was evaluated by immunohistochemistry (IHC). Toxicity using NCI-CTC v2 and immunogenicity: 1) NY-ESO-1 specific humoral immunity (ELISA); 2) NY-ESO-1 specific T-cell immunity (tetramer and ELISPOT); and 3) delayed type hypersensitivity (DTH) were assessed on weeks 0, 1, 4, 7, 10, 13, 16. Patients were monitored for progression of disease (POD). Results: Seventeen out of 46 (37%) screened patients were HLA-A*0201+. Eight of 10 enrolled patients have completed therapy, one patient is receiving treatment, and one patient was removed before initiation for POD. Treatment related adverse events (AEs) included: Grade 1 fatigue, anemia, pruritus, myalgias and hyperthyroidism and Grade 2 hypothyroidism. No Grade 3/4 AEs were seen. Five patients (50%) had NY-ESO-1+ tumor; 3 of 3 treated patients with NY-ESO1+ tumor demonstrated T cell immunity by positive tetramer (0.65%–9%) and ELISPOT (35–250 spots). Four of 5 (80%) treated patients with NY-ESO-1- tumor demonstrated T cell immunity by tetramer (1–12%) and/or ELISPOT (250–400 spots). There was no evidence of DTH reaction. With long-term followup 4 of 8 patients have recurred with median TTP of 8.5mos; 4 patients remain in complete remission at intervals of 9, 16, 22, and 37mos to date. Conclusion: Vaccination of high risk HLA A*0201+ OC patients with NY-ESO-1b and Montanide has manageable toxicity, and induces specific T cell immunity in patients with both NY-ESO-1 positive and negative tumors. Additional testing is warranted.

No significant financial relationships to disclose.
Does the platinum-free interval predict the incidence or severity of hypersensitivity reactions to carboplatin? The experience from Women & Infants’ Hospital
Authors: Schwartz J. R. , Bradley A. , Bandera C. , Brard L. , Disilvestro P. , Legare R. , Moore R. , Tejada-Berges T. , Granai C. O. , Dizon D. S.
Published: March 2020

5082

Background: Carboplatin (C) is a standard treatment for gynecologic cancers, but its use in recurrence is associated with an increased risk of hypersensitivity reactions (HSR) in those previously treated with C. However there is no way to predict those at risk for a C-HSR. We sought to evaluate whether the time between C was predictive of incidence and severity of HSRs. Methods: Patients treated with C between 1/1997 and 12/2005 were identified through our chemotherapy database. Records were reviewed for: dates and number of C regimens and cycles, age, drug allergies, cancer type, and date and symptoms of HSR. Severity was defined as mild if symptoms were rash, pruritis or severe for hypo/hypertension, vomiting, dyspnea, wheezing, chest pain, edema, rigors or generalized hives. Fisher’s exact test or Chi Square was used to compare categorized variables. Results: 126 patients were identified who had multiple C regimens. The median age was 60 (range, 40–90) and 89% were treated for ovarian cancer. 63 (50%) experienced C HSRs of which 36 (29%) were severe. The mean time between C regimens was 21 months for those with no HSRs and 24 months for those with HSRs (p = 0.1). The time between C regimens significantly predicted the incidence of HSRs (see table ). Of those receiving a 3rd regimen of C, 8/8 had a HSR and these were severe in seven (88%). Neither age nor presence of other drug allergies was associated with a risk of C HSR. Of interest, 60 patients received >8 (range 9–19) cycles with the first C regimen, and none of the patients reacted after cycle 8. Conclusions: A duration of greater than 12 months between C regimens is associated with an increased risk of both any- and severe- HSR. Our data also suggests that upfront treatment with C beyond eight cycles is not associated with an increased risk of HSR. Strategies for decreasing the risk of C HSR may be best focused on women receiving a repeat regimen after a platinum-free duration over 12 months or those receiving a 3rd regimen of C.

[Table: see text]

No significant financial relationships to disclose.
Identification of a basal-like subtype and comparative effect of epirubicin-based chemotherapy and sequential epirubicin followed by docetaxel chemotherapy in the PACS 01 breast cancer trial: 33 markers studied on tissue-microarrays (TMA)
Authors: Jacquemier J. , Penault-Llorca F. , Mnif H. , Charafe-Jauffret E. , Marque S. , Martin A. , Genève J. , Roché H.
Published: March 2020

509

Background: Immunohistochemical profiling studies with TMA classified breast cancer by luminal, normal breast like, HER-2 overexpressing, and basal-like subtypes. The aim of this study was to evaluate the impact of these subclasses in terms of therapeutic benefit for patients (pts) with node positive operable breast cancer included in the phase III trial PACS01. Methods: Among the 1999 pts randomized, 1100 paraffin blocs were collected for TMA. Pts were treated with either arm A: 6 cycles of FEC100 (546 pts) or arm B: docetaxel 100 mg/m2 replaced FEC100 for the last 3 cycles (554 pts). The median follow up was 5 years. The 33 analysed markers explored different pathways: cellular differentiation (CK5/6,8/18,14, P-Cadherin, E-cadherin, α-catenin, β-catenin, AF6, MUC1, Cav1, moesin, Cd10, CD44), proliferation/apoptosis (AuroraA, Tacc2/3, Ki67, CyclinD1, Bcl2, p21, p27), ER related (ER, PR, Gata3), and oncogene/ antioncogene (P53, HER2, EGFR1, Pten, Cmet, Fhit, FGFR, Angiogenin, topoisomeraseIIα). All antibodies were evaluated in quick score. Results: In terms of metastases free survival (MFS) 16 markers harboured a statistical significant value under 20%. The hierarchical clustering for 80% of complete data, identify a cluster of pts (n=531) characterized by the positive expression of EGFR1, Moesin, Pcadherin, and p53, considered as basal-like subtype (BLST). This cluster presented a pejorative predictive value both in Log-rank test (LR) (p=0.002) and in Cox multivariate analysis (HR=0.65; p=0.009), confirmed in overall survival (OS) (LR p<0.0001; cox HR=0.46, p<0.001). BLST pts had a significantly better MFS (LR p=0.05) in the arm B, confirmed in OS (LR p=0.005), as for a more theoretical basal signature and ER negativity (LR MFS p=0.0033, OS p=0.0052; cox MFS HR=0.71 p=0.04, OS HR=0.51 p=0.003). For a second cluster considered as luminal subtype (ER positive and BLST parameters negatives) no difference was observed whatever the arm. Conclusions: The basal-like profile identified in this study is significantly associated to a worst prognostic, but also to a better response to sequential FEC/docetaxel chemotherapy.

[Table: see text]
Phase I study of weekly topotecan and gefitinib in patients with platinum-resistant ovarian, peritoneal, or fallopian tube cancer
Authors: Slomovitz B. M. , Coleman R. L. , Levenback C. , Jung M. , Gershenson D. M. , Wolf J.
Published: March 2020

5090

Background: To determine the dose limiting toxicity and the maximum tolerated dose (MTD) of weekly topotecan in combination with standard dose gefitinib in patients with relapsed, platinum-resistant, ovarian, peritoneal or fallopian tube cancers that are EGF-R positive (>/= 1+). Methods: Patients with measurable, recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study. Initial treatment was gefitinib at a dose of 250 mg oral dose daily and topotecan at a dose of 2.0 mg/m2 on days 1, 8, and 15, with cycles repeated every 28 days. Dose escalations were planned for topotecan (Dose Levels 1–3: 2, 3, 4 mg/m2) until the MTD was reached. A conventional 3+3 algorithm was used. The 2mg/m2 dose of topotecan was chosen as a starting dose because there are reported responses to this level when it has been used as a single agent on this schedule. Results: Thirteen patients received a total of 45 cycles. Twelve patients were evaluated for toxicity and 11 patients for response. Median age range was 63 years. At the time of initial diagnosis, all twelve patients underwent tumor debulking surgery. One patient had one prior chemotherapy regimen, 6 patients had 2, 4 patients had 3 and 1 patient had more than 3 prior chemotherapy regimens. There were 3 patients treated at dose level 1, 3 patients at dose level 2 and 7 patients treated at dose level 3 (1 patient was inevaluable). One of 6 evaluable patients in the dose level 3 group had a grade 4 thrombocytopenia. Therefore, dose level 3 will used for the Phase II portion of the trial. There were no treatment related deaths. Of the 11 patients evaluated for response, there were 4 patients with stable disease (mean number of cycles 6.5, range 3–12) and 7 had progressive disease. Conclusions: Gefitinib with weekly topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. The phase II component of this study is ongoing.

No significant financial relationships to disclose.
A comparison of combination docetaxel/carboplatin versus sequential docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer
Authors: Alvarez Secord A. , Havrilesky L. J. , Higgins R. V. , Nycum L. R. , Kohler M. F. , Puls L. E. , Holloway R. , Soper J. T. , Valea F. A. , Berchuck A.
Published: March 2020

5092

Background: Combination paclitaxel and platinum-based chemotherapy has been shown to improve survival in patients with recurrent platinum-sensitive ovarian cancer. However, the incidence of neurotoxicity was significantly greater with combination therapy than with other platinum-based regimens. The aim of this study was to compare the efficacy and adverse event profile of combination versus sequential weekly docetaxel and carboplatin therapy in patients with recurrent platinum-sensitive ovarian cancer. Methods: Patients with recurrent platinum-sensitive ovarian, peritoneal, or tubal cancer were randomized to either weekly docetaxel 30 mg/m2/days 1 and 8 and carboplatin AUC 6/day 1 q 3 weeks (regimen A) or docetaxel 30 mg/m2/days 1 and 8, repeated every 3 weeks for 6 cycles followed by carboplatin AUC 6/day 1 every 3 weeks (regimen B) for 6 cycles or until disease progression. The primary endpoint was time to progression (TTP). Results: At the time of this analysis, 51 patients, with a median age of 65.1 years, had been enrolled. There were 25 randomized to regimen A and 26 to regimen B from January 2004 to April 2005. There were no differences between the groups with respect to age, performance status, prior consolidation therapy, or anatomic site of cancer. The study is still open to accrual and thus far the overall response rate was 51% (2 CR, 24 PR) with stable disease in 26%. Median TTP was 12.6 months. The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with regimen A compared to regimen B (15% vs. 3%; 44% vs. 10%), respectively. Conclusions: Combination and sequential weekly docetaxel and carboplatin have significant activity in recurrent platinum-sensitive ovarian cancer. Both regimens have a low incidence of moderate to severe neurotoxicity relative to that observed in other studies that employed paclitaxel.

[Table: see text]