bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicentric phase II randomized trial of docetaxel (D) plus estramustine (E) versus docetaxel (D) as first line chemotherapy for patients (pts) with hormone-refractory advanced prostate cancer (HRPC)
Authors: Caffo O. , Sava T. , Comploj E. , Fariello A. , Zustovich F. , Valduga F. , Frisinghelli M. , Segati R. , Sacco C. , Perin A. , Pappagallo G. 
Published: March 2020

4625 Background: D is presently considered a standard treatment for HRPC pts. E has shown a synergistic activity with D in vitro, however the role of D+E combination remains to be defined in the clinical practice. We attempted to evaluate the activity, in terms of PSA decline (PSA↓), the safety and quality of life (QoL) of D ± E in HRPC pts. Methods: eligibility criteria were: HRPC diagnosis, hormone-refractory advanced disease (PSA progression after at least two hormonal therapy), ECOG PS ≤ 2, adequate renal, hepatic and hematological functions. Pts were randomized to D 70 mg/m2 IV d1 q3w (arm A) or D 70 mg/m2 IV d1 q3w + E 280 mg/TID PO starting 1 day prior to D, for 5 consecutive days (arm B). The treatments were planned until best PSA response achievement or PSA progression. No anticoagulant prophylaxis was planned in ARM B pts. Qol was assessed by self-filled questionnaires during the treatment. Results: Between 04/2003 and 09/2005, 95 pts (median age 69 years, range 48–86, median PSA 80 ng/ml, range 5–2166 and measurable disease in 45) were randomized to arm A (49) or arm B (46). To date, 9 pts and 6 pts are still on treatment in arm A and B respectively. In arm A, pts received 257 cycles (median 5, range 1–14) with only 10 (3.9%) delays ≥ 7 days. In arm B, pts received 317 cycles (median 7, range 0–20) with only 15 (4.7%) delays. Median follow-up was 19.5 months. Grade 3–4 hematological toxicities consisted of neutropenia, 4% in arm A and 8% in B, anemia, 0% and 2% respectively and 1 pt with febrile neutropenia and grade 3 diarrhea (Arm B). Grade 3−4 non-hematologic toxicities were vomiting (1 pt) in arm A, stomatitis (2 pts) and vomiting (1 pt) in arm B. Two cases of stroke were reported in arm A. Responses, in terms of PSA↓ >50% were: 43% in arm A and 70% in arm B with PSA normalization in 8% and 38% respectively. Progression free survival (biochemical) was 20 weeks in arm A and 31 in B. Analysis concerning QoL outcomes is planned at the treatment completion of all pts. Conclusions: D-based regimens are active in HRPC with a low toxicity profile. From this preliminary data, DE combination appears promising, in terms of activity and tolerability so, front-to-front formal comparison in a phase III trial can be recommended. No significant financial relationships to disclose.
Assessment of PSA and digital rectal examination (DRE) for the detection of Gleason ≥ 7 prostate cancer in a referral population
Authors: O’Brien C. A. , Mongoue-Tchokote S. , Collins L. , Spurgeon S. , Peters L. , Beer T. M. , Mori M. , Garzotto M. 
Published: March 2020

4633 Background: The value of both PSA and DRE for prostate cancer detection have recently been called into question when examined in screening and prostatectomy series (NEJM 350:2239, J Urol 172:1297). The effectiveness of these parameters for detection of clinically significant cancer is not fully characterized. We studied their utility for the detection of aggressive prostate cancer (Gleason Score ≥ 7) in a referral population of men. Methods: Data were collected on 1,699 referred men with a serum PSA of ≤ 10 ng/ml who underwent a prostate biopsy (minimum 6 cores) between 1993 and 2004. Variables analyzed included: age, race, family history, DRE (normal vs. suspicious vs. cancer-likely) and PSA. Thirty percent of the data were randomly reserved for study validation. Logistic regression analysis was performed to estimate the odds ratio and the 95% confidence intervals. Results: Gleason grade ≥ 7 prostate cancer was detected in 157 subjects (9.2%). Using the model building data set (n = 1,184), independent predictors of Gleason ≥ 7 cancer were an elevated PSA and an abnormal DRE only (see table ). Based on these results, a clinically-applicable nomogram was constructed and using the independent validation set (n = 515). The area under the ROC was 0.70 for the model. Conclusions: Although the use of PSA and DRE have recently come under intense scrutiny, they independently predict the presence of aggressive prostate cancer in a contemporary referral population. Improvement in prostate-cancer survival associated with successful treatment of localized disease requires the successful early detection of aggressive prostate cancer. Our results demonstrate that PSA and DRE, currently recommended screening interventions by the ACS and AUA, remain useful for the detection of aggressive prostate cancer in the PSA era. [Table: see text] No significant financial relationships to disclose.
Serum HER-2/neu change predicts clinical outcome to trastuzumab-based therapy
Authors: Ali S. M. , Esteva F. J. , Fornier M. , Gligorov J. , Harris L. , Kostler W. J. , Luftner D. , Pichon M. F. , Tse C. , Lipton A. 
Published: March 2020

500 Background: Trastuzumab monotherapy has a 34% objective response rate (ORR) in patients with HER-2/neu IHC 3+ or FISH-positive first-line metastatic breast cancer (C. Vogel et al, JCO 20:719–726, 2002). Predicting response and survival to trastuzumab-based therapy is an unsolved problem. The HER-2/neu extracellular domain (ECD) is released after cleavage by the ADAM metalloproteinases, and the remaining membrane-bound internal domain is constitutively activated. Trastuzumab inhibits cleavage of the HER-2/neu ECD. Methods: A pooled analysis of 7 trials of first-line trastuzumab therapy (with or without chemotherapy) with serial serum HER-2/neu levels were included. The FDA-approved HER-2/neu ELISA (Oncogene Science/Bayer HealthCare) was used to determine serum HER-2/neu levels. A pretreatment and post-treatment serum (16–120 days) from 307 patients was available. 236 patients had data on overall survival. Kaplan Meier Life table analysis was performed to compare duration of response (DRP), time to progression (TTP), and overall survival (OS). Results: The median decrease in serum HER-2/neu levels for all patients was 31.0% (Range: 98% decrease to 239% increase). Patients with > 20% decrease in HER-2/neu levels had a significantly higher objective response rate (ORR, complete + partial response) and longer DRP, TTP and OS. The results were similar regardless of the timing of the second serum draw (≤ 30 days vs. > 30 days) after the start of trastazumab. Conclusion: Patients with < 20% decrease in serum HER-2/neu levels have decreased benefit from trastuzumab therapy. Patients who do not have a significant decrease in serum HER-2/neu levels should be considered for additional HER-2/neu-targeted therapies. [Table: see text] [Table: see text]
Surgical staging of uterine cancer: Randomized phase III trial of laparoscopy vs laparotomy—A Gynecologic Oncology Group Study (GOG): Preliminary results
Authors: Walker J. L. , Piedmonte M. , Spirtos N. , Eisenkop S. , Schlaerth J. , Mannel R. S. , Spiegel G. 
Published: March 2020

5010 Background: Feasibility of laparoscopy has been demonstrated, but the toxicity, staging, and survival has not been adequately compared to the traditional open approach. A randomized Phase III trial of 2616 patients was conducted by the GOG from 5/1996 to 9/2005. QOL and complications of surgery were previously reported at SGO. FIGO pathologic staging is the basis of this report. Methods: Clinical Stage I-IIA uterine cancer were eligible, consenting to either technique. The randomization procedures yielded two on laparoscopy arm for every one on the laparotomy arm. Scope participants were required to undergo laparotomy if the complete surgical staging was not feasible, or for resection of cancer. The staging results include: FIGO surgical stage, peritoneal cytology, number of nodes per site, and percent positive nodes at each location: right pelvic, left pelvic, right para-aortic, left para-aortic. Results: 2616 were randomized, 403 were excluded for this analysis: 84 ineligible, 76 sarcoma, 198 incomplete data, 45 were stage IV, leaving 2213 evaluable for lymph node staging of endometrial carcinoma (781 open:1432 scope). Conversion to laparotomy from laparoscopy occurred in 23.7%. Positive or suspicious cytology was found in 5.6% of laparotomy and 7.8% of laparoscopy participants (p = 0.055 n.s.). Pelvic nodes were documented (R 98.8% vs 98.9%, L 98.5% vs 98.1% n.s.) and positive pelvics (any positive 8.8% vs 8.7%; R 5.5% vs 5.8%; L 6.9% vs 6.1% n.s.) were similar. Laparoscopic surgical staging cases were less likely to have para-aortic nodes sampled (L 91.3% vs 85.0% p < 0.001; R 96.0% vs 92.5% P = 0.001), but positve nodes were no different (any positive PA 5.0% vs 4.5%; R 4.1%, 3.4%; L 2.3%, 2.7% n.s.). Final FIGO Staging results (III A: 5.5% vs 5.7% n.s.& IIIC: 9.3% vs 9.5% n.s.) were the same by randomization arm. Conclusion: These results demonstrate that laparoscopic surgical staging of endometrial cancer can be completed in 76.3%. No difference in postive cytology, node positivity rate, or FIGO stage could be attributed to the laparoscopic approach. Conversion to laparotomy is advised when incomplete staging results would yield inadequate information for treatment planning. NCI Funding: UO1CA65221, CA 27469. No significant financial relationships to disclose.
Phase II study of letrozole in estrogen receptor (ER) positive relapsed epithelial ovarian cancer (EOC)
Authors: Gourley C. , Smyth J. F. , Mackean M. , Stevenson A. , Williams A. , Rye T. , Reed N. , Vasey P. , Gabra H. , Langdon S. 
Published: March 2020

5025 Background: Letrozole is a potent oral aromatase inhibitor which rapidly suppresses circulating estrogen levels by 99% in postmenopausal women. By comparison with cytotoxic agents it is very well tolerated. We previously demonstrated an ‘endocrine sensitive’ subgroup of ovarian cancer patients with ER histoscore cutoff of ≥150 (Bowman et al, Clin Can Res 2002). Methods: This was a phase II study with a planned sample size of 33 patients. Eligible patients had relapsed EOC or primary peritoneal cancer with an ER histoscore of ≥150 and a rising CA125 that had progressed according to Rustin’s criteria. Patients were treated with letrozole 2.5mg daily until clinical or marker evidence of disease progression. The primary endpoint was response according to CA125 and RECIST criteria. Biomarker analysis by tissue microarray is also being performed. Results: 46 patients were accrued, 45 of whom were eligible. The median age was 61 (range 39–81). 24, 10 and 10 patients had received 1,2 and >2 previous lines of chemotherapy respectively. Of 43 patients evaluable for CA125 response, 7 (16%) had a response (decrease of >50%) and 16 (37%) patients had not progressed (doubling of CA125) following 12 weeks on treatment. In the CA125 responders, the nadir CA125 ranged from 0.7–49% of baseline (actual % of baseline: 0.7, 2.6, 11.1, 17.6, 23.6, 42.6, 49). Of the 7 responding patients, 5 had received only one previous line of chemotherapy. The time taken to achieve the nadir CA125 value ranged from 10 to 36 weeks, with a median of 13 weeks. Of 33 patients evaluable for radiological response, 3 (9%) had a PR and 14 (42%) had stable disease at 12 weeks. Overall, 11 patients (26%) had a PFS of >6 months and 2 patients (5%) had a PFS of ≥2 years. Conclusions: To our knowledge this is the first study of a hormonal agent in a selected ER +ve population of ovarian cancer patients. Promising efficacy of the agent is demonstrated in this population of pre-treated patients, many with a considerable bulk of disease. Given the median time of 13 weeks to response, we suggest that this strategy should be tested in ER+ve ovarian cancer patients in the adjuvant setting following first line chemotherapy No significant financial relationships to disclose.
Phase II open label randomized study of trabectedin (T) given as two different dosing schedules in women with platinum-sensitive, recurrent ovarian carcinoma: Preliminary results
Authors: Del Campo J. , Roszak A. , Ciuleanu T. , Bidzinski M. , Hogberg T. , Wojtukienicz M. , Boman K. , Poveda A. , Westermann A. , Izquierdo M. 
Published: March 2020

5031 Background: Trabectedin (Yondelis, ET-743) is a marine derived compound which binds to the minor groove of DNA distorting the DNA structure and induces apoptosis and cell cycle arrest. It has shown clinical activity in soft tissue sarcoma, ovarian, prostate and breast cancer. Methods: Patients (pts) with recurrent platinum sensitive ovarian carcinoma were randomized in a multicenter, open label study to receive T as 1.5 mg/m2 over 24 h infusion (schedule A) or 1.3 mg/m2 over 3 h infusion (schedule B) both every 3 weeks. All pts received dexamethasone premedication. Primary objective is to evaluate the response rate (RECIST) and secondary objectives are response duration, CA-125 response, time to progression and safety. Results: 107 pts were enrolled in 23 centers. Demographic and disease characteristics were well balanced. Toxicity and response data on the first 99 pts are available: median age 57 (25–78) years; ECOG PS=0: 72% and =1: 28%; pts received a median of 4 cycles (range:1–19 in A, 1–13 in B). Relative dose intensity was 84% and 93% respectively. Objective responses due to investigator’s assessment were 29% (8% CR, 21% PR) with 52% SD in A and 28% (11% CR, 17% PR) with 45% SD in B, with 11 pts not yet evaluable for response. CA 125 responses ≥ 50% occurred in 23% in A and 26% in B. TTP data will be presented. Safety: 501cycles were delivered; the most common any grade drug-related AEs per patient were (A and B) fatigue (56% and 47%), nausea (63% and 70%), vomiting (56% and 45%) and constipation (25% and 30%). Consistent with previous experience, alopecia, stomatitis and neurotoxicity were uncommon and mild/moderate. Grade 3/4 fatigue occurred in 15% in A and 4% in B. Grade 3/4 lab abnormalities were non-cumulative neutropenia (50% and 32%) and reversible ALT increase (58% and 53%). G-CSF support was not routinely given. There were 4 deaths <30 days last infusion date (3 in A unrelated to study drug, one in B due to related multiorgan failure). Conclusions: This analysis suggests that both T schedules appear active with manageable toxicity. There was a trend for less neutropenia and fatigue with schedule B. On the basis of these efficacy results, no additional phase III comparisons between these 2 schedules seem warranted [Table: see text]
Utility of a novel serum tumor biomarker HE4 in patients with uterine cancer
Authors: Moore R. G. , Brown A. K. , Miller C. M. , Badgwell D. , Lu Z. , Verch T. , Allard J. W. , Granai C. O. , Bast R. , Lu K. 
Published: March 2020

5036 Background: Approximately 40,880 new cases of uterine cancer are diagnosed in the U.S. annually resulting in 7,310 deaths. Uterine cancer is surgically staged and 75% of patients present with stage I disease. Patients with stage I tumors with intermediate to high risk factors have a recurrence rate of 20 to 30%. Serum CA125 is elevated in 75% of patients with advanced stage disease and in only 17% of patients with early stage disease. The use of CA125 for the detection of recurrent disease is limited at best. Only 25% of patients with asymptomatic recurrent disease have an elevated CA125. A better marker indicating early recurrent disease is needed. The objective of this study was to examine the value of a novel serum tumor marker HE4 in endometrial cancer. Methods: Serum samples from two prospective IRB approved studies at two institutions were analyzed to compare HE4 with CA125 in patients who had surgical staging for uterine cancer. Normal controls were obtained from healthy patients. Informed consent was obtained from all patients and blood samples were drawn pre-operatively. HE4 and CA125 levels were determined using assays from Fujirebio Diagnostic Inc. ROC curves were constructed for each tumor marker and the sensitivity at a set specificity of 95% was determined. Results: Serum from 156 controls and 233 patients with surgically staged endometrial cancer; (151 stage I, 21 stage II, 47 stage III and 14 stage IV) were examined. The area under the ROC curves (ROC-AUC) for HE4 and CA125 were determined and compared ( Table1 ). At 95% specificity, the sensitivity for differentiation of controls versus all stages was 44.9% for HE4 compared to 25.2% for CA125 (p = 0.0001). For stage I cases, HE4 showed an improvement in the sensitivity of 20.5% compared to CA125 (37.1% vs 16.6%, p = 0.0001). Conclusions: HE4 is elevated in all stages of endometrial cancer and has a greater sensitivity for discrimination from normal controls compared to CA125. As well, HE4 is elevated in early stage endometrial cancer and should be investigated as a marker for early recurrent disease. [Table: see text] [Table: see text]
In vitro drug resistance profiles correlate with DNA ploidy and p53 expression in 3,106 endometrioid and papillary serous adenocarcinomas of the uterus
Authors: Yu I. , Huang W. , Mechetner E. 
Published: March 2020

5037 Background: Although chemotherapy is widely used to treat advanced and recurrent endometrial cancer, no patient-tailored protocols were developed, resulting in intermittent and incomplete clinical response. The utility of the Extreme Drug Resistance (EDR) assay to predict clinical resistance to chemotherapy was proven in several cancer types, including ovarian cancer. This study is the first attempt to evaluate the efficacy of the EDR assay in endometrioid (E) and papillary serous (PS) tumors and correlate it with the expression of two major biomarkers, DNA ploidy and p53. Methods: 2520 E and 586_PS adenocarcinomas were tested in the EDR assay using in vitro incubation in suprapharmacologic exposures of 4-HC (the active species of cyclophosphamide), cisplatin, carboplatin, and doxorubicin. The results were defined as EDR (one standard deviation more resistant than the database median), intermediate drug resistance (IDR - between the median and EDR), and low drug resistance (LDR - lower than the median). DNA ploidy was assessed in flow cytometry; p53 expression was quantitated on paraffin sections by immunohistochemistry. Results: Compared to E, the more clinically aggressive PS tumors were significantly associated with high (IDR + EDR) in vitro resistance to all EDR-tested drugs: 4-HC (p = 0.0010; χ2 statistics), cisplatin (p = 0.0064), carboplatin (p = 0480), doxorubicin (p = 0.0001). PS tumors showed significantly higher non-diploid status (p < 0.0001) and p53-positivity (p < 0.0001). For all EDR-tested drugs, increased in vitro resistance closely correlated with the non-diploid and high p53 status. Conclusions: These data document close correlation between the EDR assay results and biological behavior of endometrial tumors in terms of their clinical aggressiveness and biomarker expression and justify further studies on combined EDR and biomarker testing in assay-guided chemotherapy. [Table: see text] No significant financial relationships to disclose.
An RT-PCR-based multi-gene prognostic signature predicts distant metastasis of node negative, ER positive breast cancer from FFPE sections
Authors: Lau K. F. , Wang A. , Chew K. , Dai H. , Hastie T. , Brandt B. , Waldman F. , Sninsky J. 
Published: March 2020

506 Background: Gene expression profiles have been shown to predict distant metastasis risk in breast cancer patients. For routine medical practice, molecular prognostic tests need to be able to quantify metastasis risk with readily available samples and optimally employ regulatory-approved platforms. Methods: 142 early stage, N-, ER+, untreated breast cancer patients were chosen. Mean age was 61.8 (31 - 89) yrs with 72% > 55 yrs. RNA was isolated from 4×10 μm FFPE sections. Using real-time RT-PCR, 200 genes selected from van ‘t Veer et al, Dai et al, Paik et al and additional candidate genes were profiled. Primary endpoint was distant metastasis free survival. A prognostic signature was identified using semi-supervised principal component method. Metastasis score (MS) was calculated from gene expression levels. Results: We identified a unique 15-gene prognostic signature and 3 normalization genes. Probability of metastasis for any time period can be calculated from MS and was evaluated for 2, 5, and 10 yrs. Using median of MS to stratify patients, the high-risk group had a hazard ratio (HR) of 4.1 (95%CI 1.77–9.54, p = 0.001) vs. the low-risk group. 5-yr and 10-yr metastasis free survival rates (std. error) were 0.76 (0.053) and 0.62 (0.064) in the high-risk group and 0.96 (0.025) and 0.90 (0.038) in the low-risk group. Multivariate Cox regression analyses indicated that molecular signature had independent prognostic value with HR of 2.97 (95%CI 1.17 - 7.52, p = 0.022) after adjusting for age, tumor size and grade. Molecular signature was more prognostic in the low-grade subgroup (HR = 6.85, 95%CI 1.81–25.88) than an unstratified analysis. AUC at 5 yr was 0.65 and 0.60 for molecular signature and Adjuvant Online (AO) respectively. The prognosticator combining both had AUC of 0.67. 10-yr metastasis probabilities from MS and AO have low correlation (R2=0.17). Conclusions: A prognostic signature based upon mRNA expression of 15 genes has been identified using FFPE sections with RT-PCR for early stage, N-, ER+ patients. Metastasis score that quantifies distant metastasis risk for any time period, not confounded with any treatment effect, can help clinicians and patients to choose among different therapeutic options. (Lau and Wang contribute equally) [Table: see text]
Topotecan (T) and carboplatin (C) in the treatment of platinum sensitive relapsed ovarian cancer (ROC): Results of a multicenter phase I/II study
Authors: Koensgen D. , Belau A. , Klare P. , Steck T. , Camara O. , Sommer H. , Oskay-Oezcelik G. , Coumbos A. , Lichtenegger W. , Sehouli J. 
Published: March 2020

5089 Background: Despite of the effectiveness of radical surgery and first-line chemotherapy, most patients (pts) with advanced ovarian cancer will relapse. Paclitaxel (P) in combination with C as second-line treatment improves the outcome of pts with platinum-sensitive ROC in comparison to C monotherapy. Due to polyneuropathy and alopecia this regimen can not be offered to all pts. Therefore, other platinum-combinations are required. We conducted a phase I/II study to define the dose limiting toxicities (DLT) and the tolerability of combination therapy with T and C. Methods: Pts with platinum-sensitive ROC and primary standard therapy were stratified according to treatment-free interval (TFI): 6–12 months (A) and ≥12 months (B). Following dose regimens were analysed: T 1mg/m2/d1–3 + C AUC5/d3 and T 0.75 mg/m2/d1–3 + C AUC5/d3, q21d. DLT was based on the first 4 courses and defined as: CTC grade 3/4 hematological and grade 2 non-hematological toxicity (excepted alopecia, vomiting), treatment delay >7d. Primary endpoints were DLT and tolerability. Secondary endpoints were remission rate (RR) and progression-free survival (PFS). Results: From 06/04 to 08/05, 28 pts were enrolled, 26 pts (A:13 pts, B:13 pts) were eligible. Median age was 61.5 years. A total of 141 cycles were analysed, median number of cycles was 6 (range A:2–8, B:1–10). DLTs were: leucopenia (n = 5) and thrombocytopenia (n = 1). MTD was reached at dose: T: 0.75mg/m2 and C: AUC5. Overall, grade 3/4 hematologic toxicities (in% of all cycles), for (A) and (B) respectively, were: anemia 4% vs. 4%, leucopenia 34% vs. 13%, neutropenia 30% vs. 31%, thrombocytopenia 7% vs. 6%. Febrile neutropenia 4.3% vs. 0%. Darbepoetin alfa was given in 13.5% of all cycles. Overall, grade 3/4 non-hematologic toxicities were infrequent (< 5%). Overall RR (95% CI) was 50% (29.7–70.1) [A: 30.8% (0.1–61.1), B: 69.3% (38.7–90.9)]. Median follow-up was 5.8 mo, median PFS (95% CI) was 7.7 mo (1.3–9.4) [A: 6.2 (1.3–7.2), B: 8.0 (7.3–9.4)]. Median overall survival was not reached. Conclusions: TC is a feasible and effective chemotherapy regimen for platinum sensitive ROC. Tolerability is not associated to TFI. The recommended dose for subsequent studies is T:0.75 and C:AUC5. No significant financial relationships to disclose.