bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase III trial of docetaxel (D), estramustine (E), and prednisone versus docetaxel plus prednisone in patients with metastatic hormone-refractory prostate cancer (HRPC)
Authors: Machiels J. H. , Mazzeo F. , Clausse M. , Filleul B. , Marcelis L. , Honhon B. , D’Hondt L. , Dopchie C. , Bonny M. , Kerger J. 
Published: March 2020

5067 Background: D alone or in combination with E improves survival of pts with metastatic HRPC. Whether E is necessary in combination with D is controversial. Preclinical data suggest a synergistic activity between D and E. Phase II as well as small randomized trials support this hypothesis, although indirect comparisons between the large phase III studies are not in favor of D/E combination. We conducted a randomized, prospective, multicentric study to compare D versus D/E. Methods: 150 metastatic HRPC were randomized (minimisation, stratification parameters: PSA level, ECOG, previous E use (38 pts), and center) between D (35 mg/m2 on day 2 and 9, every 3 wks) and D in combination with E (280 mg PO tid on days 1 to 5 and 8 to 12, coumadin 1mg/d). E was the only difference between the two treatment arms. All the pts received prednisone (10 mg/d). The primary endpoint was PSA response rate (decrease in PSA > 50% from baseline) and the study was powered to detect a 25% difference in PSA response rate. Results: No significant difference was found for PSA response (D/E: 50/68 (73%); D: 48/69 (69%)), time to PSA progression (median 205 days for D/E and 210 days for D), duration of PSA response (median 185 days for D/E and 220 days for D), progression-free survival (median 186 days for D/E and 195 days for D), response rate according to RECIST, and overall survival (median 617 days for D/E and 629 days for D). PSA < 4 ngr/mL occurred in 28/68 pts (41%) in D/E and in 17/69 (25%) in D (p=0.04). More pts had at least one grade 3/4 NCI-CTC toxicity in D/E (33/75 pts; 45%) compared to D (16/75 pts; 21%) (p=0.003). The main difference was grade 3/4 digestive toxicity (D/E:15% and D:4%; p=0.017). Serious adverse events were reported more frequently in D/E than D: 20 vs 9 (p=0.03). In D/E, the most frequent grade 3/4 toxicities were digestive (15%) and venous thrombosis (12%). In D, the most frequent grade 3/4 toxicity was anemia (9%) and venous thrombosis (8%). Conclusions: Our study did not show any clinically relevant advantage in term of efficacy for the addition of E to D. Both regimens were well-tolerated although the toxicity profile was in favor of D without E. Our study does not support the addition of E to D to treat pts with HPRC. [Table: see text]
Final results from a phase II trial of systemic chemotherapy in a small cell urothelial cancer: Evidence supporting neoadjuvant chemotherapy from the M.D. Anderson Cancer Center
Authors: Siefker-Radtke A. O. , Kamat A. M. , Grossman H. , Williams D. L. , Dinney C. P. , Millikan R. E. 
Published: March 2020

5083 Background: Previously reported retrospective data supported a potential role for neoadjuvant chemotherapy in small cell urothelial cancer (SCUC). We now report final results from a phase II clinical trial in SCUC. Methods: Since 2001, 30 patients with biopsy proven SCUC received alternating doublet chemotherapy with Ifosfamide + Doxorubicin, and Etoposide + Cisplatin. Patients with surgically resectable disease (<=cT4aN0M0) received a total of 4 cycles followed by cystectomy, while those with unresectable disease (>=cT4b, N+, or M+) received 2 cycles beyond maximal response. Results: Neoadjuvant chemotherapy was given in 18 patients (cT2:14, cT3:4), while 12 patients were treated for metastatic SCUC. For those receiving neoadjuvant therapy, the median OS is 58 months, with a 5-year survival of 48%; 8 remain alive and NED beyond 2.5 years. There have been only 5 deaths for the neoadjuvant group (3 SCUC, 1 post-op infection, 1 AML). For those with metastatic disease, the median OS is 14 months. Two were rendered resectable with chemotherapy (cT4b:1,N+:1); 1 died of recurrent SCUC, while the other is currently undergoing therapy for TCC of the ureter. Brain metastases developed in 7 patients (cT3b:2, initial M+:5). Chemotherapy has been well-tolerated with only 2 G4 toxicities (catheter infection and neutropenia). The most frequent G3 toxicities include transfusion (10), neutropenic fever (7), infection (5), and vomiting (3). There was only one post-surgical death; a case of sepsis in a patient with diverticulitis and abscess requiring sigmoid colon resection. Conclusions: These prospective results, which are consistent with our previously reported retrospective review, provide additional support for 4 cycles of neoadjuvant chemotherapy in the setting of SCUC. Unfortunately, once metastases are present, the prognosis remains poor with few long-term survivors. These results may also predict a patient subset for which prophylactic cranial irradiation may be potentially beneficial. No significant financial relationships to disclose.
Prediction of residual retroperitoneal mass histology following postchemotherapy retroperitoneal surgery for metastatic nonseminomatous germ cell tumors: Role of MDR-1 and mismatch repair genes
Authors: Heidenreich A. N. , Pfister D. , Thüer D. , Engelmann U. H. , Ohlmann C. H. 
Published: March 2020

5088 Background: Following inductive chemotherapy for metastatic nonseminomatous germ cell tumours (NSGCT) about 35% and 15% of patients undergoing residual tumor resection (RTR) demonstrate mature teratoma and vital cancer, respectively. It was the aim of our study to evaluate the expression of mdr-1, hMLH1 and hMLH2 in primary NSGCT and their resected residual tumors. Methods: 185 patients with NSGCT underwent RTR of retroperitoneal masses. Immunohistochemical investigations of mdr-1, hMLH1/2 were performed on paraffin-embedded tissue section of the primary tumour and the resected lymph nodes using monoclonal, commercially available antibodies. Staining was analysed according to a semiquantitative scoring system; furthermore, detailed morphometry was performed. Preoperative serum and clinical parameters were assessed to predict necrosis/fibrosis or teratoma in residual tumors. Statistical analysis was performed by uni- and multivariate analysis to correlate data with histology of the RTR specimens. Parameters were statistically significant if p<0.05. Results: A total of 122 patients (65.9%) had necrosis, 23 patients (12.4%) and 40 patients (21.6%) had viable cancer and mature teratoma, resp. After multivariate analysis pre-chemotherapeutic AFP-levels, tumor size before RTR, mature teratoma in the primary and mdr-1 expression in the primary were independent predictors of final necrosis. Positive predictive values were 74%, 76%, 78% and 88% resp., sensitivity was 81%, 52.8%, 65% and 86%, resp.; specificity was 59%, 79.3%, 81% and 90% resp.. Nonseminomatous elements demonstrated a significantly higher staining intensity for hMLH1 than seminomas, whereas staining intensity for hMLH2 was lower (p=0.03). IHC for hMLH1/2 of GCT with necrosis was higher as compared to GCT exhibiting mature teratoma or vital cancer approaching statistical significance (p=0.07). Conclusions: Pre-chemotherapy AFP levels < 15 ng/ml and a residual mass < 2 cm are associated with a favourable histology in the RTR specimen. The addition of mdr-1 expression in the primary NSGCT improves sensitivity to 88% and represents a clinically useful prediction marker. No significant financial relationships to disclose.
Results with salvage chemotherapy with high dose carboplatin + etoposide and peripheral blood stem cell transplant in male choriocarcinoma
Authors: Brames M. , Papiani G. , Einhorn L. 
Published: March 2020

5091 Background: Choriocarcinoma in males is seen usually as a small component of a mixed germ cell tumor. Pure choriocarcinoma accounts for a poor prognosis, usually presenting with high level of human chorionic gonadotropin (hCG > 50,000 mIU/ml) and with pulmonary and non-pulmonary visceral metastases. Results with salvage chemotherapy in the past have been very poor with very few long-term survivors. Methods: Retrospective review of 184 germ cell patients treated with salvage high dose chemotherapy (HDCT) at Indiana University between 2–96 and 12–04 was presented (Proc Amer Soc Clin Oncol 24:228, abstract 4549, 2006). Thirteen of these patients had pure choriocarcinoma of the testis or choriocarcinoma syndrome (normal testes by palpation and ultrasound, normal serum alpha-fetoprotein, advanced hematogenous metastases, high level of hCG). Before HDCT, all the patients were treated with one or two regimens of standard cisplatin combination chemotherapy. HDCT regimen consisted of carboplatin 700 mg/m2 and etoposide 750 mg/m2 i.v. given for 3 consecutive days. A second course was given after hematologic recovery. Results: Toxicity was previously described (JCO 18:3346, 2000).The median survival was 19 months (range 5–90 months). Six patients (46%) are alive and continuously disease-free (cNED) with a median follow-up of 37 months (range 19–75). One additional patient is currently NED following subsequent chemotherapy and surgery. 3 of 7 patients with pure choriocarcinoma are cNED and 3 of 6 with choriocarcinoma syndrome are cNED. Six of 10 patients receiving HDCT as initial salvage therapy are cNED compared to 1 of 3 as third-line treatment. Conclusions: Salvage HDCT offers long-term disease-free survival and potential cure in patients with pure choriocarcinoma or choriocarcinoma syndrome that progressed after standard cisplatin combination chemotherapy. No significant financial relationships to disclose.
Phase I/II study of sunitinib malate in combination with gefitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: Patel P. H. , Kondagunta G. V. , Redman B. G. , Hudes G. R. , Kim S. T. , Chen I. , Motzer R. J. 
Published: March 2020

5097 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGF- and PDGF- receptors with substantial antitumor activity against mRCC (JAMA 2006;295:2516). This study was conducted to evaluate the safety and efficacy of sunitinib in combination with gefitinib, an EGF-receptor inhibitor. Methods: Eligibility included mRCC with clear cell component. The phase 1 part of the study was conducted to determine the maximum tolerated dose (MTD) of sunitinib in combination with gefitinib, and subsequently pts were enrolled in the phase 2 part to further evaluate safety and antitumor activity. Pts were treated with sunitinib at assigned dose level (37.5 mg or 50 mg) orally daily for 4 weeks on, followed by 2 weeks off (Schedule 4/2) and gefitinib at 250 mg daily. The primary endpoint for the phase 2 part of the study was objective response according to RECIST. Results: Forty-two pts were enrolled; 11 pts in phase 1 and 31 pts in phase 2. Median age was 65 years (range: 29–78) and 35 pts (83%) had =2 metastatic sites. Twenty-eight pts (67%) had prior cytokine therapy, 11 pts (26%) had no prior cytokine therapy, and 3 pts (7%) received prior vaccine therapy. Two dose limiting toxicities (DLTs) were observed at the 50-mg dose level (grade 3 fatigue and grade 2 ejection fraction decline), and 37.5 mg on Schedule 4/2 in combination with gefitinib 250 mg daily was determined to be the MTD. The median duration on treatment was 8.3 months for phase 1. Thirty-six pts are evaluable for response and 6 are too early. Eleven pts (30%) achieved a partial response and 15 pts (42%) stable disease. The most common grade 3 treatment-related adverse events observed in phase 1 were diarrhea and nausea (n=2) and for phase 2 were diarrhea (10%) and gastrointestinal hemorrhage (6%). Two pts from phase 2 were withdrawn from the study due to treatment-related adverse event; ejection fraction decline and cardiac arrhythmia, both of which were reversible after treatment discontinuation. Conclusions: The study established dose and feasibility for sunitinib in combination with gefitinib. Early evaluation of the data suggests tolerability for the combination and relative efficacy data compared to sunitinib monotherapy will be assessed with longer patient follow-up. No significant financial relationships to disclose.
A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)
Authors: Jac J. , Giessinger S. , Khan M. , Willis J. , Chiang S. , Amato R. 
Published: March 2020

5107 Background: RAD001 is an oral mammalian target of Rapamycin (mTOR) inhibitor. Three mechanisms of anti-tumor activity; shuts down tumor response to nutrients and growth factors; cell cycle arrest at late G1 and anti-angiogenesis via VEGF. Molecular alterations in the mTOR modular pathway increase sensitivity in PTEN deficient tumors such as RCC. Endpoints: time-to-progression (TTP), response rate (RR), overall survival (OS), toxicity, and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included; predominant clear cell, progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) = 2, no more than 1 prior therapy, and no active CNS involvement. RAD001 is given orally at a dose of 10mg daily without an interruption (28-day cycle), with dose modifications for toxicity. Re-evaluation was assessed every 2 cycles (8 weeks). RECIST criteria is utilized. TTP and OS are determined from entry into the study. Results: 41 pts have been enrolled. 37 pts are evaluable for response/toxicity. 2 pts toxicity only. 2 pts screened failures. 31 were male/8 female, median age 60 (38–80) years. 31 pts received prior therapy. 23 pts had a ZPS of 0, 13 /1 and 3/2. Sites of disease included; lung, nodal, liver, bone, adrenal, and kidney. 9 pts had 1 metastatic site, 17 pts/2 and 13 pts/3 or more. 15 pts continue to receive RAD001. 12 pts had partial responses, 19 pts were stable for 3+ months. Median duration of therapy is 8+ (range 01–20+) months. Treatment related adverse events; mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, hypertriglyceridemia, hypercholesterolemia, thrombocytopenia, anemia and elevated LFTs. PET scans have demonstrated decreased metabolic activity in responding or stable pts. Median overall survival is 11.5+ months (range 01–20+). Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC demonstrated by partial response rate. Anti-tumor activity is further suggested by prolonged TTP =3 months. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented. An additional 40 pts who failed prior sunitinib or sorafenib therapy are being enrolled. No significant financial relationships to disclose.
A consensus prognostic factor model for survival in patients with metastatic renal cell carcinoma: A Kidney Cancer Association’s International Kidney Cancer Working Group (IKCWG) study
Authors: Royston P. , Bacik J. , Elson P. , Manola J. B. , Mazumdar M. 
Published: March 2020

5109 Background: Numerous well-designed retrospective studies of prognostic factors (pf) for survival (S) in metastatic renal cell carcinoma (mRCC) patients (pts) have been conducted since 1986. However, no single model for describing S in this population has been universally accepted. Methods: Authors of several existing prognostic indices, and others, formed the IKCWG to develop a single validated S model. The IKCWG has established a comprehensive database of previously reported clinical pf from 3748 previously untreated mRCC pts entered on institution review board approved clinical trials conducted by 11 centers in Europe and the United States from 1975–2002. Results: Median age at study entry was 58, 70% of pts were male, 89% had ECOG performance status (PS) 0 or 1; 75% had prior nephrectomy. 72%, 30%, and 19% of pts had lung, bone, and liver metastases (mets), respectively. 72% received interferon-a and/or interleukin-2 based treatments (tx); 25% were txd with chemotherapy/hormones only; 3% received other tx. 88% of pts have died; median S was 11.1 months (m). All examined factors except sex, age, and histology impacted S at p<.001 in univariable analysis. Multivariable analysis using a log-logistic model stratified by center and multivariable fractional polynomials was performed to identify independent predictors of S. Missing data were handled using multiple imputation methods. Using p=.0044 as the criterion for variable selection to avoid overly complex models, a model comprising tx, PS, number of met sites, interval from diagnosis to tx, and pre-tx hemoglobin, WBC, LDH, alkaline phosphatase and calcium was identified. The 25th and 75th percentiles of the prognostic index formed by multiplying each factor by its regression coefficient were used as cutpoints to form three risk (r) groups with median S times (SE) of: favorable r (n=937; 27.8 (0.4) m), intermediate r (n=1874; 11.4 (0.2) m), and poor r (n=937; 4.1 (0.1) m). Conclusions: 9 clinical factors can be used to model S in mRCC and form 3 distinct prognostic groups. Additional model building to determine if model complexity can be reduced further, validation in independent data and comparison to existing prognostic models are underway. No significant financial relationships to disclose.
Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer
Authors: Perez E. A. , Romond E. H. , Suman V. J. , Jeong J. , Davidson N. E. , Geyer C. E. , Martino S. , Mamounas E. P. , Kauffman P. A. , Wolmark N. 
Published: March 2020

512 Background: The joint efficacy analysis of NCCTG N9831 and NSABP B-31 demonstrated improved outcomes with the addition of trastuzumab (H) to doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) in women with surgically removed HER2- positive breast cancer (NEJM 2005). Following this report, patients randomized to AC→T and less than 6 months from completion of chemotherapy were eligible to receive H. We have updated the initial combined results of these two trials. Methods: Primary and secondary efficacy endpoint were disease free survival (DFS) and overall survival (OS). Cox modeling was performed. Hazard ratios are adjusted for nodal status, tumor size, T schedule, hormone receptor status, and trial (also age for OS). Results: Among the 3,969 women enrolled (ages: 22 to 80yrs), there have been 619 events (H group: 222, non-H: 397). First events were: recurrence (511), contralateral breast disease (18), other second primary cancers (48), and death without recurrence or second primary cancers (42). The median follow-up among the 3,711 women still alive is 2.9 years (range up to 6,4 years). The 4 yr DFS rate and 4 yr OS rate respectively were: 85.9% (95%CI: 84.0–87.8%) and 92.6% (95%CI: 91.2–94.2%) in H group and 73.1% (95%CI: 70.6–75.8%) and 89.4% (95%CI: 87.6–91.2%) in non- H group. Hazard ratio for adjuvant (H/non-H) was 0.49 (P<0.0001; 95%CI: 0.41–0.58) for DFS and 0.63 (P=0.0004; 95%CI: 0.49–0.81) for OS.The rates of a first event per 1,000 women/year during yrs 1–4 were: 26.7, 52.9, 49.6 and 23.2 for H and 42.3, 102.3, 107.6 and 61.5 for non-H. The impact of crossover on clinical outcome will be explored. Conclusions: With an increase in the median follow-up of 11 months and with 225 additional events, the demonstration of substantial improvement in outcomes with the addition of trastuzumab to chemotherapy persist. This improvement continues in spite of some degree of cross-over occurring after the initial results were reported.Updated data regarding crossover outcomes and H duration (as they relate to disease free survival) will be presented. [Table: see text]
Phase II monotherapy study of YM155, a novel survivin suppressant, administered by 168-hour continuous infusion in previously treated hormone refractory prostate cancer (HRPC)
Authors: Karavasilis V. , Mita A. , Hudes G. , Quinn D. , Ferrari A. , Kocak I. , Keating A. , Bartes P. , Charleston D. , de Bono J. 
Published: March 2020

5135 Background: In a PC-3 tumor cell model YM155 inhibited survivin mRNA transcription and survivin protein expression and showed potent (nM) anti-proliferation activity with strong signs of tumor regression. In a phase I study, two highly refractory HRPC patients exhibited a > 50% reduction of PSA from baseline. Methods: Patients with metastatic HRPC who received prior taxane chemotherapy were eligible. The primary endpoint is PSA response rate (decline by ≥ 50%). Other endpoints include objective tumor response by RECIST and evaluation of toxicity. A two stage Simon study design required one response in stage I (N=13) and 3 responses in stage II (N=14). If 4 responses are achieved then an additional 33 pts (N=60) will be enrolled to further characterize the efficacy and safety. Patients are considered evaluable if they complete 2 cycles. YM155 is given as a 168 hour continuous infusion every three weeks (1 cycle) at a dose of 4.8 mg/m2/day. Results: First two stages are enrolled with treatment ongoing. Data on 32 pts is provided. Median age is 67 y/o (range 53 - 81) with ECOG PS of 0 - 2. All but one patient received at least one prior taxane containing regimen. Two patients are PSA responders to date. One achieved response at cycle 2 (currently at cycle 3) and one at cycle 6 (currently at cycle 10). The median number of cycles is 3 (range 1 - 10). Two patients discontinued due to adverse events; in only one patient was the event (fever) considered related to study drug. Five/32 patients reported grade 3, 4, or 5 AE considered related to drug (coagulopathy secondary to coumadin therapy followed by intracranial hemorrhage, fatigue, URI, decreased Hgb, thrombocytopenia). Seven/32 patients remain on drug including the two responders. Conclusions: The preliminary data of YM155 in HRPC demonstrates activity and has an acceptable toxicity profile. No significant financial relationships to disclose.