bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of sunitinib malate (SU11248) in combination with gefitinib in patients with metastatic renal cell carcinoma (mRCC)
Authors: Ronnen E. A. , Kondagunta G. V. , Lau C. , Fischer P. , Ginsberg M. S. , Baum M. , Kim S. T. , Chen I. , Baum C. M. , Motzer R. J. 
Published: March 2020

4537 Background: Sunitinib malate (SU11248) is an oral multitargeted tyrosine kinase inhibitor of VEGF and PDGF receptors. Two phase II trials with sunitinib given as second line therapy in patients with mRCC showed a ≥40% response rate (JCO 2006;24:16–24; Proc ASCO 23,380s). Combining sunitinib and gefitinib (an EGFR inhibitor) may enhance antitumor activity by providing a broader spectrum of tyrosine kinase inhibition. The maximum tolerated dose (MTD) of sunitinib in combination with gefitinib was assessed in this Phase I trial. Methods: Patients with mRCC previously treated with cytokine therapy were enrolled in the study. Cohorts of 4–6 patients received escalating doses of sunitinib and a fixed dose of gefitinib. Dose levels of sunitinib were 37.5 mg and 50 mg. Dose limiting toxicity (DLT) was defined as Grade 4 hematologic toxicity, Grade 3 nonhematologic toxicity of ≥7 days or a Grade 2 cardiac toxicity. Six-week treatment cycles comprised of sunitinib daily for 4 weeks followed by 2 weeks off and continuous gefitinib at 250 mg daily except in Cycle 1 where gefitinib was begun on Day 10. Results: In the first dose level (n=4, 37.5 mg of sunitinib and 250 mg of gefitinib), no DLTs were observed. In the second dose level (50 mg of sunitinib and 250 mg of gefitinib), there were 7 patients enrolled, but 1 patient had dose reduction for hypertension during the sunitinib monotherapy part of the study and was not included in the cohort defining MTD. 2 of 6 patients experienced a DLT (Grade 2 decline in ejection fraction, persistent Grade 3 fatigue) and the MTD was determined as 37.5 mg of sunitinib with 250 mg of gefitinib. Grade 3 adverse events included: diarrhea (n = 2) and hand/foot syndrome (n = 2). Laboratory abnormalities included grade 4 neutropenia (n = 1), grade 3 neutropenia (n = 2), and grade 3 thrombocytopenia (n = 2). Overall, 5 of 11 patients demonstrated a partial response and patient accrual to the phase 2 portion of the study is underway. Conclusions: The combination of sunitinib and gefitinib in mRCC patients was well tolerated and MTD was determined. The efficacy and toxicity of this combination is being assessed in a phase II component of this trial. [Table: see text]
Self-reported paresthesias, Raynaud’s phenomena, tinnitus, and hearing impairment in a large cohort of long-term testicular cancer (TC) survivors
Authors: Brydoy M. , Oldenburg J. , Klepp O. , Bremnes R. M. , Wist E. , Dahl O. , Fossa S. D. 
Published: March 2020

4547 Background: Persisting side-effects of treatment may impair the well-being of TC survivors. The aim of this study was to assess long-term Raynaud’s phenomena, oto-, and neurotoxicity related to prior therapy. Methods: A follow-up survey was conducted in men treated for TC 1980–1994 in Norway. The 1319 eligible responders had a median follow-up time of 11 years (range 4–21) and were allocated to four separate treatment groups: Surgery (Surg), Radiotherapy (Rt), and chemotherapy (Cisplatin [Cis] ≤ 850 mg and Cis > 850 mg). The questionnaire included six items assessing the relevant toxicities. The responders’ scores were dichotomized [minor (“not at all” or “a little”) vs. major (“quite a bit” or “very much”)] and analyzed by logistic regression with Surg as reference. Results: The proportion of cases (%) reporting major symptoms and the corresponding Odds ratios (OR) varied significantly between treatment groups ( table ). Rt was not statistically significantly different from Surg for any symptom, but showed a trend for higher scores of paresthesias in the feet. Cis > 850 mg differed significantly for all symptoms with major symptoms reported by 25–49% with the highest OR (8.1) for Raynaud’s phenomena in hands. Apart from Raynaud’s phenomena, paresthesias in feet were the only symptom significantly different in Cis < 850 mg compared to Surg. Conclusions: Toxicities induced by cisplatin-based chemotherapy persist in many TC survivors. A cold climate may contribute to the high perception of Raynaud’s phenomena in Norwegian TC survivors. [Table: see text] No significant financial relationships to disclose.
Chemo-hormonal therapy for biochemical progression of prostate cancer
Authors: Taplin M. , Xie W. , Morganstern D. , Bubley G. , Ernstoff M. , Regan M. 
Published: March 2020

4559 Background: Androgen deprivation therapy (ADT) is effective for relapsed prostate cancer, but is rarely curative. The purpose of this trial was to determine the feasibility, toxicity and PSA response of chemotherapy and ADT for men with PSA relapse. Methods: Eligible men had a rising PSA and no metastases after prostatectomy and/or radiation for localized disease. Treatment consisted of four cycles of docetaxel (70 mg/M2) every 21 days and estramustine 280 mg three times daily on days 1–5. After chemotherapy, goserelin acetate and bicalutamide 50 mg daily were prescribed for 15 months. Results: Sixty-two patients were enrolled at four institutions: median age 65 (range 49–78), median PSA 3.01 ng/mL (range 0.08–47.04), 24% Gleason 8–10. A complete PSA response (CR) was defined as PSA at or below assay-specific lower limit (0.01–0.2 ng/mL). The proportion of patients with CR after chemotherapy, after ADT and at one year off ADT was 53%, 63% and 36%. Testosterone was > 100 ng/dL (median 250 ng/dL) one year off ADT in 97%. Patients with a PSA < 3.0 ng/mL had a significantly longer time to progression (p-value 0.0002). At the time of last follow-up 24/56 (43%) who are at least one year off ADT have not progressed. Median TTP is 34 months from treatment initiation (maximum 74 months free from progression). Toxicity was manageable with no toxic deaths: there were 4 thromboses on chemotherapy and 38% of cycles were associated with grade III/IV neutropenia with 5 cases of documented infections. Conclusion: Chemotherapy prior to hormone therapy was feasible for early prostate cancer relapse. Forty-three percent of men who are at least one year off ADT with recovered testosterone have not progressed. This approach is being tested in a randomized trial with investigation of predictors of response. No significant financial relationships to disclose.
Preliminary results of a randomized placebo-controlled double-blind trial of weekly docetaxel combined with imatinib in men with metastatic androgen-independent prostate cancer (AIPC) and bone metastases (BM)
Authors: Mathew P. , Thall P. F. , Johnson M. M. , Oh W. K. , Meluch A. A. , Morris M. J. , Troncoso P. , Bucana C. D. , Fidler I. J. , Logothetis C. J. 
Published: March 2020

4562 Background: To further examine preclinical (Uehara, JNCI 2003) and clinical (Mathew, JCO 2004) evidence that the platelet-derived growth factor receptor (PDGFR) inhibitor, Imatinib, may modulate taxane activity in AIPC with BM, a randomized trial was conducted. Methods: 144 men with progressive AIPC with BM, no prior taxane, ECOG Performance Score (PS) ≤ 2, stratified by PS, hemoglobin, alkaline phosphatase and number of prior regimens, were planned for equal randomization to i.v. Docetaxel 30mg/m2 D 1, 8, 15, 22 q42 + Imatinib 600 mg daily (DI) or placebo (DP) for an improvement in time-to-progression (TTP) from 4.5 to 7.0 months (two-sided α = 0.05,β = 0.20). Secondary endpoints included toxicity, tumor response and phospho-PDGFR expression. An IRB review of gastrointestinal adverse events led to a recommendation to halt accrual early. Results: 104 evaluable men (52/arm) accrued between April 2003 and July 2005 were followed for a median of 7 months (range 0.5–23.4). The median TTP was 4.4 months (95% CI: 3.2–8.7) for DI and 5.3 months (95% CI: 3.4–11.3) for DP (p = 0.49, log-rank test). Median overall survival was 21.3 months for DI and not attained for DP (p = 0.56). Partial response was observed in 11 (3 DI, 8 DP), stable disease in 23 (14 DI, 9 DP), progressive disease in 56 (27 DI, 29 DP). Excess Grade 3 AEs with DI were principally fatigue (16 vs 6), gastrointestinal (11 vs 6), and arrhythmia (5 vs 1). Five cases of perforated sigmoid diverticulitis (4 DI, 1 DP; one death) were associated with high-dose steroid use (Fisher’s exact test p < 0.0001). Expression of phospho-PDGFR on tumor cells (≥2+ intensity) was established by immunohistochemistry in 12/14 (86%) of informative bone marrow biopsies. After cross-over to DI from DP, 5/23 (22%) patients were progression-free at 12 weeks without partial response. Conclusion: Notwithstanding the likely high prevalence of activated PDGFR in AIPC BM, Imatinib does not detectably modulate Docetaxel activity and excess toxicity was noted in this population. In-vivo monitoring of p-PDGFR and bone markers will qualify these findings. [Table: see text]
A blinded, randomized controlled trial of neo-adjuvant celecoxib in patients with early prostate cancer
Authors: Sooriakumaran P. , Macanas-Pirard P. , Fox S. , Coley H. , Bucca G. , Lovell D. , Henderson A. , Smith C. , Langley S. , Laing R. 
Published: March 2020

4563 Background: Celecoxib inhibits tumorigenesis in many in vitro and in vivo models by anti-angiogenesis, induction of apoptosis, and inhibition of tumour cell proliferation and hypoxia. Methods: 45 cT1–2 prostate cancer patients were block randomized 2:1 to four weeks celecoxib 400mg b.d. or no drug prior to radical prostatectomy (RP). Tumour immunohistochemistry was performed for cell proliferation (Ki-67), angiogenesis (CD-31, VEGF, VEGF-R2), hypoxia (HIF-1), apoptosis (TUNEL), and COX-2. All scoring was performed blind by PS and a random 20% were validated blindly by an immunopathologist (SBF). In 19 patients (12 celecoxib-treated, 7 control), peri-operative peripheral zone biopsies were subjected to cDNA microarray analysis to identify differences in gene expression profiling (GEP) between the groups. Results: There was ‘substantial’ (kappa >0.6) or ‘almost perfect’ (kappa >0.8) inter-observer agreement in immunoscoring for all stains. Baseline scores were not significantly different between the celecoxib and control groups. In the celecoxib group, RP scores were significantly lower for Ki-67 (p = 0.036), and non-significantly lower for hypoxia (p = 0.15), KDR (p = 0.16), COX-2 (p = 0.19), microvessel density (p = 0.53), and VEGF (p = 0.83); tumour apoptosis was non-significantly higher (p = 0.26). MANOVA of the full model of stains showed that the difference between the two groups approached statistical significance (p = 0.058), and this was visualized with principal component analysis. GEP revealed that 76 genes were significantly differentially expressed between the celecoxib and control groups using uncorrected t-tests. In the celecoxib group, the tumour suppressor gene p73 and genes associated with protection against oxidative stress were significantly up-regulated; genes associated with cell adhesion were significantly down-regulated, consistent with a reduction in metastatic potential. Conclusions: Celecoxib appears to have marked anti-cancer effects on prostate tumours, most notably affecting cell cycle regulation, oxidative stress, and cell signalling. It may therefore be a promising agent in the management of prostate cancer and warrants further investigation. No significant financial relationships to disclose.
Impact of the radical prostatectomy surgical technique and surgeon experience on freedom from cancer recurrence
Authors: Bianco F. J. , Eastham J. A. , Vickers A. J. , Serio A. M. , Pontes J. , Kline E. A. , Scardino P. T. 
Published: March 2020

4569 Background: We have shown a direct relation between positive margin (PM), morbidity outcomes and surgeon volume, technique after radical prostatectomy (RP). Significant variation occurs even among high volume providers. Our aim was to analyze the surgeon effects on cancer control after RP. Methods: We evaluated 8196 consecutive cT1–3NxMx naive men who underwent RP by one of 76 surgeons within 4 institutions between 1987 and 2003. We calculated the 5-yr probability of recurrence (BCR, PSA elevation >0.4 ng/ml × 2 or initiation of secondary therapy for a PSA rise) for each surgeon assuming a log-logistic survival distribution. A meta-analysis controlling for case mix: PSA, Gleason score, stage, PM and surgical expertise (i.e. cumulative number of surgeries performed) to evaluate for differences in BCR rates between surgeons was performed. We applied the I-square statistic to determine what proportion of the variation represented genuine differences v. chance alone. Results: 33 surgeons performed > 40 RP with 17 surgeons having > 100 procedures during the study period. BCR events were recorded in 1361 patients. The overall 5-yr freedom from BCR with 2524 patients remaining at risk was 80% (79%, 81%) . Extracapsular extension, seminal vesicle invasion, nodal metastasis, PM, Gleason score and PSA were independent predictors of BCR. The surgical volume also correlated independently with BCR. Importanntly we found significant variability on freedom from BCR between high volume surgeons. The I-squared statistic from the meta-analysis was 0.63. That is, approximately 63% of the difference in BCR rates among surgeons can be explained by genuine differences in surgical skill and approach, and approximately 37% is compatible with chance alone. For a sensitivity analysis, we repeated the analysis excluding surgeons who performed less than 100 procedures. In this sub-analysis, the I-squared statistic remained very significant at 0.48. Conclusions: Our data shows that in men treated by RP, the BCR outcomes of men are not exclusively determined by the biology and stage of prostate cancers (explained in most models), but to the surgical skill. Clinical trials evaluating BCR outcomes must prove equivalency among providers so that results are not biased by them. No significant financial relationships to disclose.
Clinical impact of disseminated tumor cells in patients with non-metastatic prostate cancer treated by definitive radiotherapy
Authors: Berg A. , Berner A. , Lilleby W. , Bruland Ø. S. , Fosså S. D. , Nesland J. , Kvalheim G. 
Published: March 2020

4575 Background: Detection of disseminated tumor cells (DTCs) in bone marrow (BM) has been proven to be an independent prognostic factor in breast cancer. To our knowledge, we here present the first larger study of radically treated prostate cancer (PC) with sufficiently long-term follow-up where the association between DTCs at diagnosis and clinical outcome has been studied. Methods: We screened 272 cT1–4pN0M0 PC patients for DTCs in BM-aspirates between 1994 and 2004. Monoclonal antibodies against cytokeratins (AE1/AE3) and standardized immunocytochemical methods were applied for detection. BM-status was compared with clinical and histopathological factors at diagnosis in all patients and with long-term clinical outcome in 131 patients. They all started treatment including definitive radiotherapy (RT) before June, 2000 and had a relatively poor prognosis defined as cT3–4 or Gleason score (GS) ≥ 7B (4 + 3) or PSA ≥ 10 μg/l. Kaplan-Meier plots were generated by BM-status with the following end-points: Overall death, cause-specific death, distant metastases (DM) as first clinical relapse, local failure as first clinical relapse and biochemical failure. Results: DTCs were detected in 18% of the patients and were significantly associated with increasing percentage Gleason grade 4/5 (p = .035, Mann-Whitney) but not with dichotomized GS, tumor-stage or PSA. In the follow-up cohort (median observation time 6.9 years), the 7-year cumulative risk of DM was 21% in BM-positive patients vs. 6% in BM-negative patients (p = .069, log rank). No association was found between DTCs and other end-points. A sub-group analysis of 73 patients with GS ≥ 7B yielded a 34% 7-year cumulative risk of DM in BM-positive patients vs. 10% in BM-negative patients (p = .039, log rank). DTCs did not predict DM in 55 patients with GS ≤ 7A (3 + 4). In a multivariate analysis, dichotomized GS (RR = 7.8 [95% confidence interval (CI) = 1.0–60.7], p = .049) and BM-status (RR = 3.0 [95% CI = .9–9.4], p = .066) had independent impact on DM. Conclusions: The presence of DTCs in BM at diagnosis of non-metastatic PC is associated with the histological differentiation of the primary tumor and seems to predict development of DM after definitive RT. No significant financial relationships to disclose.
Can patients (pts.) with refractory germ cell tumors (GCT) be cured after progression following high dose chemotherapy (HDCT) with tandem transplant? Results with paclitaxel + gemcitabine
Authors: Lewis D. A. , Brames M. J. , Einhorn L. H. 
Published: March 2020

4588 Background: A previously published ECOG study of paclitaxel (P) plus gemcitabine (G) in refractory germ cell tumors achieved a 21% response rate (6 of 28 pts.) (JCO 20:1859, 2002). Two patients are continuously NED for 4+ years. Neither had prior HDCT. High dose salvage chemotherapy with carboplatin + etoposide and peripheral blood stem cell transplant has curative potential. Subsequent chemotherapy after progression following HDCT has only rarely achieved durable remission. We have retrospectively reviewed pts. treated at Indiana University with P + G after failure to cure with initial cisplatin combination chemotherapy and salvage HDCT (± other salvage regimens). Methods: 184 patients received salvage HDCT from February 1996 to December 2004. After further progression, 33 pts. were treated with P 100 mg/M2 over 1 hour and G 1000 mg/M2 over 30 minutes days 1, 8, and 15 every 4 weeks for a maximum of 6 courses. Pts. were ineligible if they received prior P or G. 26 pts. received P + G as 3rd line, 6 as 4th line and 1 as 5th line chemotherapy. Results: Toxicity was primarily myelosuppression and neuropathy, as previously described with P + G (JCO 20:1859, 2002). There was no treatment related mortality. 10 of 33 pts. achieved objective response including 4 partial (2 to 6 months duration) and 6 complete responses (C.R.). 4 of the 6 C.R.s are continuously NED with P + G alone at 14+, 34+, 44+, and 45+ months from start of P + G. One additional C.R. is currently NED 54+ months after P + G, with 2 subsequent resections of carcinoma. Conclusions: Long-term disease free survival and potential cure is possible with P + G in this patient population after progression following HDCT. [Table: see text]
The familial influence on bilateral testicular germ cell cancer: Medical Research Council study TER2
Authors: Harland S. J. , Daugaard G. , Horwich A. , Mead G. M. , Fossa S. D. , Sokal M. , Morgenstern D. , Oliver R. , Cook P. A. , Stenning S. P. 
Published: March 2020

4590 Background: There is evidence that hereditary predisposition is important in the aetiology of testicular cancer but the mode of inheritance is unknown. Methods: To test the hypothesis that bilateral disease (5% of testis cancer) is a manifestation of hereditary predisposition, a family questionnaire was sent to patients with bilateral disease (cases) and responses compared with institutional controls with unilateral disease (two approached for every case), matched for year of first diagnosis. The primary outcome measure was the risk of testis cancer in the brothers of cases and controls, and a relative risk of between 4.1 and 5.0 was anticipated based on the model of Nicholson and Harland (BJC 1995 71:421–426). Results: Responses from 191 cases and 373 controls have been analysed. No evidence of reduced fertility was found in the parents or grandparents of cases compared to those of controls. Cases (48%) were less likely to have children than controls (64%). The mean (SD) age of onset of testicular cancer was lower in cases (31 (9)) than controls (35 (9)), p < 0.001. The incidence of testis cancer in the relatives of cases and controls are shown in the table . Conclusions: The 4.6-fold greater risk to brothers of cases confirms the role of a familial predisposition in bilateral testicular cancer. Given the incomplete ascertainment for brothers, there is likely to be a greater risk to brothers than fathers. No major effect of an X-linked gene is found. These findings are in keeping with previously described hereditary models for testicular cancer. [Table: see text] No significant financial relationships to disclose.
Bevacizumab, erlotinib, and imatinib in the treatment of patients with advanced renal cell carcinoma: Update of a multicenter phase II trial
Authors: Thompson D. S. , Greco F. A. , Spigel D. R. , Sosman J. A. , Burkett E. , O’Rourke T. J. , Hart L. , Hainsworth J. D. 
Published: March 2020

4594 Background: Most patients with clear cell RCC have loss of von-Hippel-Lindau (VHL) gene function, ultimately leading to overexpression of VEGF, transforming growth factor (TGF-α), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). In this phase II trial, we evaluate the combination blockade of VEGF, and the EGF and PDGF receptors as treatment for metastatic RCC. Methods: Eligibility: metastatic clear cell RCC; 0–2 previous systemic regimens; ECOG PS 0–1; no previous anti-angiogenesis or EGF receptor inhibitor therapy; no active CNS metastases; adequate organ function; no history of thromboembolic disease; informed consent. All patients received bevacizumab 10 mg/kg IV q 2 wks, erlotinib 150 mg PO daily, and imatinib 400 mg PO daily. Patients were evaluated for response after 8 weeks; treatment continued until tumor progression. Results: 92 patients entered this trial between 6/04 and 4/05. Pertinent clinical characteristics: no previous systemic treatment, 71%; Motzer prognostic category low/intermediate/high 47%/50%/3%. 84 patients (91%) received at least 8 weeks of therapy. Objective responses were seen in 11 patients (12%); an additional 52 patients (57%) had stable disease/minor response at first reevaluation. After a median follow-up of 11 months, projected median and 1-year progression-free survivals are 9 months and 40%, respectively. One-year overall survival is 62%. The addition of imatinib to bevacizumab/erlotinib added substantial toxicity. Grade 3/4 toxicity included: diarrhea, 48%; skin rash, 27%; fatigue, 23%; nausea/vomiting, 20%. 2 patients discontinued treatment as a result of toxicity; all patients who received treatment for > 8 weeks required dose reductions of imatinib and/or erlotinib. Conclusions: The addition of imatinib, a PDGF receptor inhibitor, to bevacizumab/erlotinib does not appear to substantially improve the efficacy of the 2-drug combination. This 3-drug combination produced moderate to severe toxicity in the majority of patients, primarily exacerbations of diarrhea, fatigue, and skin rash. Further development of this 3-drug regimen is not recommended. [Table: see text]