bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunosenescence in testicular cancer survivors treated with chemotherapy.
Authors: Bourlon Maria Teresa , Velazquez Hugo Eduardo , Hinojosa Juan , Lima Guadalupe , Rios-Corzo Ricardo , Jimenez-Martinez Karina , Zarco-Letzel Gabriela , Llorente Luis , Atisha-Fregoso Yemil
Published: September 2018

e16037

Background: Cytotoxic (Ctx) chemotherapy can cure patients with advanced testicular cancer. Notwithstanding, Ctx agents could promote molecular aging and induce cellular senescence in vivo. This phenomenon has been studied in breast cancer patients exposed to adjuvant chemotherapy, however, the potential induction of premature immunosenescence in testicular cancer survivors (TCS) exposed to chemotherapy remains unknown. Methods: Case-control study. Cases were 18-55 yo TCS, treated with chemotherapy (≥3 BEP cycles), disease-free for ≥3 m. Controls were healthy subjects matched by sex and age ± 1 y. Selected subpopulations of isolated peripheral blood mononuclear cells (PBMC) depicted in Table, were analyzed flow cytometry. Statistics: Adjusted counts or relative percentage for each population were compared using student-t test or Mann-Whitney U test as appropriate. Results: We included 15 TCS and 15 controls. Mean age was 32.6 yo (24-54 y). Mean time since last chemotherapy was 53.13 months (3-192 m). All 15 patients were treated with at least 3 BEP cycles ± TIP/VIP cycles. There were no differences in total leucocyte (5128 ± 1917 vs 5850 ± 2141, p=0.36), and lymphocyte (1539 ± 592 vs 1889 ± 825, p=0.4) counts among cases and controls. Cases have a diminished percentage of CD3+ (63 ± 10 vs 71 ± 11, p=0.05) and CD4+ cells (36±8 vs 43 ± 9, p=0.03). There were no differences in pct of CD8+ or CD19+. However, there was an increase in late differentiated CD8+/CD57+ cells (31 ± 14% vs 20 ± 11%, p=0.02); and a decrease in CD4+/CD28+ cells (90 ± 9% vs 97 ± 4%, p=0.02) in cases. We observed paradoxical changes in B cell subpopulations with an increment in naïve (79 ±10 vs 67% ± 14% p=0.02) and a decrease in memory (18 ± 9 vs 31 ± 13%, p=0.01) B cells. Conclusions: TCS after chemo develop changes compatible with immunesenescence in T cell (CD3+) compartment, and an increment in naïve B cells. [Table: see text]
Retrospective review of clear cell and non-clear cell renal carcinomas: Characteristics and course in the pre-TKI (tyrosine kinase inhibitor) and post-TKI era.
Authors: Gupta Kanika , Nizam Amanda , Millado Kristen , Liu Jiaqi , Guebre-Xabiher Hiwot , Nguyen Hong , Siegel Robert S. , Aragon-Ching Jeanny B.
Published: September 2018

e16052

Background: Renal cell carcinoma (RCC) confers a lifetime risk of 1.6% of developing cancers. Early, localized cancers have high cure rates after surgical treatment, but locally advanced/distant metastatic disease remains a devastating disease. The use of TKIs has been considered a mainstay of treatment for clear cell pathology, but other histologic subtypes such as papillary, chromophobe, and mixed subtypes, which is considered non-clear cell RCC, also make up a heterogeneous pattern and course of disease. This retrospective study characterizes renal cell carcinomas and their treatments. Methods: A retrospective chart review of the last 15 years was performed using data from a single-institution center at the George Washington University Cancer Center Tumor Registry Data. Statistical analysis was performed using the Fisher’s test, Chi-squared test, T-test, and Kaplan-Meier survival curves. Results: 1043 patients with RCC were identified. Preliminary data analysis was performed on 92 of these patients. 48 had pure clear cell renal cell carcinoma (CCRCC) and 44 had non-clear cell carcinoma (NCC). Mean age of diagnosis was similar for both groups (58.25 years for CCRCC vs 62.14 years for NCC, p = 0.0977). However, hemoglobin levels at diagnosis were statistically significantly lower for CCRCC (p = 0.0261), as were calcium levels (p = 0.0187). All patients underwent surgical or local treatment. Only 2 patients received chemotherapy and 5 patients received molecularly targeted therapy. While not statistically significant, patients with CCRCC had surgery sooner after diagnosis than NCC (71 days vs 92 days), had longer time to metastatic disease (1033 days vs 820 days), and improved overall survival (1955 days vs 1446 days). Conclusions: NCC was a less favorable pathology than CCRCC with apparent later institution of surgical intervention as well as shorter time to metastatic disease and worse overall survival. Identifying patients with more aggressive disease earlier allows for the potential role for more aggressive therapies that may result in improved outcomes.
Survival outcomes and patterns of utilization of cytoreductive nephrectomy in the tyrosine kinase inhibitors (TKI)-era in metastatic clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC): Analyses from the National Cancer Database (NCDB).
Authors: Aragon-Ching Jeanny B. , Wang Hongkun , Trump Donald L.
Published: September 2018

e16068

Background: Use of TKIs is standard of care for metastatic ccRCC and cytoreductive nephrectomy has improved survival even in metastatic ccRCC. The use of cytoreductive nephrectomy in the TKI era post-2005 for nccRCC histologies is unknown. We sought to determine trends and explore differences in characteristics of ccRCC and nccRCC, use of cytoreductive nephrectomy and survival outcomes for varying stages. Methods: Using a de-identified dataset acquired from the NCDB from 2004 to 2014, extraction of demographic information on patients divided into ccRCC versus nccRCC. Descriptive statistics was used for summarizing patients’ characteristics. Chi-Square test was used for comparing categorical variables. Two-sample t-test was used for comparing continuous variables. Kaplan-Meier method was used to analyze patients’ survival data. Results: 302,339 (82%) ccRCC and 66,530 (18%) nccRCC patients were identified. nccRCC included papillary (n = 42,251), sarcomatoid (n = 5769), chromophobe (n = 17,671) and collecting duct (n = 839). The median age for both groups was 63 years, more common in males (ccRCC = 61%; nccRCC = 69%), and mostly Caucasians (ccRCC = 86%; nccRCC = 75%). Most patients were treated in comprehensive community and academic research programs (ccRCC = 81%; nccRCC = 83%). Majority of patients were diagnosed with AJCC Stage I (ccRCC = 57%, nccRCC = 62%). Stage IV was diagnosed in 14% of ccRCC and 9% of nccRCC. The utilization of nephrectomy declined for ccRCC at 36% in the year 2014 compared to 44% in 2005, whereas it declined more for nccRCC with 47% in 2014 compared to 70% in 2005. The median survival time for Stage I was comparable in both groups (ccRCC = 140 mos, 95% CI 138.8 – 142.16; nccRCC = 140 mos, 95% CI 138 – unestimable). However, median survival was worse for stage IV in nccRCC (ccRCC = 9 mos; 95% CI 8.8 – 9.17; nccRCC = 7.43 mos; 95% CI 7.16 – 7.79). Conclusions: In stage IV patients with nccRCC, cytoreductive nephrectomy is used less often and overall survival appears inferior compared to ccRCC.
Dynamics of immune-mediated thyroid dysfunction in patients with advanced renal cell carcinoma receiving checkpoint inhibitor therapy.
Authors: Osorio Juan Carlos , Patil Sujata , Coskey Devyn Taylor , Carlo Maria Isabel , Feldman Darren R. , Hellmann Matthew David , Voss Martin Henner
Published: September 2018

e16071

Background: Checkpoint inhibitors (CPI) are quickly gaining relevance in the management of metastatic renal cell carcinoma (RCC). Treatment is generally well tolerated, but immune-induced thyroid dysfunction (TD) is reported in up to 10% of patients (pts) across trials. The dynamics of this phenomenon are undefined; hence there are no proposed standards for endocrine surveillance on therapy. Here we report on a cohort of RCC pts treated with CPI at Memorial Sloan Kettering Cancer Center with serial prospective assessment of thyroid function on therapy. Methods: Thyroid function tests (TFT) were assessed at baseline and serially on therapy. We recorded trends for hyper- and hypothyroidism and determined median time to development of TD by standard statistical methods. T4 replacement therapy was investigated by individual chart review. The association of TD with outcomes on CPI therapy was assessed by non-parametric tests. Results: Of 59 pts with serial TFT assessment, 20 were hypothyroid and 39 were euthyroid at baseline. 50% of previously hypothyroid pts required adjustment of T4 dosage. Thirteen of 39 euthyroid pts (36%) developed new TD requiring thyroid replacement. TD occurred early (median time to onset: 1.4 months, range 0.9-9.6), and in six of the 13 pts (46%), transient thyroiditis preceded hypothyroidism. None of the pts with thyroiditis required treatment, and the median duration from onset of thyroiditis to development of hypothyroidism was 1.5 months (range 0.7-2.8). All pts with hypothyroidism required replacement therapy; none required discontinuation of immunotherapy due to TD. TD was not associated with difference in objective response rate (fisher’s exact, p = 0.163), regression in target lesions (wilcoxon rank-sum, p = 0.135), or PFS (log rank p = 0.8214). Conclusions: TD is common in RCC pts receiving CPI therapy. In this cohort, onset of TD was early, thyroiditis was always transient, and no new cases were detected beyond 10 months. Confirming these findings in larger cohorts will provide meaningful data to guide management of TD when using this new class of agents outside of clinical trials.
Organ-preserving surgery for localized renal cell carcinoma: Current approaches.
Authors: Dimitriadi Sergey N , Kit Oleg Ivanovich , Frantsiyants Elena Mikhaylovna , Ushakova Natalya Dmitrievna , Rozenko Dmitry , Shvyrev Dmitry Aleksandrovich , Faenson Aleksandr V. , Goncharov Sergey I.
Published: September 2018

e16077

Background: Introduction of modern organ-preservingapproaches in surgical treatment of kidney cancer is limited by the duration of warm ischemia used during the partial nephrectomy (PN), including surgery for elective indications. Some resection procedures require prolonged warm ischemia time resulting in acute kidney injury and development of renal failure in the postoperative period. The purpose of the study was to analyze the effectiveness of a new organ-preserving surgery method for kidney cancer. Methods: 46 patients with clinically localized renal cancer, R.E.N.A.L. score 6-10, underwent PN for elective indications. Patients were divided into two groups: the first group – 20 patients (8 patients – laparoscopic PN (LPN), 12 – open PN (OPN)) with bilateral perirenal procaine blockade (BPPB) before the resection. The second group included 26 patients (19- LPN, 7– OPN) receiving surgery without BPPB. BPPB was performed under US-control. 50 ml of 0.25% procaine solution was successively injected to the perinephric fat in upper, middle and lower kidney segments at both sides. Acute kidney injury (AKI) was diagnosed by serum creatinine level increase by 50% of the initial level and higher. Results: Patients in both groups were comparable by age – 58.35±7.5 (44–70) and 58.7±5.6 (50–65) years, and resection difficulty by R.E.N.A.L. score – 7.35±1.1 (6–10) and 7.15±1.2 (6–10), respectively. Median warm ischemia time did not differ significantly in both groups and was 20.0±2.99 (15–25) and 18.42±2.93 (15–25) min., respectively. Morphologically, all patients were diagnosed with renal cancer, surgical margins were negative. 9 (34.6%) patients of the second group developed AKI, while no AKI was registered in the first group. Urinary fistula and delayed bleeding were not observed. Conclusions: The results suppose renal protective effect of BPPB during partial nephrectomy for kidney cancer with warm ischemia time of 15-25-minutes.
Prospective phase II study of sunitinib rechallenge in metastatic renal cell carcinoma (mRCC): A G.I.O.N. trial.
Authors: Porta Camillo , Ferrari Vittorio D. , Zucali Paolo Andrea , Fornarini Giuseppe , Bernardo Antonio , Falconeri Andrea , Ferrari Alessandra , Santarossa Sandra , Pappagallo Giovanni L. , Bearz Alessandra
Published: September 2018

e16081

Background: Sunitinib is a 1st-line standard of care in mRCC. Lack of cross-resistance to sequential VEGF-targeting drugs and the possibility of a successful rechallenge with Sunitinib have been postulated. Whether mRCC patients (pts) could benefit from rechallenge with Sunitinib after progressing on 1st-line Sunitinib and 2nd-line Everolimus was the aim of this phase II study Methods: 39 mRCCpts were prospectively treated with Sunitinib (50 mg/daily, 4:2); main inclusion criteria were: histologically proven RCC with clear cell component, previous 1st-line Sunitinib with a Disease Control Rate lasting at least 10 months, 2nd-line Everolimus, and written informed consent. The primary end-point of this study was 6-months progression-free survival (PFS). A Simon’s 2-stage design was used; after testing Sunitinib on 12 pts in the first stage, the trial would have been terminated if 5 or fewer had a PFS of less than 6 months. Otherwise, the trial would have proceeded to the second stage, enrolling a total of 38 pts. If the total number of pts free of progression at 6 months would have been less than or equal to 18, Sunitinib would have been rejected Results: As a whole, 39 pts (30 males, 9 females) were enrolled. The study quickly moved from the first stage to its completion and ultimately succeeded; indeed, 6-months PFS was 60%, median PFS being 8.6 months (average: 9.59, range: 0.7-24.6 months). In terms of safety no unexpected toxicities were observed. Tx-related grade 3-4 AEs observed in ≥5% of the pts were: hand-foot skin reaction, fatigue, nausea, hypertriglyceridemia, hypophosphatemia, hypocalcemia, hyperglycemia, and neutropenia. One case each of myocardial infarction, atrial flutter and spontaneous pneumothorax were also reported, but resolved Conclusions: Despite an ineluctable time-lead-bias, median PFS on Sunitinib rechallenge was high (8.6 months), clearly showing that many pts may become sensitive again to VEGFRs-inhibition. Although many agents are presently available from 2nd-line on, in countries where treatment options are still limited, Sunitinib rechallenge could still represent a reasonable treatment option. EudraCT number: 2012-000473-23. Clinical trial information: 2012-000473-23.
A phase II clinical study evaluating the efficacy and safety of neoadjuvant and adjuvant sunitinib in previously untreated patients with metastatic renal cell carcinoma (mRCC)(NeoSun).
Authors: Welsh Sarah , Fife Kate , Matakidou Athena , Mullin Jean , Machin Andrea , Qian Wendi , Ingleson Victoria , Dalchau Katy Marie , Whittaker Pamela , Warren Anne , Priest Andrew N , Zaccagna Fulvio , Barrett Tristan , Gallagher Ferdia Aidan , Riddick Antony , Armitage James Neil , Eisen Timothy George Quentin
Published: September 2018

e16087

Background: Sunitinib improves clinical outcomes in patients (pts) with mRCC. The single arm phase II NeoSun trial was designed to investigate its added value to nephrectomy, and to explore translational biological and imaging biomarkers. Methods: Pts with mRCC, scheduled for nephrectomy, no prior systemic therapy were recruited to receive 50mg OD sunitinib for 12 days, then post-surgery on a 4 week-on, 2 week-off, repeating 6 week cycle until disease progression. Diffusion-weighted, BOLD and dynamic contrast enhanced MR imaging (DW-MRI, DCE-MRI) and research blood sample collection were performed at baseline and end of 12 days. CT Imaging was performed at baseline, pre- and post-surgery, and then every 2 cycles. The primary endpoint was objective response rate (RECIST). Secondary endpoints included changes in diffusion DW-MRI, DCE- MRI of the tumour following 12 days suntinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Results: 14 pts received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All 14 underwent total nephrectomy, and 13 recommenced sunitinib post-operatively. The mean number of post-surgery cycles was 11 (range 2 – 22). 58.3% (7/12) of pts achieved confirmed response (95% CI: 27.7 - 84.8%).91.7% (11/12) achieved objective clinical benefit (95% CI: 61.5 - 99.8%). Median OS is 33.7m and median PFS is 15.7m. Amongst those achieving PR/CR, median response duration is 8.7m. No unexpected surgical or sunitinib-related toxicities or complications were observed and the mean number of days from surgery to hospital discharge was 5.9 (range 3.0 – 17.0).There was a trend forOS to be better in pts with high baseline plasma VEGF-A (p = 0.06) or VEGF-C (p = 0.02) expression. A larger % tumour volume reduction after 12 days treatment is correlated with a smaller baseline % necrosis (coefficient = -0.51, p = 0.03). Conclusions: Sunitinib is effective and safe when given before and after nephrectomy to previously untreated pts with mRCC. Neoadjuvant studies such as NeoSun can safely explore translational biological and imaging endpoints. Clinical trial information: 2005-004502-82.
Efficacy of sequencing of cytotoxic and endocrine therapies in veterans with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Lamble Nina Mosallaei , Graff Julie Nicole , Beer Tomasz M.
Published: September 2018

e16501

Background: The optimal sequencing of therapies in the treatment of mCRPC has not been established. We examined the efficacy of one to two lines of endocrine therapy with chemotherapy sequencied before or in between endocrine therapies versus without chemotherapy. Methods: We prospectively enrolled 103 male veterans from 2013 to 2016 receiving abiraterone or enzalutamide for mCRPC therapy. Participants received usual care. Through chart review, for each line of therapy, we analyzed progression-free survival (PFS), defined as PSA increase 25% and 2ng/mL above nadir and confirmed by a second value, and PSA response rate, defined as a 50% PSA reduction from baseline at treatment initiation, for participants receiving various sequences of endocrine therapies with or without docetaxel chemotherapy. Results: We observed no statistically significant differences between the above measures except for an improvement in PFS when comparing those that received two lines of endocrine therapy without chemotherapy between treatments to those with who received chemotherapy between treatments ( p-value = 0.027, Log-rank test). Conclusions: There were no compelling clinically significant differences noted in PFS or PSA response rate amongst the various sequences of endocrine and cytotoxic therapies. Our results suggest that various sequences of therapy may yield similar results. Larger randomized studies analyzing sequencing of therapies will help determine if cross-resistance arises with use of multiple therapies. [Table: see text]
A first-in-human phase 1 study of proxalutamide (GT0918), a dual MOA androgen receptor blocker in patients with advanced CRPC.
Authors: Zhou Tie , Xu Wei-Dong , Xu Chuang-Liang , Gao Xu , Hou Jian-Guo , Ren Shancheng , Yang Bo , Wei Guolan , Sun Ye , Chen Chunyun , Guo Chuangxing , Tong Youzhi , Zhou Karl , Sun Ying-Hao
Published: September 2018

e16511

Background: Proxaluatmide is a novel dual MOA androgen receptor (AR) blocker with potent AR antagonist activity and capability to down-regulate AR level. We conducted a first-in-human phase 1 study to investigate safety, tolerability, and pharmacokinetics of GT0918 in patients with advanced CRPC. Methods: All participating patients must be confirmed with advanced CRPC progressed on SoC, PS 0-1, went through 2 periods of time of both single-dose and repeated-dose PK. Patients received GT0918 once orally followed by PK in first 7 days, and then once daily continuously for 28 days for DLT evaluation and repeated-dose PK. PK of drug elimination was done at the end of first cycle (7 days off-treatment). By the end of first 28-day cycle, DLT was evaluated and dose escalation was determined by modified Fibonacci's rule of 3+3 design. If patient tolerated GT0918 well and had no sign of tumor progression, he continued on the study medication thereafter. Results: Ninteen patients were enrolled and 16 patients were treated with GT0918 at five dose levels: 50 mg (n = 2), 100 mg (n = 4), 200 mg (n = 3), 300 mg (n = 3) and 400 mg (n = 4). No DLT was observed. MTD was not reached. GT0918-related adverse events were relatively mild (CTCAE grade 1 or 2), including hypercholesterolemia, peripheral edma, fatigue, flush, constipation and anorexia. PK study showed plasma drug concentrations increased as dose increased from 50mg to 300mg and saturation observed between 300mg and 400mg. Compared single dose (D1) with repeated dose (D35), the elimination half-life (T1/2) were shown 14-35h and 28-51h, respectively. With consideration of overly drug exposure and saturation of oral absorption, 100-400mg were recommended to be the dose range for Phase 2 for further clinical evaluations and dose selection. Clinical activities have been observed in numbers of patients in 100/200/300/400mg dose cohorts. Conclusions: Proxalutamide (GT0918) dosed orally once a day continuously for 12 weeks was generally well tolerated. GT0918 showed promising preliminary anti-tumor activity. Dose range of 100-400mg was recommended for Phase 2 trial and for 24 weeks of treatment.
Enzalutamide (E) versus abiraterone acetate (AA) in the treatment of metastatic, castration-resistant prostate cancer: Results of an indirect comparison with network meta-analysis.
Authors: Cherubini Chiara , Bianchi Emanuela , Drudi Fabrizio , Tamburini Emiliano , Fantini Manuela , Nicoletti Stefania , Stocchi Lucia , Nicolini Mario , Montanari Francesco , Gianni Lorenzo , Tassinari Davide
Published: September 2018

e16519

Background: To compare efficacy and safety of E and AA in the treatment of metastatic, castration-resistant prostate cancer. Methods: Efficacy and safety of E and AA were compared using the data of the PREVAIL, AFFIRM, COU-AA-302 and COU-AA-301 trials. All the data extracted from the selected trials were reported ad Hazard Ratio (HR) or Odds Ratio (OR). Overall survival was assumed as index of efficacy, and was the primary end point of our analysis, all the side effects, grade III-IV side effects, serious side effects, side effects leading to treatment discontinuation or death were assumed as indexes of safety and were the secondary end points of our analysis. Overall survival was assessed both in the entire population and in the subgroups of patients chemotherapy-naïve or docetaxel-resistant. An alpha error of 5% was assumed as index of statistical significance. Results: The outcome of 5191 patients were reviewed. 1671 patients had been treated with E, 1339 with AA and 2181 with placebo. Comparing E vs AA no differences were observed for overall survival in the entire population (HR = 0.955, IC95% = 0.796-1.144, p = 0.616), overall survival in chemotherapy-naïve patients (HR = 0.947, IC95% = 0.723-1.24, p = 0.692), overall survival in docetaxel-resistant patients (HR = 0.961, IC95% = 0.753-1.228, p = 0.75), all side effects (OR = 0.414, IC95% = 0.054-3.196, p = 0.463), grade III-IV side effects (OR = 1.36, IC95% = 0.253-7.318, p = 0.72), serious side effects (OR = 0.742, IC95% = 0.137-4.006, p = 0.729), side effects leading to treatment discontinuation (OR = 0.743, IC95% = 0.132-4.193, p = 0.736), and side effects leading to death (OR = 0.572, IC95% = 0.089-3.657, p = 0.556). Conclusions: Although E and AA differ for pharmaceutical structure and mechanism of action, they seem to be comparable both for indication (pre- or post-docetaxel treatment in patients with metastatic, castration-resistant prostate cancer), and for efficacy or safety (in chemotherapy-naïve and docetaxel-resistant patients). It follows that compliance, patients characteristics and costs can play a role in the decision making process of clinical practice.
New treatment for advanced and hormone refractory prostate cancer (HRPC) with an oral cholesterol derivative (hydroxysterol 24-ethyl-cholestane- 3β,5α,6α-triol).
Authors: Habib Nabil , Hage George , Daaboul Hamid Elia , Jabbour Abdo Elias , Zeitouni Hind , Khalife Ryiad
Published: September 2018

e16531

Background: Hydroxysterols and oxysterols are oxygenated derivatives of cholesterol. They are involved in the regulation of some aspects of neoplastic cell growth and proliferation, as demonstrated in vitro in a variety of human cancer cells including prostate cancer cells.These effects can be dependent on the activation of the oxysterol-binding liver X receptors (LXRs). LNCaP prostate tumor cells stimulated with synthetic LXR agonists showed G1 to S-phase cell cycle arrest through the suppression of Skp2.Prostate cancer is the most frequent cancer in men and most patients become resistant to upfront treatments with hormones. At advanced stages most refractory patients are symptomatic and their life expectancy is limited. (24-ethyl-cholestane- 3β,5α,6α-triol) is a new hydroxysterol developed by us. It is the first oxysterol to be tested in the clinic. It is also one of the safest in this class of compounds. Methods: We have treated with this new drug 14 patients suffering from advanced and hormone-refractory prostate cancer (HRPC). Their median age was 73 (60-88). Seven with a Gleason 7, 5 with a Gleason 8 and 2 with a Gleason 9. Eleven had stage IV disease, Eight with bone metastasis, 4 with advanced loco-regional disease and 2 with visceral metastasis. Ten patients were symptomatic. Four patients had received also 1 line of chemotherapy and 2 others received 2 lines of chemo. Four patients were also previously treated with radiotherapy. Patients received daily 10 mg/Kg of oral (24-ethyl-cholestane- 3β,5α,6α-triol) divided into 3 equal doses, until disease progression. Results: Ten patients experienced either a biological or a radiological partial response (PR), Two patients had a stable disease (NC) and two patients had a disease progression (PD). The median duration of response was 2 years. Patients did not report any side-effect from treatment. Eighty percent of symptomatic patients had a remarkable symptom control. Conclusions: These encouraging results make this new and safe drug a good candidate for further clinical trials either alone or in combination with other drugs in the treatment of HRPC.
Costs of pre-hospice care among metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone + prednisone (ABI) and enzalutamide (ENZ).
Authors: Li Sophia S , Engel-Nitz Nicole , Blauer-Peterson Cori , Behl Ajay S. , Dawson Nancy Ann
Published: September 2018

e16534

Background: mCRPC patients are likely to receive oral therapies such as ABI or ENZ prior to hospice care. Payers and clinicians perceive hospice care as improving the quality of life for advanced prostate cancer patients dying of cancer, but literature suggests that it may be underutilized. A previous study found a longer time to starting hospice for patients initiated on ABI (vs. ENZ) with no significant difference in time spent in hospice. Understanding the active-treatment period prior to hospice may shed light on the overall burden of treatment without discounting the benefits of hospice. This study examined total pre-hospice per patient per month (PPPM) costs among mCRPC patients who utilized hospice care and treated with ABI or ENZ. Methods: A retrospective study of a large national health claims database identified patients initiated on ABI or ENZ from 09/2012 to 06/2015. Patients included had: ≥1 claim with a prostate cancer diagnosis (ICD-9-CM 185.xx) from 6 mo. pre- to 30 days post-index; ≥6 mo. pre- and ≥3 mo. post-index health plan enrollment. Index was date initiated on first oral therapy (ABI/ENZ). The subset of patients who entered hospice care were identified. Descriptive analyses assessed total PPPM costs (pharmacy, ambulatory, ER, inpatient, other medical costs) for subset of pre-hospice patients and all patients. Generalized linear model (GLM) assessed adjusted pre-hospice costs. Since the GLM used a log-link function with cost as a dependent variable, results are interpreted as a ratio of costs. Results: Among 1,516 mCRPC patients, 213 had utilized hospice care (ABI: 161, ENZ: 52). Total pre-hospice PPPM cost was greater for patients initiated on ENZ (ENZ = $19,485 ABI = $13,252; p = 0.048). Adjusted analysis found a 25.8% greater PPPM cost for those patients (Cost Ratio = 1.26, p = 0.038). Among all 1,516 patients, total all-cause PPPM cost was higher in ENZ but not statistically significant (ENZ = $11,268 ABI = $10,520; p = 0.090). Total prostate cancer related PPPM cost was statistically significant (ENZ = $10,327 ABI = $9,477, p = 0.038). Conclusions: Total pre-hospice PPPM cost is 26% lower for mCRPC patients initiated on ABI vs. ENZ.
Predictors of radiologic progression free survival (rPFS) during abiraterone acetate (AA) treatment in a randomized phase II study of AA maintenance in combination with docetaxel (D) after disease progression to AA in metastatic castration resistant prostate cancer (mCRPC): ABIDO-SOGUG trial.
Authors: Castellano Daniel , Méndez-Vidal María José , Puente Javier , Sáez M Isabel , Font Pous Albert , Duran Ignacio , Santander Carmen , Sanchez-Hernandez Alfredo , Arranz Arija Jose Angel , Alonso Teresa , Mellado Begoña , Lázaro Quintela Martin , Gonzalez del Alba Aranzazu , Esteban Emilio , Maroto Pablo , Cassinello Javier , Climent Miguel Ángel
Published: September 2018

e16536

Background: AA improves OS and rPFS in asymptomatic/minimally symptomatic mCRPC patients. D is currently one of the standard treatments after progression to AA. However, the value of maintaining AA along with D despite progression to AA has not been tested. ABIDO trial aims to evaluate efficacy and safety of AA + D maintenance after disease progression to first line AA in mCRPC. Clinicopathologic features associated with rPFS during first line AA are presented. Methods: ABIDO trial is a randomized, phase II, open-label study with two stages. In stage I pts receive AA (1000 mg + prednisone (P) 10 mg qd) until progressive disease. In the stage II pts will be randomized to receive three-weekly D 75 mg/m2plus P 10 mg/d with (arm A) or without (arm B) AA 1000 mg/d. Pts had no visceral metastases, ECOG PS 0-1, and adequate organ functions. Clinicopathological predictors for rPFS to first line AA were estimated using the Kaplan-Meier method and independent associations were evaluated using Cox regression models. Results: 143 pts were included. Analyzed variables were: median age was 70y, 60% of pts had ECOG 0, 84% bone metastases (18% > 4), 42% BPI score 2-3, 53% Gleason > = 8, 30% PSA > 80 ng/mL, 38% node involvement and 11% had at least one lymph node > = 3 cm; 53% of pts achieved 4 weeks PSA reduction > 50%.Median rPFS was 18 months. Univariate analysis identified as significant variables: PSA, BPI, Gleason, node involvement, 4 weeks PSA reduction > 50%, and total volume of lymph node metastasis. On multivariate analysis, BPI (0-1 vs 2-3) (hazard ratio [HR] 1.81; p = 0.039), Gleason ( < 8 vs > = 8) (HR 2.51; p = 0.005), node involvement (no nodes, nodes < 3 cm and at least 1 node > = 3 cm (HR 2.8; p = 0.001 and 3.57; p = 0.009) and PSA reduction > 50% (HR 3.06; p < 0.001) were independently associated with rPFS. Median rPFS was superior in pts with 3 or more good prognostic factors (14m vs not reached; p < 0.001). Conclusions: BPI, Gleason, node involvement and 4-week PSA response were identified as independent prognostic factors for rPFS in first line AA treated patients. Clinical trial information: NCT02036060.
Insurance status and patterns of late diagnosis and cancer treatment: A population-based study.
Authors: Lu-Yao Grace L. , He Jianming , Giri Veda N. , Klassen Ann
Published: September 2018

e16553

Background: This population-based study assesses the relationship between insurance status and patterns of prostate cancer diagnosis and treatment among men under age 65. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 114,871 prostate cancer patients who were diagnosed before 65 between January 2007 and December 2013. Insurance type was classified as uninsured (3.1%), Medicaid (5.1%) and other including private insurance and coverage from the military or Veterans Affairs (91.8%). We used logistic regression model to quantify the relative risk of being diagnosed with metastasis or regional disease, and the relative likelihood of receiving radical prostatectomy or radiotherapy among those with localized cancer adjusted by, age, race, marital status, region, and diagnosis period. Results: Medicaid or uninsured patients are more likely to have late diagnosis (diagnosed with positive lymph node or metastasis) than patients with non-Medicaid insurance (Table 1). Among men diagnosed with localized prostate cancer, Medicaid and uninsured patients are less likely to receive prostatectomy. Medicaid patients are more likely to have radiotherapy than un-insured (see table). Conclusions: Compared with patients with non-Medicaid insurance, Medicaid and uninsured patients are more likely have late diagnosis and less likely to have radical prostatectomy for localized cancer, after accounting for differences in age, race, marital status, region, and diagnosis period. [Table: see text]
Utility of a novel biopsy instrument with long side-notch needle in the selection of patients for active surveillance.
Authors: Kanao Kent , Kajikawa Keishi , Kobayashi Ikuo , Muramatsu Hiroyuki , Morinaga Shingo , Nishikawa Genya , Kato Yoshiharu , Watanabe Masahito , Nakamura Kogenta , Sumitomo Makoto
Published: September 2018

e16581

Background: Active surveillance (AS) is now an accepted strategy for men with low-risk prostate cancer (PCa). A critical factor for successful AS is the best possible patient selection. We recently develop a novel 18-G biopsy instrument based on an existing instrument, by extending the side-notch length from 19 to 25 mm and the stroke length from 22 to 28 mm, to take a longer tissue core and to reach the anterior portion of the prostate.In this study, we evaluated utility of the novel biopsy instrument in the selection of patients for AS. Methods: A total of 167 PCa patients diagnosed with the long-notch needle (n = 62; long-notch group) or normal-notch needle (n = 105; normal-notch group), who subsequently underwent prostatectomy, were retrospectively analyzed. All patients were diagnosed with 12 transrectal ultrasound-guided standard cores.The sampled core length, correlation between total tumor length in biopsy specimens, and total tumor volume in prostatectomy specimens were compared between the two groups. Gleason score (GS) upgrading was also compared. Prostatectomy specimens of patients who met the criteria of the PRIAS study were compared for the two groups. Results: The mean length of tissue taken with the long-notch needle was significantly longer than that taken with the normal-notch needle (16.3 vs. 22.4 mm, p < 0.001). The correlation coefficient between total tumor length in biopsy specimens and total tumor volume in prostatectomy specimens of the long-notch group was higher (r = 0.701) than that in the normal-notch group (r = 0.611). GS upgrading in the long-notch group was significantly lower than that in the normal-notch group (25.8 vs. 41.0%, p = 0.0479).Only 1 patient with tumor volume > 0.5 cc and GS 4+3 or more was included among the 5 who met the criteria of the PRIAS study in the long-notch group, while 6 patients were included among the 10 who met the criteria in the normal-notch group. Conclusions: We developed a novel biopsy instrument with a 25 mm side-notch for longer tissue samples, increased correlation between tumor volume in biopsy and prostatectomy specimens, and decreased GS upgrading. These results suggested the utility of the long-notch needle in the selection of patients for AS.
Phase II study of perioperative combination chemotherapy with triweekly carboplatin and weekly dose dense paclitaxel and radical hysterectomy for locally advanced cervical cancer (SGSG-016 study).
Authors: Nagao Shoji , Kogiku Ai , Nonaka Michiko , Shiroyama Yuko , Oishi Tetsuro , Yamaguchi Satoshi , Takehara Kazuhiro , Shimada Muneaki , Kigawa Junzo
Published: September 2018

e17022

Background: The primary objective of this study was to assess efficacy and safety of triweekly carboplatin plus weekly dose dense paclitaxel (ddTC therapy) before and after radical hysterectomy without radiotherapy (RH) for women with locally advanced cervical cancer. Methods: Patients with FIGO stage IB2, IIA2, or IIB cervical cancer received 3 cycles of carboplatin at an area under the curve of 6 on day 1 and paclitaxel at 80mg/m2on day 1, 8, and 15 every 21 days followed by RH. Patients with one or more high-risk factors for recurrence including lymph vascular invasion, parametrial invasion, lymph node matastasis, or positive margin received additional 3 cycles of ddTC therapy after RH. Results: Between September 2014 and July 2016, 50 women including 13 with FIGO stage Ib2, 5 with stage IIa2, and 32 with stage IIb were enrolled in this study. There were 37 squamous cell carcinoma, 10 adenocarcinoma, 2 adenosquamous carcinoma, and 1 large cell neuroendocrine carcinoma. Median age was 46 years (range 30-78). Forty-three women (86%) completed planed 3 cycled of chemotherapy before surgery. The overall response rate was 92% (18 complete response, 28 partial response, 3 stable disease, 1 progressive disease). Forty-nine patients (98%) completed planed radical hystsrectomy, but a patient with invasion to bladder musculature received concurrent radiation therapy instead of surgery. Eleven patients (22%; 10 with SCC, 1 with large cell neuroendocrine carcinoma) achieved pathological complete response. Eleven other patients with one or more high-risk factors received 3 cycles of ddTC therapy after surgery. Grade 3/4 hematological toxicities included neutrocytopenia (58%), thrombocytopenia (2%) and anemia (24%). One patients experienced neutropenic fever. Grade 3/4 non-hematological toxicities were observed in 4 patients (1, grade 3 nausea; 1, grade3 carboplatin allergy; 1, grade 3 paclitaxel allergy; 1 grade 3 elevetaed liver enzyme). Conclusions: Administration of ddTC therapy before and after RH has good efficacy and acceptable toxicity in women with locally advanced cervical cancer. Clinical trial information: UMIN000024136.
Correlation of isotope count with sentinel node positivity in vulvar cancer.
Authors: Woelber Linn Lena , Joosse Simon , Grimm Donata , Mahner Sven , Burandt Eike , Schmalfeldt Barbara , Klutmann Susanne , Prieske Katharina
Published: September 2018

e17033

Background: Sentinel node biopsy (SNB) has become standard of care in early stage vulvar cancer. As the correlation of isotope count with the presence of metastases remains unclear, often several active nodes are excised per groin. This can result in increased morbidity in node-negative disease despite of SNB. In the current analysis we assess, whether resection of the hottest node could be sufficient to detect sentinel lymph node (SNL) metastasis. Methods: All patients with primary vulvar cancer receiving a SNB with radioactive tracer at the University Medical Center Hamburg-Eppendorf between 2008 and 2015 were evaluated. The day before surgery, patients received four peritumoral intradermal deposits at 3, 6, 9 and 12 o’clock with an overall mean dosage of 85±12MBq99mTc–nanocolloid. Planar lymphscintigraphy was performed one hour after injection. Intraoperatively, a handheld gamma counter was used to identify the SNL. Results: 146 patients with SNB were included; thereof 145 pts underwent bilateral SNB, resulting in 291 analyzed groins. A median of 2 (range 1-7) SNL per groin were removed. From 95/291 (32.6%) groins more than 2 SNL were excised. Median overall SNL isotope count was 1400. In 52 groins, a positive SNL was detected (unilateral in 38 patients, bilateral in 7). The median number of positive SNL per groin was 1 (range 1-4). There was no difference of median count in negative compared to positive SNL (median count 1396 vs. 1614; p=0.90). The SNL with the highest isotope count carried metastases in 36/48 groins (75.0%; in 4 cases the highest count was unknown). In 12/48 (25.0%) positive groins, the SNL with the highest count was not the metastatic SNL (11/12 second highest count). Median count of these 12 SNL was 58.8% of the highest count with a range from 6.0% to 74.0%. Conclusions: The highest isotope count does not reliably detect the positive SNL in vulvar cancer. To prevent mostly fatal groin recurrences, surgeons should continue to remove all SNL accumulating relevant radioactive tracer over minimal background activity.
A comparison of measured and estimated glomerular filtration rate (GFR) for carboplatin dose calculation in women with ovarian cancer (OC).
Authors: Ocen Joanita , Frazer Ricky Dylan , Wright Sarah , Lewis Paul D , Bertelli Gianfilippo
Published: September 2018

e17051

Background:Carboplatin based chemotherapy is widely used to treat women with Ovarian cancer (OC) in the adjuvant, neoadjuvant and palliative settings. Carboplatin is normally dosed by the Calvert formula: [GRF+25] x AUC, with a target AUC (area under the plasma concentration curve) of 5-6 mg/ml/min. GFR (glomerular filtration rate) can be precisely measured with radionuclide based ligands such as 51Cr-ethylenediamine tetraacetic acid (51Cr-EDTA), but in clinical practice is often estimated using formulae incorporating serum creatinine, weight and age, such as the Cockcroft–Gault (CG) or Wright (WR) formulae. It is unknown, however, if these formulae allow a sufficiently accurate dosing of carboplatin in OC patients. Methods:We retrospectively compared measured (EDTA-based) and estimated (CG and WR formulae) GFR and the resulting carboplatin doses, in women with stage 1c to IV OC treated with carboplatin AUC 6 at our centre between 2015 and 2016. All patients (pts) had concurrent 51Cr-EDTA GFR and serum creatinine measurement before starting carboplatin. Accuracy and bias of The WR and CG formulae were analysed using mean absolute percentage error (MAPE) and mean percentage error (MPE). Results:92 pts were included in the study (median age = 69 years (r. 25 -89), median serum creatinine 63.5 umol/L (r. 38 – 168)). MPE was -37.3 and -26.0 and MAPE was 38.0 and 32.2 for the WR and CG formulae, respectively. If the WR or CG formulae had been used instead of EDTA to calculate the dose of carboplatin, the discrepancy would have been at least 10% in 77.1% and 69.8% of pts, respectively; a discrepancy of 50% or more would have occurred in 10% and 13% of pts. Conclusions:Neither the WR nor CG formulae precisely predict renal function in ovarian cancer pts. They often overestimate GFR, meaning that if these formulae are used instead of isotope-based measurement of GFR, most pts will receive a higher dose of carboplatin. Our findings are relevant for clinical practice and for the design and interpretation of clinical trials, where the choice between EDTA- or formulae- based calculations of carboplatin dose are often left to investigators’ preference.
Phase I study combining olaparib and tremelimumab for the treatment of women with BRCA-deficient recurrent ovarian cancer.
Authors: Adams Sarah Foster , Rixe Olivier , Lee Ji-Hyun , McCance Dennis J. , Westgate Sheri , Eberhardt Steven C. , Rutledge Teresa , Muller Carolyn
Published: September 2018

e17052

Background: With evidence that BRCA dysfunction is associated with increased T cell recruitment to tumor sites, and that PARP-inhibition may increase the immunogenicity of tumor cells, we evaluated the combination of a PARP-inhibitor and CTLA4 immune checkpoint antibody in BRCA1- ovarian cancer models. Our results demonstrated significant therapeutic synergy and durable treatment responses in preclinical studies. Based on this, a Phase I study was conducted to assess the tolerability of this regimen in women with BRCA mutation-associated recurrent ovarian cancer. Methods: Eligibility criteria included a documented BRCA1 or BRCA2 germline mutations and a diagnosis of recurrent ovarian, tubal, or primary peritoneal cancer with measurable disease. Both platinum-sensitive and platinum resistant patients were eligible. Patients with prior exposure to PARP-inhibitors or to immune therapy with the exception of CTLA4 antibodies were also eligible. Exclusion criteria included current use of anti-inflammatory agents or a prior history of autoimmune disease. Treatment consisted of Olaparib at 300mg twice daily, as well as monthly infusions of Tremelimumab at a dose of 10mg/kg, with plans for a dose reduction if toxicity was encountered. Patients completing two full treatment cycles were evaluated for evidence of toxicity, particularly immune-related adverse events, to define a dose for Phase II testing. Results: Three women were treated at the starting dose of 300mg BID of Olaparib and 10mg/kg monthly of Tremelimumab for two cycles without evidence of any dose-limiting toxicities or grade 3 adverse events. All patients experienced grade 1 and 2 toxicities, including immune related toxicities consistent with prior studies of immune checkpoint inhibitors. All three patients showed evidence of treatment response by cycle 3 based on CA125 levels and a decrease in tumor size on CT scans. Conclusions: The combination of PARP-inhibition and CTLA-4 blockade is tolerable in heavily pre-treated women with recurrent BRCA-associated ovarian cancer. Preliminary results also demonstrate evidence of therapeutic effect, supporting ongoing evaluation of this regimen in Phase II trials. Clinical trial information: NCT02571725.
Harnessing IMGN853-mediated cell cytoxicity response by modulating FRα expression in ovarian cancer.
Authors: Kumar Rajesh , Wei Wei , Lauffer Sam , Fulci Giulia , Birrer Michael J.
Published: September 2018

e17061

Background: Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women in the United States. Standard treatment includes debulking surgery followed by platinum based chemotherapy. While most tumors respond to this treatment, 70% of the tumors recur and develop into a chemo-resistant disease. There is a need for new therapies targeting recurrent chemoresistant OC. To address this need, Mirvetuximab Soravtansine (ImmunoGen, Waltham, MA) has developed an antigen-drug conjugate (ADC) containing DM4, a highly potent maytansinoid derivative that induces the cell cycle arrest, conjugated to an antibody targeting folate receptor alpha (FRα). Mirvetuximab Soravtansine (IMGN853), was tested in Phase I clinical trials on women with recurrent OC and showed low grade toxicity profile and activity in platinum-resistant disease. The goal of this study is to characterize the mechanism(s) leading to IMGN853 resistance in OC and test whether anticancer drugs targeting these mechanisms could be used in combination with IMGN853 for an additive/synergistic therapeutic effect. Methods: In vitro experiments were performed to detect and modulate FRα expression. Results: We show that sensitivity of OC cell lines to IMGN853 correlates with the expression levels of FRα (R = 0.82). Long-term exposure of sensitive cells to sublethal doses of IMGN853 induces drug resistance which correlates with decreased FRα expression. Anti-cancer drugs such as dexamethasone (Dex), which induces glucocorticoid receptors, or epigenetic modulators (Trichostatin A and 5-Azacytidine) induce FRα expression in SKOV3 and OVCAR8 OC cells, suggesting the possibility to use these drugs to maintain sensitivity of OC cells to IMGN853 and increase its therapeutic window. The therapeutic benefits of combining each of these drugs with IMGN853 will be further tested in mice using ovarian cancer patients’ derived xenografts with different FRα expression levels. Conclusions: These findings have clinical implications as they indicate that OC sensitivity to IMGN853 is modulated in part by changes in FRα levels. Resistance to this drug may be overcome by simultaneous treatment with Dex or other anti-cancer drugs such as TSA or AZA.