bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of epidermal growth factor receptor (EGFR) mutation, immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) in esophageal squamous cell carcinoma (ESCC)
Authors: Sunpaweravong P. , Suwiwat S. , Sunpaweravong S. , Puttawibul P. , Varella-Garcia M. , Mitarnun W.
Published: March 2020

4085

Background: ESCC remains a devastating cancer in Southern Thailand and novel therapeutic approach needs to be explored. EGFR tyrosine kinase (TK) inhibitor is a potential therapeutic agent against EGFR-expression tumors including ESCC. Forty-nine percent of ESCC patients in our institution overexpressed EGFR protein and 15% had EGFR gene amplification as published previously. Mutations within EGFR TK domain, particularly in exon 19 and 21, EGFR amplification or polysomy, and EGFR overexpression on IHC have all been associated with sensitivity and benefit to EGFR inhibitor treatment. To our best knowledge, no data on EGFR mutations in ESCC have been reported. This prompted us to perform analysis of EGFR mutations and correlate the status of each of these characteristics in ESCC. Methods: We studied 35 patients with ESCC whose data on EGFR IHC and FISH were available. DNA extraction was performed using a QIAamp DNA Kit. PCR for EGFR detection, using the oligonucleotide primers for amplification of exon 19 and 21, was sequenced and analyzed, using ABI Prism 377 sequencing analysis system and the Big Dye Terminator V3.0 Ready Reaction Cycle Sequencing Kit (ABI Prism). Results: Among 35 ESCC specimens evaluated, no EGFR somatic mutations in exon 19 or 21 were detected. Conclusions: EGFR mutations in exon 19 and 21 of ESCC were not identified in this study. EGFR overexpression and amplification do not correlate with EGFR mutation in Thai patients with ESCC. A clinical study of an EGFR inhibitor in esophageal carcinoma has been going on in our institution and the molecular markers as predictive factors need to be further evaluated and correlated with treatment outcome.

No significant financial relationships to disclose.
Clinical and molecular evaluation of patients with esophageal adenocarcinoma from the United States and Japan
Authors: Gibson M. , Orita H. , Brock M. , Xu L. , Yang S. , Heitmiller R. , Herman J. , Gabrielson E. , Forastiere A.
Published: March 2020

4087

Background: Esophageal adenocarcinoma (EAC) is more common than squamous cancer (ESC) in the US versus Japan (J); however, EAC in J is now more frequently recognized. We assessed features of EAC in J and US patients to determine if the cohort of EAC in Japan is similar to the US. Methods: Patients with EAC who underwent primary curative surgery were identified by reviewing all surgical cases from 1998 to the present at Johns Hopkins Hospital (n = 57) and Juntendo University Hospital (n = 20). Clinical variables included: gender, age, pathologic stage, date of surgery and of death. Methylation of APC, E-cadherin, MGMT, ER, p16, DAP-kinase and TIMP3 was determined with methylation specific-PCR for each J patient and compared to historical control US EAC patients. Logistic regression and survival analysis were used to evaluate the relationship between clinical variables and methylation status to outcome in these two patient groups. Results: Age and gender were similar in each cohort. Gender (50M/6F in US; 16M4F p = 0.29). Median age (65.5 in US; 64 in J). Path stage was lower in US patients but not significant compared to J patients. Stage distribution US: stage I (n = 30), IIA (n = 2), stage IIB (n = 6), stage III (n = 9) and stage IV (n = 4). Stage distribution in J: stage I (n = 6), IIA (n = 5), stage IIB (n = 5), stage III (n = 3) and stage IV (n = 3). Path stage unavailable in 5 US patients. Overall median survival was 4.2 years. Median survival for US was 2.9 years but not reached for J (note 15/20 J patients outcome not known). For the combined cohort, age and path stage (adjusted for clinical co-variates) correlated with worse survival. Age HR 1.05; 95% CI 1.01–1.09. Pathologic Stage HR 1.4; 95% CI 1.19–1.65. These were also predictive within each subgroup. The fraction of patients with methylation is available for three genes: APC (66% US; 70% J). p16 (39% US; 20% J). MGMT (63% US; 75% J). Conclusions: Clinical data are similar for US and J patients with EAC. Early stage in US patients may by due to induction chemoRT in the US. Predictors of survival (age and pathologic stage) are also similar. This suggests that EAC is similar in US and J patients, perhaps reflecting similar environmental and molecular causes. Methylation data for all 7 genes and their correlation with outcome will be presented at the meeting.

No significant financial relationships to disclose.
KRAS mutation analysis in patients (pts) with locally advanced pancreatic cancer (LAPC) treated with gefitinib and chemoradiation therapy (CT-RT) in a phase I trial
Authors: Chen H. , Raben D. , Schefter T. , Kane M. , McCarter M. , Olsen C. , McCoy K. , Eckhardt S. G. , Gumerlock P. H.
Published: March 2020

4106

Background: Correlative studies that incorporate biomarkers to rapidly analyze response to new agents are needed. Unique to pancreatic cancer is the high incidence of KRAS mutations (over 90%). This pilot study evaluated plasma KRAS mutations for disease monitoring in LAPC pts treated on a Phase I trial combining CT-RT with the EGFR inhibitor, gefitinib. Methods: DNA was extracted from plasma of 11 pts collected at 3 timepoints: pre-gefitinib, pre-CT-RT, and post-gefitinib+CT-RT. Matched tissue DNA was obtained from 4 pts with available paraffin blocks. KRAS codon 12 mutations were detected using a two-stage RFLP-PCR assay. Cell line controls: Calu-1 (mutant KRAS) and LNCaP (wild-type KRAS). Mutations were confirmed by direct DNA sequencing. Results were related to pt clinical data. Results: KRAS mutations were detected in the pre-gefitinib plasma of 5/11 pts, and in the matched tumor tissue of 3/4 pts. Of the 5 pts with plasma KRAS mutations, 2 pts with no detectable mutant KRAS in the plasma post-gefitinib+CT-RT had overall survival of 8 and 21 months, whereas 2 pts who retained mutant KRAS had overall survival of only 2 and 5 months, and one pt withdrew early. Of the 3 tumor tissues containing mutant KRAS, the mutations were also detectable in the matched plasma in 2 pts (67%). KRAS codon 12 mutations spectrum: 4 GGT→GAT, 2 GGT→GTT and 1 GGT→AGT. Conclusions: Plasma KRAS mutations are readily detectable in LAPC pts, and the clearance or persistence of plasma KRAS mutations after treatments reflected the clinical course in some cases. The use of plasma KRAS mutation as a marker of survival and response will be further assessed in a recently approved phase I trial using a proteasome inhibitor with chemoradiation at the University of Colorado.

No significant financial relationships to disclose.
Phase II study of gemcitabine, capecitabine and bevacizumab for advanced pancreatic cancer (APC) with ECOG PS 0–1
Authors: Javle M. M. , Iyer R. V. , Yu J. , Wilkinson D. Q. , Nava H. R. , Phelan J. T. , Litwin A. M. , Haney J. M. , Gibbs J. F. , Kuvshinoff B. W.
Published: March 2020

4117

Background: Gemcitabine and capecitabine chemotherapy may result in improved survival for patients (pts) with APC and good performance status. Preclinical synergy between these agents and bevacizumab (BV) and encouraging results of angiogenic inhibition in PC formed the rationale for this study. Endpoints: Primary: progression-free survival (PFS), Secondary: response rates, overall survival, toxicity assessment and quality of life (QOL). Methods: Pts with APC (inoperable stage III or IV), ECOG PS 0–1, normal organ and marrow function were eligible. Schema: Avastin 15 mg/kg, q 21 days; capecitabine 650 mg/m2 bid x 14 days, both starting day 1; gemcitabine 1000 mg/m2 days 1 & 8; cycles repeated q 21 days. The study has a power of 0.8 at 0.05 significance level to determine if PFS is ≥ 4.1 months with study regimen (2.5 months with gemcitabine). Results: Twenty-six (of planned 34) pts have been enrolled; 22 pts were evaluable for response (4 too early). Median age 64 years (range 38–79), 12 are male, one stage III, 25 stage IV. Median of 3 cycles/pt (range 1–16) with a total 105 cycles. Responses (RECIST): 7 partial responses (32%; 95% CI: 14%-55%), 12 stable disease, 3 progressive disease. The median PFS is 8.2 months (C.I. 4.7–11.3). Estimated median overall survival is 9.1 months (C.I. 8.3-undetermined). Five% improvement in QOL occurred in 7/15 pts (95% C.I: 21–73%). Grade 3 toxicities: proteinuria (n=1), neutropenia (n=2), thrombocytopenia (n=1), pulmonary embolism (n=2), nausea (n=2), emesis (n=2), diarrhea (n=1), infection (n=1), anemia (n=1) and hemorrhage (n=1). Grade 4 toxicities: neutropenia, cerebrovascular accident and diarrhea (n=1, each). One treatment related death occurred (hemorrhage). Conclusion: In this interim analysis, encouraging response rates, PFS and QOL improvement occurred with the addition of BV to gemcitabine and capecitabine. Toxicity profile is acceptable. Accrual is ongoing. Acknowledgement: Study is supported by a grant from NCCN and by Genentech.

[Table: see text]
Conditional survival in gallbladder carcinoma: Results from the SEER 11 dataset
Authors: Thomas C. R. , Fuller C. D. , Starling G. D. , Wang S. J.
Published: March 2020

4130

Background: Traditionally, survival is reported as 5-or10-yr survival from diagnosis. However, the 5-yr probability of demise changes considerably with each year survived in many cancers. Clinicians may utilize conditional survival to estimate risk over time. Gallbladder cancer is a rare neoplasm with little extant data with regard to risk assessment for patients with one or more years survival post-therapy. The specific aim of this study is to assess the conditional survival of patients with gallbladder adenocarcinoma using data extracted from the Surveillance, Epidemiology, and End Results (SEER 11) Program. Methods: Cumulative observed survival rates were calculated by the life-table method using SEER data for 3744 patients with histologically confirmed gallbladder adenocarcinoma (diagnosed from 1973 to 2001). On the basis of the cumulative survival estimates, we derived the conditional survival, defined as the calculated probability of survival having already survived a specified number of years from diagnosis, with sub-stratification by extent of disease. Results: Conditional survival calculations reveal dismal 5-year survival at diagnosis (Figures 1 and 2), with increasing probability of survival per each year survived. However, conditional survival plateaus at approximately 60–70% at 4 years post-diagnosis, with little change in conditional survival until 10 years. Conclusions: This dataset represents the largest pooled data for gallbladder carcinoma, and is markedly larger than any given institutional series. Consequently, while imperfect, this data represents a useful estimate for patients with considerable post-diagnosis survival. Although the disease-free survival outcomes for patients with gallbladder adenocarcinoma remain low, for those patient surviving even 1 year post-diagnosis, conditional survival estimates increase rapidly.

[Table: see text]

No significant financial relationships to disclose.
New feasibility study design with hepatocellular carcinoma: A phase I/II study of TSU-68, an oral angiogenesis inhibitor
Authors: Kanai F. , Yoshida H. , Teratani T. , Sato S. , Tateishi R. , Obi S. , Yamashita M. , Kawabe T. , Shiina S. , Omata M.
Published: March 2020

4145

Background: Hepatocellular carcinoma (HCC) is a devastating disease with limited treatment options at advanced stages. HCC is a highly vascular tumor in which angiogenesis contributes to its pathogenesis. TSU-68 is an oral anti-angiogenesis compound that blocks VEGFR-2, PDGFR, and FGFR. Methods: This is an open-label phase I/II study to characterize the safety, tolerability, pharmacokinetic (PK) profile and efficacy of TSU-68 at 800mg/po daily in adults with unresectable HCC. Patients (Pts) previously treated with surgery, radiofrequency ablation, transcatheter arterial embolization, chemotherapy, or radiotherapy were eligible. Pts were stratified into three groups based on hepatic function: level 1 (no cirrhosis), level 2 (Childs-Pugh A) or level 3 (Childs-Pugh B). The safety, tolerability and PK of TSU-68 were assessed sequentially from level 1 by enrolling 3 pts in each level. The response was evaluated based on RECIST. Results: 15 pts were enrolled: median age = 67 years (range 53–74 years), male/female = 11/4, cirrhosis/no cirrhosis = 12/3, HCV/HBV/alcohol = 12/2/1. 2 pts at level 3 who received 800 mg/d experienced DLTs (CTC grade 3 abdominal pain and ascites). The dose was reduced to 400 mg/d in an additional 3 pts at level 3 (no DLT observed). The most common adverse events were: hypoalbuminemia, diarrhea, abdominal pain, fever, and AST/ALT elevation. PK data from 12 pts (3 at level 1; 3 at level 2; 6 at level 3) indicated that the area under the curve (AUC) of TSU-68 was similar from level 1 to 3, and biologically active levels of TSU-68 could be reached at a dose of 400 mg/d. One pt had a partial response, 7 pts had stable disease (2 pts for over 12 months) and 7 pts had progressive disease. Tumor necrosis was observed in 8 pts. Conclusions: The study design based on hepatic function is useful to assess the safety of anti-tumor agent in pts with impaired liver function. A dose of 400 mg/d TSU-68 is well tolerated in pts with HCC. While the study is still on going, the preliminary results suggest that TSU-68 has anti-tumor activity against HCC.

No significant financial relationships to disclose.
Endoscopic thermal ablation therapies for hepatocellular carcinoma; multi-center study
Authors: Sakaguchi H. , Seki S. , Iwai S. , Kadoya H. , Ido K. , Isoda N. , Tsuji K. , Teramoto K. , Suzuki M. , Kioka K.
Published: March 2020

4147

Background: Differences of efficacy between radiofrequency ablation (RFA) and microwave coagulation (MWC) for hepatocellular carcinoma (HCC) is still unknown. So we performed multi-center study to assess factors contributing to survival among patients treated by endoscopic thermal ablation for single HCC. Methods: 396 patients in six institutions with single HCC who were firstly treated by endoscopic thermal ablation were enrolled in this study and assessed retrospectively. Among 396 patients, 347 were treated under general anesthesia and 49 were treated local anesthesia. 144 were treated by MWC and 252 were treated by RFA. 383 were ablated laparoscopically and 13 were done thoracoscopically. 230 HCCs were located superficial position of liver and 166 were deep position. Classification with Child-Turcotte-Pugh score, the Japan Integrated Staging score, and the Cancer of the Italian Program scoring system were performed. All patients were analyzed survival rates by Kaplan-Meier method and differences among groups were compared by the log-rank test. Results: Five year survival rates of all 396 patients were 63% and ten year survival rates were 42%. Differences between general and local anesthesia were not significant (p = 0.28). Differences between MWC and RFA were not significant (p = 0.77). Location of HCCs were not significant (p = 0.89). Differences among groups classified by Child-Turcotte-Pugh score were significant (p = 0.017). Classification by the Japan Integrated Staging score was not significant (p = 0.24). However, classification by the Cancer of the Italian Program scoring system were significant (p = 0.001). Conclusions: Endoscopic thermal ablation therapies for HCC was effective. Differences of efficacy between RFA and MWC were not found.

No significant financial relationships to disclose.
Phase III intermittent MAB vs continuous MAB
Authors: Calais Da Silva F. M. , Calais Da Silva F. , Bono A. , Brausi M. , Whelan P. , Queimadelos A. , Portillo J. , Portillo J. , Kirkali Z. , Robertson C.
Published: March 2020

4513

Background: Patients with locally advanced or metastatic prostate cancer cannot be cured with any of the therapeutic tools available today. Methods: After an initial induction treatment of three months, with CPA 200 mg for two week’s and then monthly depot injections of LHRH analogue (decaptyl) plus 200 mg of CPA daily in 766 patients with locally advanced or metastatic prostate cancer, 626 patients whose PSA decreased below 4 or to 80% below their initial value, were randomised to intermittent or continuous therapy. Results: Among the 314 patients on Intermittent therapy, 50% have been off therapy for at least 52 weeks following the initial LHRH therapy, 29% have been off therapy for over 36 months. For the 197 patients whose PSA went down to ≤ 2 ng/ml, the median time off therapy was 74 weeks. When these patients returned to therapy they had a median of 14 weeks of treatment, followed by a second period off therapy, median 70 weeks. Patients with PSA < 2 ng/ml have spent a median of 82% of their time receiving no therapy.After a median follow up of 51 months, 321 patients have died: 162 in the Intermittent arm compared to 159 in the Continuous arm (HR = 1.03 [95% confidence interval 0.83, 1.28; p = 0.79]). Estimated survival at 5 years was 53.8% in the Intermittent Group and 51.0% in the Continuous Group.Subjective or Objective progression was noted in 224 patients, 113 on the intermittent arm and 111 on the continuous arm with a hazard ratio of 1.09 (95% CI 0.84, 1.42), p=0.52. The main differences in quality of life between the two arms of the study were confined to sexual function.Sexual activity was significantly greater (p<0.01) in the intermittent arm with 41% of men reporting sexual activity at 9 months, 40% at 15 months and 35% at 21 months.The most commonly reported side effects were hot flushes, were more frequently among those on Continuous Therapy, 30% of continuous patients compared to 20% of intermittent patients, p < 0.01. Conclusions: There is no evidence that Intermittent therapy leads to a significantly elevated hazard of dying (p = 0.79) or to a greater subjective or objective progression (p = 0.52) and with less impact on quality of live and less medication, patients with PSA < 2 ng/ml on randomisation have spent a median of 82% of their time receiving no therapy. We think that intermittent therapy is an option to use in regular clinic.

No significant financial relationships to disclose.
Medical Research Council trial of 2 versus 5 CT scans in the surveillance of patients with stage I non-seminomatous germ cell tumours of the testis
Authors: Mead G. M. , Rustin G. J. , Stenning S. P. , Vasey P. , Aass N. , Huddart R. , Sokal M. , Kirk S.
Published: March 2020

4519

Background: Surveillance is a standard management approach for stage 1 non seminomatous germ cell tumours (NSGCT), yet there is no agreement on the number of CT scans that are required to detect relapses. A randomised trial of 2 versus 5 CT scans was performed to determine whether the number of scans influenced the prognostic group (J Clin Oncol 15:594–603, 1997) at relapse. Methods: Patients with clinical stage 1 NSGCT opting for surveillance were randomised to chest and abdominal CT scans at either 3 and 12 or 3, 6, 9, 12, and 24 months, with all other investigations (clinical exams, markers, chest X-rays) carried out at equal frequency in the two arms. 3/5 patients were allocated to the 2 scan schedule. 400 patients were required to exclude a 3% increase in the proportion of patients relapsing with IGCCCG intermediate or poor prognosis disease with 90% power at the 5% significance level (1-sided). Results: 247 patients were allocated to 2 CT scans and 167 to 5 CT scans. With a median follow up of 40 months 37 (15%) relapses have occurred in the 2 scan arm and 33 (20%) in the 5 scan arm. No patients were poor prognosis at relapse but 2 (0.8%) of those relapsing in the 2 scan arm were intermediate prognosis compared to 1 (0.6%) in the 5 scan arm a difference of 0.2% (90% CI −1.2%, +1.6%). The mean diameter of abdominal mass at relapse was 2.1 cm in the two scan arm and 2.2 cm in the five scan arm. After chemotherapy a residual mass was present in 35% in the 2 scan and 36% in the 5 scan arm. No deaths have been reported. Conclusions: This study can exclude with 95% probability an increase in the proportion of patients relapsing with intermediate or poor prognosis disease of more than 1.6% if they have 2 rather than 5 CT scans as part of their surveillance protocol. CT scans at 3 and 12 months after orchidectomy should be considered as the new standard and will be associated with a reduction in radiation exposure.

No significant financial relationships to disclose.
[18F]-FDG-PET in germ cell tumors following chemotherapy: Results of the German multicenter trial
Authors: De Wit M. , Hartmann M. , Brenner W. , Weiβbach L. , Amthauer H. , Franzius C. , Kliesch S. , Krege S. , Heicappell R. , Bares R. , Bokemeyer C.
Published: March 2020

4521

Background: The aim of this study was to evaluate the viability of residual masses following chemotherapy in patients (pts) with germ cell cancer (GCT) using FDG-PET. Methods: Pts with diagnosis of GCT at primary diagnosis or at relapse were included if residual masses (> 1 cm) were present following chemotherapy. 140 pts, 27 with primary extragonadal GCT, aged 15.7–59.2 (mean age: 32.7 years) treated in 18 centers were examined with concurrent FDG-PET and CT. FDG-PET was performed in fasting state. Images were reconstructed by filtered back projection. All PET-scanners were calibrated using the same phantom. The presented data are based on visual scan analysis. All pts underwent surgery for residual masses. Thus, all results were validated by histology. Results: Histology of the primary tumor included 20 seminoma and 109 NSGCT, while 11 pts had no primary histology. 88 pts (63%) had no persistent GCT. 120 pts (86%) demonstrated residual masses in retroperitoneal lymph nodes; in 56 pts (40%) residual masses were localized in the thorax and in 8 pts elsewhere (multiples possible). 40 pts (29%) presented active residual carcinoma and 54 (39%) presented residual teratoma (combination possible) following chemotherapy. Correct classification of the residual mass by FDG-PET was achieved in 79 of 140 (56%), while CT scans were correct in 58 of 140 pts (42%). 46 of 89 patients with a positive FDG-PET turned out to have viable tumor while in 36 out of 52 patients with a negative scan no lymph node metastases were found. FDG-PET turned out to show a sensitivity of 73% and specificity of 44%. Positive and negative predictive value (PPV, NPV) were 48% and 69% and accuracy 56%, respectively. In NSGCT 58 pts had no active tumor and 28 were true negative with FDG-PET resulting in a specificity of 47% and a NPV of 67%. 36 patients were true positive with a PPV of 54% and a sensitivity of 72%. Conclusion: FDG-PET for GCT following chemotherapy has a higher accuracy than CT, but sensitiviy is still too low to avoid subsequent resections in patients with NSGCT.

[Table: see text]

No significant financial relationships to disclose.
Efficacy and safety of sunitinib malate (SU11248) in bevacizumab-refractory metastatic renal cell carcinoma (mRCC)
Authors: Rini B. I. , George D. J. , Michaelson M. D. , Rosenberg J. E. , Bukowski R. M. , Sosman J. A. , Stadler W. M. , Margolin K. , Hutson T. E. , Baum C. M.
Published: March 2020

4522

Background: Sunitinib malate (SU11248) is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR) family, platelet-derived growth factor receptor (PDGFR) and other related receptors. It has demonstrated anti-tumor activity in cytokine-refractory mRCC patients (pts). The activity of sunitinib in pts refractory to VEGF binding agents such as bevacizumab, however, has not been evaluated. It was hypothesized that tumor resistance to bevacizumab may be driven, in part, through pathways sensitive to inhibition by sunitinib. A phase II study evaluating the activity of sunitinib in bevacizumab-refractory mRCC was thus conducted. Methods: Pts with mRCC who demonstrated RECIST-defined disease progression within 3 months after bevacizumab-based therapy were treated with sunitinib (50 mg daily, 4 weeks of a 6-week cycle). Additional eligibility included measurable disease, clear cell histology, ≤ 2 prior systemic regimens, prior nephrectomy, performance status 0 or 1 and adequate organ function. The primary endpoint was objective response by RECIST criteria. A single-stage design was employed to test the null hypothesis that the true response rate is ≤ 5% versus the alternative hypothesis that the true response rate is ≥ 15%. Results: Accrual of 60 patients has been completed. Baseline characteristics include a median age of 59 years; 92% of pts had ≥ 2 metastatic sites and 23% had prior radiotherapy. Thirty-two of 60 pts enrolled are evaluable for response; 28 pts are too early for assessment. Twenty-six pts (81%) demonstrated some degree of tumor shrinkage, including, 4 pts (13%; 95% CI 4%, 29%) demonstrating an objective partial response. The most common treatment-related adverse events (AEs) included fatigue, diarrhea, dysgeusia, and nausea. Serious treatment-related AEs included fatigue, diarrhea, nausea and one fatal cerebral hemorrhage; 3 pts withdrew due to an AE. Conclusions: Sunitinib has substantial antitumor activity in bevacizumab-refractory mRCC pts, suggesting that sunitinib may inhibit signaling pathways involved in bevacizumab resistance. The precise mechanisms of response to sunitinib in bevacizumab-refractory tumors will require additional studies.

[Table: see text]
Sorafenib plus interferon-α2b (IFN) as first-line therapy for advanced renal cell carcinoma (RCC): SWOG 0412
Authors: Ryan C. W. , Goldman B. H. , Lara P. N. , Beer T. M. , Drabkin H. A. , Crawford E.
Published: March 2020

4525

Background: Sorafenib is a RAF and multiple receptor tyrosine kinase inhibitor active in RCC. IFN has modest activity in RCC and has immunologic, anti-angiogenic, and anti-proliferative effects. Sorafenib and IFN may simultaneously target anti-angiogenic and MAP kinase pathways, providing the basis for this phase II combination study. Methods: Eligible patients (pts) had metastatic or unresectable RCC with a clear cell component, no prior systemic therapy, performance status 0–1, measurable disease. Treatment: IFN 10 x 106 IU s.c. 3x/week and sorafenib 400 mg p.o. BID. Response assessment was performed q8 weeks. This was a single-stage trial with a planned sample size of 55. Primary endpoint was RECIST response rate. Results: Of 67 registered pts, 58 are eligible & evaluable. Pt characteristics: median age 61 years (42–84), male:female (40:18), prior nephrectomy 86%. MSKCC prognostic categories (42 pts) were good:intermediate:poor (28%:67%:5%). With a median follow-up of 6.5 months, 79% (46/58) of pts are alive, 41% (24/58) remain on treatment. Assessment of progression-free survival is premature. Overall response rate (53 pts) is 19% (95% CI: 9%, 32%) with CR 2% and PR 17% (9% confirmed, 8% unconfirmed). Toxicities affecting >50% of subjects were: fatigue, anorexia, diarrhea, nausea, rigors/chills, fever, anemia, leukopenia. Most common Grade 3+ toxicities were fatigue (24%), leukopenia (10%), anorexia (6%), diarrhea (6%), hyponatremia (6%). All pts experienced some toxicity, with 36 (62%) experiencing at least one Grade 3+ toxicity. Hand-foot syndrome, a common side effect of sorafenib, was seen in only 10% of pts. Conclusions: The overall response rate of 19% for the combination of sorafenib and IFN in advanced RCC is greater than expected with either IFN or sorafenib alone. Toxicity is typical of IFN and notable for minimal hand-foot syndrome. Further studies with this combination are warranted.

[Table: see text]
Phase II trial of sorafenib plus interferon-alpha 2b (IFN-α2b) as first- or second-line therapy in patients (pts) with metastatic renal cell cancer (RCC)
Authors: Gollob J. , Richmond T. , Jones J. , Rathmell W. K. , Grigson G. , Watkins C. , Peterson B. , Wright J.
Published: March 2020

4538

Background: Sorafenib is a VEGFR/PDGFR-β/Raf inhibitor that improves PFS in metastatic RCC with a RR of 2%. IFN-α improves OS in RCC with a RR of ≈10%. Methods: Based on the activity of sorafenib and IFN-α in RCC, a phase II combination trial was undertaken. Pts with RCC of any histology were eligible if they had received ≤1 prior treatment (excluding IFN-α). Treatment consisted of 8-wk cycles of sorafenib 400 mg po bid + IFN-α2b 10 MU sc tiw. Cycles were repeated until disease progression with 2-wk breaks between cycles permitted. This single-stage trial has a planned n = 40; primary objectives are RR and tolerability. Results: From November 2004-December 2005, 31 pts were enrolled. Pt characteristics included: median age 47, M/F: 23/8, PS 0/1: 25/6, clear cell/papillary: 24/3, no prior Rx/prior high-dose IL-2: 17/12, prior Nx: 26. Toxicities (n = 27) were mostly grade 1/2: fatigue (78%), anorexia (74%), rash (70%; 11% grade 3), diarrhea (67%), weight loss (63%), hypophosphatemia (59%; 33% grade 3), nausea (56%), neutropenia (48%; 19% grade 3), alopecia (44%), and oral mucositis (26%). Dose reductions of both agents for toxicity occurred in 58% of pts. The most common reasons for dose reduction were grade 3 rash or neutropenia and grade 2 fatigue or anorexia. Among 24 pts evaluable for response, the RR by RECIST criteria was 42% (38% PR, 4% CR). An additional 46% had stable disease for at least 1 cycle, including 8% with ≥20% regression. Responses were seen in lungs, pleura, kidney, liver, pancreas, and nodes. Three of the 10 responses occurred in patients who had failed prior high-dose IL-2. Conclusions: Sorafenib + IFN-α2b is a well-tolerated outpatient regimen with substantial antitumor activity in both untreated and IL-2-resistant metastatic RCC. Further investigation of this regimen in RCC is warranted.

[Table: see text]
Hormonal status and the quality of life of testicular cancer survivors
Authors: Wiechno P. J. , Sadowska M. A. , Kubiak K. S. , Demkow T. , Kaminska J.
Published: March 2020

4548

Background: Testicular cancer is a highly curable neoplasm and treated patients may potentially survive many decades. The aim of the study was to assess the rate of hormonal abnormalities among testicular cancer survivors and the effect of these changes on patients’ quality of life. Methods: Men with complete remission of testicular cancer lasting over 2 years were eligible. Patients completed State-Trait Anxiety Inventory (STAI), Hospital Anxiety and Depression Scale (HADS), Beck’s Depression Inventory (BDI), International Index of Erectile Dysfunction (IIEF), Sexual Functioning Questionnaire (SFQ) and rated their physical and psychological well-being, quality of life and relationship with partners. Levels of the following hormons were determined: testosterone, estradiol, thyreotropin, folicule stimulating hormone (FSH), luteinizing hormone (LH) and prolactin. Relations between hormone levels and questionaires results were analysed. Results: A total of 326 men were tested from November 2004 till December 2005. Median age was 37 years (range: 18–72). Median disease free survival was 59 months (range: 19–291). Only 24% of patients had all tested hormones within normal ranges. The most common of endocrine abnormalities were gonadotropins over normal (LH - 55% and FSH - 49% of cases) and lowered testosterone (15%). Percentage of patients with abnormal anxiety levels was 27% (STAI) and 28% (HADS), depression rate was 15% (BDI) and 18% (HADS), 40% of patients had erectile disfunction. Hormone levels and scores of the used scales corelated strongly with patients’ age, then a linear regression analysis was performed to exclude the influence of age factor. It was shown that higher depression levels in BDI are found amongst patients with elevated LH (p = 0.010) or FSH (p = 0.017). Men with higher than normal FSH were more anxious in STAI (p = 0.026). Patients with overnormal LH shown more sexual problems in SFQ (p = 0.030). Abnormal gonadotropins levels corelated with a deteriorated physical well-being (p = 0.028). Men with abnormal estradiol were more prone to erectile disfunction (p = 0.009). Conclusions: Hormonal abnormalities are frequent among testicular cancer survivors and have negative impact on the patients’ physical and psychological well-being as well as on their sexual functioning.

No significant financial relationships to disclose.
A meta-analysis of individual patient data from randomized trials assessing chemotherapy with and without estramustine in patients with castration-refractory prostate cancer
Authors: Fizazi K. , Hudes G. R. , Berry W. R. , Kelly W. K. , Eymard J. C. , Logothetis C. , Le Maitre A. , Pignon J. P. , Michiels S.
Published: March 2020

4561

Background: Estramustine phosphate is a mustard-estradiol conjugate, with evidence of both hormonal and non-hormonal effects. In phase II trials, the response rates of microtubule inhibitors are increased when combined with estramustine. Morbidity includes notably thrombosis in about 7% of cases. Whether combining estramustine with chemotherapy increases survival in castration-refractory prostate cancer (CRPC) is still controversial. Methods: Data from all published and unpublished prospective randomized trials assessing chemotherapy + estramustine versus chemotherapy alone in CRPC were sought using electronic database searching, hand searching, and by contacting experts in the field. The primary endpoint was overall survival (OS). The analysis was performed on an intention-to-treat basis. The stratified logrank test was used and an overall hazard ratio (HR) was computed using a fixed effect model. χ2 heterogeneity tests were used to test for statistical heterogeneity. All p-values were two-sided. Multivariate analysis was performed using a Cox model stratified by trial. Results: Individual data were obtained from all 5 randomized trials conducted in the PSA era that had been identified (n = 610). The control arms consisted of docetaxel (1), paclitaxel (1), ixabepilone (1), and vinblastine (2). With a median follow-up of 2.8 years, 510 deaths had occurred. OS was significantly better in the estramustine arm (HR = 0.82 [95% CI: 0.69–0.97]; p = 0.02). Overall, the risk reduction (RR) of death related to estramustine was 18% (± 8). There was no significant interaction (p = 0.66) between the RR of trials using vinblastine (RR = 15% [± 12]) and in those using taxanes or ixabepilone (RR = 21% [± 11]). The estimated 1-year OS rate was 57% and 50% in the estramustine arm and in the control arm, respectively. The 18-months OS rate was 43% and 35%, respectively. There was no interaction between the effect of estramustine and age, performance status, or serum PSA in the Cox model. Conclusions: Combining estramustine with chemotherapy increases OS over chemotherapy alone in patients with castration-refractory prostate cancer.

[Table: see text]
The probability of a positive bone scan in patients who were treated with adrogen ablasio therapy for rising PSA after radical prostatectomy
Authors: Dotan Z. A. , Sathyamoorthy K. , Bianco F. J. , Stephenson A. J. , Eastham J. A. , Fearn P. , Schöder H. , Scher H. I. , Scardino P. T. , Kattan M. W.
Published: March 2020

4574

Background: Physicians often order periodic bone scans to check for metastases in patients treated with androgen ablation therapy (ADT) for rising PSA (biochemical recurrence; BCR) following radical prostatectomy. However, most of these scans are negative. We studied patient characteristics to build a predictive model for a positive scan (+BS) in that setting. Methods: From our prostate cancer database we identified all patients with detectable PSA after radical prostatectomy that were treated by ADT for BCR only. There were 511 BS performed in patients treated with ADT for BCR. Among them, 151 BS were performed for patients with BCR only with out previous evidence of bone metastases (1–8 BS for patient with median of one). We analyzed the following potential predictors for a positive bone scan at the time of each bone scan: preoperative PSA, history of neoadjuvant ADT (NA-ADT), time to BCR, pathologic findings (surgical margin, extracapsular extension, seminal vesicle invasion, lymph node metastases, and Gleason score), PSA before the BS (trigger PSA), PSA doubling time and time from BCR to BS. The results were incorporated into a predictive model. Results: Among the 151 BS, only 35 (23%) were positive for metastases. In multivariate analysis, only trigger PSA (P < 0.001, OR 1.84) and NA-ADT (P = 0.02, OR 1.32) predicted a +BS. Probability of +BS according to PSA of 0–2, 2.1–4, 4.1–10, 10.1–20 and above 20.1 were 4.7%, 15.3%, 29.6%, 46.1% and 63.3% respectively. A nomogram was constructed for predicting the probability of +BS, and was found to have a concordance index of 0.83. Calibration of the nomogram according to bootstrap analysis showed that the nomogram is reasonably accurate. Conclusions: Trigger PSA and a history of neoadjuvant ADT were associated with a +BS. Omitting scans in low-risk patients could reduce substantially the number of scans ordered.

No significant financial relationships to disclose.
Biological significance of serum VEGF measurement in renal cell carcinoma
Authors: Patard J. , Rioux-Leclercq N. , Bensalah K. , Fergelot P.
Published: March 2020

4596

Background: VEGF plays an important role in Renal Cell Carcinoma (RCC) tumor angiogenesis and is a relevant molecular target. Our objective was to correlate serum VEGF measurement to clinical, biological and pathological variables in renal tumors. Methods: 206 patients who were operated for a renal tumor at our institution were prospectively assessed for serum VEGF measurement (enzyme-linked immunosorbent assay, R&D systems). Informed consent was obtained in all cases. Symptoms at presentation, pre-operative biology (haemoglobin, WBC count, platelet count, serum creatinin, calcemia, CRP, ASAT, ALAT, gamma-glutamyltransferase (γGT), Alkaline Phosphatases), TNM stage, Fuhrman grade and final pathology (benign vs malignant histology, histologic subtype) were systematically recorded. Qualitative and quantitative variables were compared by using Chi-square (Fischer exact test) and Student t tests, respectively. Results: There were 128 males (62.1%) and 78 females (37.9%). 185 tumors were malignant at histology (89.8%) including 155 tumors with clear cell histology (83.8%). Median serum VEGF level was 361 ng/ml (41–3090). Mean serum VEGF was not significantly different between benign and malignant tumors as well as between clear cell and non clear cell carcinomas (p: 0.4 and 0.8 respectively). Serum VEGF was strongly associated with symptoms, T Stage (p: 0.0001), N Stage (p: 0.004), Fuhrman grade (p: 0.007) and tumor necrosis (p: 0.004) but not with M Stage (p: 0.3). Serum VEGF was also found to be strongly associated with: haemoglobin, CRP, platelet count (p: 0.0001) and Alkaline phosphatases (p: 0.001). A weaker association was found between serum VEGF and γGT, ASAT (p: 0.05) or ALAT (p: 0.09). Finally serum VEGF was associated with cancer specific survival (p: 0.01). Conclusion: Serum VEGF is strongly associated with most usual clinical, biological and pathological prognostic parameters in RCC. Serum VEGF measurement should be further evaluated for prognostic purpose as well as for treatment monitoring.

No significant financial relationships to disclose.
Phase II trial of weekly docetaxel and oral capecitabine in metastatic hormone-refractory prostate cancer
Authors: Marur S. , Heilbrun L. , Kucuk O. , Cher M. L. , Forman J. , Heath E. , Vaishampayan U.
Published: March 2020

4634

Background: Docetaxel based chemotherapy for hormone-refractory prostate cancer (HRPC) has demonstrated survival benefit. The combination of docetaxel-capecitabine has demonstrated synergistic anti-tumor effect, which is attributable to docetaxel-mediated up-regulation of thymidine phosphorylase (TP). Hence, a phase II trial is being conducted to assess efficacy and tolerability of weekly docetaxel and capecitabine in metastatic HRPC. Methods: Patients with metastatic HRPC, who have not received prior chemotherapy for metastatic disease were eligible to receive docetaxel 36 mg/m2/week IV on days 1,8, and 15 and Capecitabine 1250 mg/m2 /day in two divided doses on days 5–18. Cycles were repeated every 28 days and response was assessed every 2 cycles. The primary end point was response rate. A two stage Simon study design required 15 patients to be accrued in first stage and additional 13 patients in second stage. Results: First stage was completed and response was adequate to proceed to second stage. 21 patients have been registered to this ongoing trial. Baseline characteristics included median age of 71 (range 47–80 years); median performance status of 1; median PSA at study entry of 60.6 ng/ml (range 1.2–3716.9); Of the 21 patients, 16 had bone pain pretherapy, Gleason score ≥ 8 in 14; 8 had measurable disease; 8 had new bone metastases and 14 had PSA progression. 83 cycles have been administered (median 4, range 1–10 cycles). To date 18 patients were assessable for toxicity and response. Grade 3 and 4 neutropenia was noted in 3 patients and Grade 3 hand-foot syndrome in 2 patients. There were no treatment related deaths. A PSA partial response (PR) defined as ≥ 50% decline sustained for ≥ 4 weeks was observed in 14/18 (77%) with ≥90% PSA decline in 7/18 (39%) patients. PR noted in 5/8 measurable disease patients. Stable disease by bone metastases in 15/18. Median time to PSA progression was 5 months (95% CI of 3.5–7.2+ month). Conclusions: The combination of capecitabine and weekly docetaxel demonstrated encouraging activity and acceptable toxicity profile.

[Table: see text]
Blood-based biomarkers for detecting aggressive prostate cancer at time of biopsy
Authors: Nam R. K. , Marshall K. W. , Zheng R. , Zhang H. W. , Narod S. A. , Liew C. C.
Published: March 2020

4637

Background: To date, we have applied our unique methodology (the Sentinel Principle) to identify blood-based gene expressed biomarkers for several diseases including osteoarthritis, bladder cancer and psychiatric disorders. It is well known that new biomarkers for prostate cancer detection are needed, particularly aggressive forms of prostate cancer. Our objective was to identify gene expression signatures and to characterize a set of biomarkers from whole blood to identify patients with aggressive forms of prostate cancer at the time of prostate biopsy. Methods: We conducted a two staged study. The first stage was for gene discovery using microarrays (Affymetrix U133Plus2.0 GeneChips) among 47 patients (all Caucasian) who underwent a prostate biopsy for prostate cancer. We included 16 patients (cases) diagnosed with aggressive forms of prostate cancer defined as having a histologic grade of Gleason Score 7 or more and 31 patients with no evidence of cancer at biopsy (controls). The second stage was a validation study (108 patients) using real-time RT-PCR methods. Logistic regression was used to assess the ability of linear combinations of specific transcripts to distinguish cancers from controls. Results: In the first stage, we identified 1661 probes that were significantly different in blood gene expression profiles between cases and controls (p<0.05). In the second stage, real-time RT-PCR assays validated four genes among 33 cases and 75 controls: three up-regulated genes: A 1.4 fold, p<0.001, B 1.2 fold, p=0.03, C 1.3 fold, p=0.08; and one down-regulated gene D 0.70, p=0.008. Linear combination of these 4 genes discriminated the cases from controls with a sensitivity of 90% and specificity of 53% (AUC: 0.80, 95% C.I.: 0.713∼0.871). The performance of PSA (4 ng/ml cut-off) in the same 108 sample set was 91% sensitivity and 13% specificity (AUC: 0.67, 95% CI: 0.75∼0.98). The performance of combining the four blood biomarkers with PSA yielded an AUC of 0.86 (95% C.I.: 0.77∼0.91) with a sensitivity 90% and specificity 70%. Conclusions: When used with PSA, these four blood-based biomarkers improved the overall accuracy to identify patients with prostate cancer at biopsy. These results would have important implications for new biomarkers discovery for prostate cancer detection.

[Table: see text]
Platelet microparticles (PMP): A predictive factor of overall survival in hormone-refractory prostate cancer (HRPC) patients treated by chemotherapy
Authors: Banu A. , Helley D. , Banu E. , Fischer A. M. , Scotte F. , Bouziane A. , Oudard S.
Published: March 2020

4639

Background: Several studies suggest a causal relationship between platelets activation and cancer metastasis. Activated platelets release PMP, VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) which could play a role in patient outcome. Methods: Eligible chemonaive HRPC patients (pts) were required to have: ECOG performance status (PS) ≤2, progressive disease after antiandrogen withdrawal. Before chemotherapy, we quantified PMP in whole blood by flow cytometry using an anti-CD41 monoclonal antibody and plasmatic VEGF and bFGF by ELISA. As primary endpoint, we prospectively evaluated the impact of PMP on overall survival (OS) by Cox regression and log-rank test. Secondary, we studied the correlation between PMP and platelets, and their relationship with OS, incorporating an interaction term in the modelling (PMP and platelets). Results: Between July 2001 and April 2004, thirty-eight HRPC pts were treated by chemotherapy [docetaxel (92%), mitoxantrone (8%)] in our center. Median age was 69 years, with median values of hemoglobin 125 g/L, baseline prostate-specific antigen (PSA) 37.7 ng/mL, PMP 6 867 per μL, VEGF 18.1 pg/mL and bFGF 2.8 pg/mL. Significant correlations were observed between PMP and ECOG PS, hormone-sensitivity duration, Gleason and platelets. Median OS was significantly lower in pts with high PMP values (>6 788 per μL), compared to low PMP pts: 16.7 months (95% CI, 5.1–28.2) vs 25.2 months (95% CI, 20.2–30.3), P = 0.025, log-rank. Univariate analysis by Cox regression showed a significant relationship between OS and PMP level [HR = 0.41 (95% CI, 0.19–0.92), P = 0.04]. PMP kept their significance after adjusting by multivariate analysis for baseline hemoglobin, number of metastatic sites, and PSA doubling-time [HR = 0.37 (95% CI, 0.16–0.87), P = 0.02)]. An interaction term (PMP and platelets) was also predictive on OS (P = 0.01). Conclusions: PMP and their interaction with platelets were a predictive factor of OS in HRPC pts. Our analysis showed that the dynamic interaction between PMP and platelets has a major impact on outcome of HRPC pts.

No significant financial relationships to disclose.