bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of cholesterol and triglyceride increases on time to progression in renal clear cell cancer patients treated with everolimus.
Authors: Pantano Francesco , Procopio Giuseppe , Silletta Marianna , Ortega Cinzia , Guida Francesco Maria , Venditti Olga , Prati Veronica , Imperatori Marco , Spoto Chiara , Verzoni Elena , Intagliata Salvatore , Vincenzi Bruno , Tonini Giuseppe , Rizzo Mimma , Santini Daniele
Published: March 2020

e15528

Background: An increased level of cholesterolemia (C) and triglyceridemia (T) secondary to an impairment of lipidic metabolism is a well known side effect of all mTOR inhibitors including everolimus. In the phase III pivotal study of everolimus in mRCC patients, an increase of C and T was reported in 77 and 73 % of patients, respectively. Increase of C and T may represent a surrogate parameter related to mTOR pathway inhibition. On these basis, we assessed the value of C and T increase as a factor predicting the efficacy of everolimus in metastatic clear cell renal cancer. Methods: We retrospectively evaluated 46 patients ( 36 male: 10 female; mean age 61.4 years +/- 11.5) with metastatic clear cell renal cancer who received a second/third line with everolimus after at least one tyrosine-kinase inhibitor (TKI). From routinely performed blood test, we retrieved the value of total C and T the day before the first everolimus admnistration and during the entire duration of treatment. We also considered for each patient variations of glycemia, blood pressure and BMI before and after beginning of treatment, as parameters of metabolic syndrome. Time to progression (TTP) and survival were evaluated. Results: Among all the potential predictive factors considered, only the increase of cholesterol and triglyceride (> 20% compared to the baseline) within 2 months from the start of everolimus correlated with efficacy. Median TTP of the 19 patients with total early C upraising was statistically significant higher than in 27 patients without upraising (14.1 months vs 5.5 months, P= 0.009). Conversely, only a positive trend favoring patients with C upraising was recorded in median survival (24.9 months vs 16.0 months, P= 0.163 ). Both median TTP and median survival were found to be statistically significant higher in the 25 patients experiencing T upraising than in the 21 patients who did not (respectively, 13.0 months vs 4.9 months, P= 0.007 and 26.4 months vs 13.4 months, P= 0.018). Conclusions: Early C and T modifications predict everolimus efficacy in renal clear cell cancer.
Side-effect analysis of sunitinib (S) in patients treated with metastatic renal cell cancer (mRCC): Single center experience in the National Institute of Oncology, Hungary—Influence of dose reduction/modification and application schedule on the efficacy of S.
Authors: Nagyivanyi Krisztian , Biro Krisztina , Bodrogi Istvan , Gyergyay Fruzsina Eva , Kuronya Zsofia , Nemeth Hajnalka , Geczi Lajos
Published: March 2020

e15530

Background: S, an active and relatively well tolerated treatment for mRCC, based on the result of a global phase III study. Methods: Retrospectively, 383 patient’s data with clear cell mRCC were collected, who were treated with S in our department between 01/nov/2005 and 31/dec/2012. S was used in 1st or 2 nd line setting. The first few dozen subjects were involved in a clinal trial after progression on first line INF therapy. In Hungary S became reimbursed by the public health insurence from 01/jan/2008 in second line, and from 01/feb/2010 in first line. All patients had definitely favorable or intermediate risk based on MSKCC risk group criteria. The starting dose of S was mostly 50 mg (schedule 4 weeks on followed by 2 weeks off). Results: We investigated the prevalence of necessity of dose reduction/modification or pretence to follow an out of ordinary application form. We registered the frequency and modality of the different types of side effects, we also studied the outcome of patients. Incidence of grade 3+4 side effects was nearly 60%. The most common side effects were fatigue (63%), mucositis/stomatitis (40,2%), hand-foot syndome (16,1%), diarrhea (34%), hypertension (34%), nausea (2%), anaemia (8,6%), leukopenia (4,6%), thrombopenia (20%) and hypothyreosis (20%). Objective response rate based on RECIST and progression-free survival (PFS) were also recorded. The efficacy of treatment was nearly similar to the global clinical trial results. CR was rare (4,2%), most of our patients had PR (31,1%) or SD (51,2%) as best response. In first line setting the results were even better (CR 10,5%, PR 44% and SD 57,5). Conclusions: S is effective and safe agent to treat patients with mRCC. Due to side effects, dose reduction / modification is often needed but rarely requires treatment discontinuation. The early detection and right management of side effects is crucial to maintain the patients on the treatment. Unfortunately the deviation from the standard care may bias the efficacy.
Everolimus treatment-associated interstitial lung disease (ILD) as a prognostic factor in Japanese patients with metastatic renal cell carcinoma.
Authors: Hongo Fumiya , Oishi Masakatsu , Ueda Takashi , Kimura Yasunori , Nakamura Terukazu , Naya Yoshio , Mikami Kazuya , Miki Tsuneharu
Published: March 2020

e15531

Background: Interstitial lung disease (ILD) is one of the adverse events during treatment with everolimus for metastatic renal cell carcinoma (mRCC). Japanese study of everolimus treatment-associated ILD as a prognostic factor is rare. Methods: We retrospectively assessed the incidence and outcome of ILD in mRCC patients treated with everolimus. Between April 2010 and August 2012, 25 cases were treated with everolimus after the failure of one or two TKIs in our institute. All adverse events were graded in accordance with NCI CTCAE, version 3.0. Results: A total of 25 patients received treatment with everolimus and included 18 male and 7 female patients ranging in age from 21 to 84 years (median 62). According to MSKCC risk criteria, 6 cases were at favorable risk, 16 cases were at intermediate risk, and 3 cases were at poor risk. The median treatment term was 4 months (range 2-17 months). SD was reported in 19 cases and PD in 6 cases. Progression free survival was 3.5 months and overall survival was 12 months. ILD was found in 7 cases (28%). One was G1, five were G2, and one was G3. Corticosteroid therapy was initiated in 3 cases. In 5 of 7 ILD cases, everolimus was re-challenged. In our series, patients with ILD showed significantly better progression free survival than those without ILD (PFS was 8 months vs 3 months. Log-rank, P<0.001). There were no significant differences between the two groups in overall survival (12 months in patients with ILD vs 10 months in patients without ILD. Log-rank, NS). Conclusions: Everolimus appears to have been effective and well-tolerated in our institute. Re-challenge with everolimus was feasible after improving everolimus-induced ILD in cases of grade 1-2. To confirm these findings, the efficacy and AE profile of everolimus in Japanese patients should be investigated.
Safety and efficacy of axitinib in pretreated patients with metastatic renal cell carcinoma: A single center experience of the Medical University of Vienna, Austria.
Authors: Vogl Ursula Maria , Ponhold Lothar , Locker Gottfried J , Zielinski Christoph , Klingler Christoph , Kramer Gero , Schmidinger Manuela
Published: March 2020

e15535

Background: Axitinib is a highly selective inhibitor of VEGFR-1, 2 and 3 and has recently been approved for second-line treatment of metastatic renal cell cancer (mRCC). We present data of 43 patients treated with axitinib in second-line and beyond. Methods: Medical records of all patients who were treated with axitinib between July 2009 and December 2012 were retrospectively reviewed. Axitinib was prescribed at a dose of 5 mg bid and escalated to 7 or 10 mg bid in the absence of hypertension and other dose-limiting toxicities. Objective response rate (ORR) was assessed by RECIST. Progression free survival (PFS) and overall survival (OS) were calculated from the first day of axitinib until progression and/or death, respectively. Results: Fourty-three patients with a median age of 65 years (range: 17-84) are currently evaluable for analysis. The majority of patients (58.1%) had an ECOG Performance status of 0 and were classified MSKC- intermediate risk (62.8%). All patients had undergone surgery for the primary tumor and 53.5% had three or more metastatic sites. Fifty-five percent of the patients received axitinib in third or fourth-line (14% and 41.9%, respectively). Prior therapies included sunitinib (86%), everolimus (35%) and pazopanib (35%) and 62.8% had progressed on sunitinib before axitinib was initiated. Objective remission and disease stabilization were observed in 14.3% and 40% of the entire population. The median PFS and OS were 6.8 months (95% CI: 5.5 – 8.0) and 17.2 months (95% CI: 10.8 – 23.6), respectively. Dose escalation to 7 or 10 mg bid was feasible in 40% of the patients. Fatigue (76.7%), hypertension (65.1%) and hypothyroidism (53.5%) were among the most commonly observed all grade toxicities. Conclusions: Axitinib showed considerable efficacy in both second-line and beyond second-line patients. Generous dose escalation based on a “treat to hypertension”-concept may have led to a longer PFS than previously reported from a purely VEGFR-TKI-refractory patient population.
The predictive value of hENT 1 molecule for gemcitabine treatment in bladder cancer.
Authors: Sener Dede Didem , Kilicaslan Aydan , Akinci Muhammed Bulent , Demirci Umut , Tahtaci Gozde , Yalcin Bulent
Published: March 2020

e15540

Background: Human equilibrative nucleoside transporter 1 (hENT1) is the nucleoside transporter protein which plays the main role for transportation of gemcitabine into the cells. We aim to assess the predictive value of the hENT 1 molecule in bladder cancer patients treated with gemcitabine based chemoterapy. Methods: Clinically and histologically documented stage III and stage IV invazive bladder cancer patients were included in the study. The patients were assessed retrospectively. All patients were received gemsitabine-platine based chemotherapy as the first line treatment. Spesific hENT1 antibody staining was performed on the chemo-naive bladder tumor specimens immunuhistochemically. Vascular endotel and lymphocytes served as an external positive control for hENT 1 immunuhistochemistry. Staining intensity was graded as 0,absent; 1+, less intens than control tissue, 2, equally positive as control tissue; 3, more intense than control tissue. Tumor spesimens with having 3+ intensity staining in >50% of the tumor cells were accepted as showing high expression of hENT 1. Results: Fifty one patients were included in the study. The median age was 67 (range 41-85). Ninety two percent(n=52) of patients were male. Twenty six (46.4%) and 25 (44.6%) patients were stage III and stage IV disease at the beginning of the therapy, respectively. Thirty four (60.7%) patients were in neoadjuvant treatment group and 17 (30.4%) patients were in metastatic group. Tumor grades could be assessed in 33 patients; 2 (11.4%) were low grade and 31 (88%) were high grade. The median folllow up period was 13 (range 1-58) months. In neoadjuvant group 5 (14%) patients have low hENT 1 level and 21 (60%) patients have high hENT 1 level. In metastatic group 1 (5%) patients have low hENT1 level and 13 (95%) patients have high hENT 1 level. We found no statistically significant difference between hENT 1 low and hENT 1 high groups in terms of response to therapy in metastatic and neoadjuvant groups (p=0.426 and p=0.684 respectively). Conclusions: More stuides are needed to demonstrate the real role of hENT 1 molecule in terms of response to gemsitabine treatment.
Clinical prognostic factors associated with outcome in renal cell cancer (RCC) patients with prior tyrosine kinase inhibitors or immunotherapy treated with everolimus.
Authors: Amato Robert J. , Flaherty Amber Lea , Zhang Yufeng , Stepankiw Mika
Published: March 2020

e15544

Background: Everolimus was approved for treating RCC patients who failed sunitinib or sorafenib by the Food and Drug Administration in 2009. We sought to develop a predictive clinical model predicting benefit for patients treated with everolimus as 2nd- or 3rd-line therapy for metastatic RCC. Methods: The study included 66 patients with RCC who failed immunotherapy or tyrosine kinase inhibitors to identify risk factors for progression-free survival (PFS) and overall survival (OS). Forty-one patients were updated with outcomes from the original phase II study (Amato 2009 Cancer) and an additional 25 patients were added from the expansion study. Kaplan-Meier method was used to calculate PFS and OS. Univariate and multivariate analyses were constructed using COX Proportional Hazard model and step-wise procedure. The model was validated by measuring the overall concordance index using the rms R package. Results: For the entire population, median PFS was 5.9 months (range, 0.4-34.5), and median OS was 16.1 months (range, 1.3-39.5). The univariate analysis revealed 5 factors associated with PFS and 9 factors associated with OS. From the multivariate analysis, 3 variables were kept in the final PFS model (LDH>203, no lung metastases, lymphocytes <25). Patients were assigned to 1 of 2 risk groups: ≤1 factor (favorable risk, median PFS 9.7 months) or ≥2 factors (poor risk, median PFS 2.8 months). Four variables were kept in the final OS model (lymphocytes <25, LDH >203, presence of bone metastasis, platelets ≥300). Patients were assigned to 1 of 3 groups: ≤1 factor (favorable risk, median OS 29.6 months), 2 factors (intermediate risk, median OS 14.3 months), or ≥3 factors (poor risk, median OS 7.2 months). Conclusions: A prognostic model was developed composed of 3 readily available clinical parameters for PFS and 4 clinical parameters for OS to help stratify patients into favorable, intermediate, and poor prognosis groups for the treatment of everolimus in clear cell RCC patients. These risk groups can be used by physicians to identify patients most likely to respond to everolimus. Results of the analysis will be presented.
Clinical prognostic factors associated with outcome in renal cell cancer (RCC) patients treated with modified vaccinia ankara plus tumor-associated antigen 5T4 (MVA-5T4).
Authors: Pandey Prasamsa , Xiong Youxin , Zhang Yufeng , Stepankiw Mika , Amato Robert J.
Published: March 2020

e15545

Background: Development of MVA-5T4 as an immunotherapeutic vaccine led to studies demonstrating it is safe and highly immunogenic as a monotherapy or combination (Amato 2008 Clin Cancer Res, Amato 2008 J Immunother, Amato 2009 J Immunother). Antitumor activity has been minimal. We examined identifiable clinical factors to develop a prognostic model to select patients for vaccine immunotherapy. Methods: Clinical data from 3 phase II studies were received for a total of 50 patients treated with MVA-5T4 alone, MVA-5T4 plus interferon-α or MVA-5T4 plus interleukin-2. Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS). Univariate and multivariate analyses were constructed using COX Proportional Hazard model and step-wise procedure. The model was validated by measuring the overall concordance index. Results: For the entire population, median PFS was 3.6 months (range 0.9-42.8 months), and median OS was 12.4 months (range 1.0-45.6 months). Univariate analysis revealed 10 clinical factors associated with PFS and 9 clinical factors associated with OS. Multivariate analysis identified 5 factors associated with PFS benefit (ECOG status ≥1, lymphocytes <25, >2 metastatic sites, neutrophils ≥69, albumin <4) and 6 factors associated with OS benefit (ECOG status ≥1, >2 metastatic sites, neutrophils ≥69, platelets >300, prior treatment with tyrosine kinase inhibitors/immunotherapy, Furham grade of 3/4). The prognostic model was divided into 3 categories. Patients with 0-1 factors (favorable) had a median PFS of 9.4 months and OS of 26.2 months, patients with 2-3 factors (intermediate) had a median PFS of 3.0 months and OS of 9.1 months, and patients with 4+ factors (poor) had a median PFS of 2.0 months and OS of 2.0 months. Conclusions: This analysis identified 7 available clinical factors that can classify patients with mRCC into 3 risk groups with various outcomes. Further validation of this model will identify which patients most likely to respond to MVA-5T4 as well as other vaccines. This will allow for the appropriate application of treatment to patients most likely to benefit.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of patients with brain metastases (BM) from renal cell cancer (RCC).
Authors: Naskhletashvili David , Gorbunova Vera , Bychkov Mark , Bekyashev Ali , Karahan Vladislav , Aloshin Vladimir , Michina Zoya , Medvedev Sergey , Prozorenko Evgeny , Markovich Alla
Published: March 2020

e15546

Background: About 2–11% of all patients (pts) with RCC develop BM, leading to a poor prognosis and a median survival of <6 months after whole brain radiotherapy. The role of targeted therapy in the management of BM is controversial. This study was designed to evaluate EGFR TKIs in RCC pts with BM. Methods: eligible pts had confirmed RCC and BM (≥1 lesion of ≥10mm diameter) aged >18 years with ECOG performanse status (PS) of 0–2. From June 2009 to January 2013, 11 pts with RCC and BM were enrolled in this study. 10 pts (91%) had extracranial metastases. 6 pts received sunitinib (50mg/day, 4 weeks, every cycle), 4 pts received sorafenib (800 mg/day) and 1 patient received pazopanib (800 mg/day) until radiologically-verified progressive disease. The primary endpoints were objective response rate (ORR) - complete and partial response in the brain and in the extracranial lesions, progressive-free survival (PFS) and overall survival. Demographics were: median age - 59 years (range 44–74 years); male/female - 10/1; PS 1/2 - 7/4; previously treated/untreated - 10/1; number of BM: ≤3/>3 - 6/5. Previous treatment: nephrectomy – 10 pts (91%), cytokines – 6 pts (54,5%), targeted therapy (before BM) – 4 pts (36,4%). Local control of BM: previous neurosurgery – 2 pts (18,2%), radiosurgery – 4 pts (36,4%), previous neurosurgery + radiosurgery – 2 pts (18,2%). Results: ORR in the brain was 27,3% (3 partial responses). All partial responses in the brain achieved in patients who received targeted therapy and radiosurgery. Stable disease in the brain was 54,5% (6 pts). 1 patient with stable in the brain received targeted therapy and radiosurgery, 5 pts received targeted therapy. ORR in the extracranial lesions was 20% (2 partial responses). Stable disease in the extracranial lesions was 50% (5 pts). The median of PFS was 6 months. The median of overall survival was 10 months. Conclusions: surgery and radiotherapy, including radiosurgery, must be considered as optimal local treatment for pts with RCC and BM. Targeted drugs have demonstrated their ability to achive a clinical and X-ray verified objective effect (as stabilization in most cases) in treating of pts with disseminated RCC and BM.
Correlation of pathologic findings after brief neoadjuvant sorafenib (neoS) with results of dynamic-contrast enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in patients (pts) with locally advanced or metastatic clear cell renal cell carcinoma (RCC).
Authors: MacVicar Gary R. , Miller Frank , Rustogi Rahul , Chen Zong-Ming , Martone Brenda K. , Kuzel Timothy
Published: March 2020

e15554

Background: Many pts receiving tyrosine kinase inhibitors for RCC manifest stable disease as their best response by RECIST criteria. We hypothesized that tumor necrosis by DCE and DW-MRI after brief treatment with neoS may correlate with pathologic findings. We investigated in a pilot study whether these MRI changes may serve as an imaging biomarker predictive of clinical outcome. Methods: Pts with locally advanced or metastatic clear cell RCC undergoing nephrectomy or metastastectomy were treated with neoS 400mg PO bid for 28 days prior to surgery. The feasibility and safety of neoS was determined. Tumor necrosis detected by DCE and DW MRI’s pre- and post-neoS were compared and correlated with survival and pathologic findings at surgery. RECIST/WHO criteria were also compared. Results: 9 pts were enrolled, and all underwent surgery after neoS, 4 weeks (n=7) or less for toxicity (n=2). Clear cell/sarcomatoid histology was noted in 8 pts, and papillary in 1. All pts had T3 or T4 disease. 7 had M1 disease. No surgical complications occurred. 7 pts (78%) experienced Grade 3 toxicities, including hypertension (n=1), pancreatitis (n=1), hand-foot syndrome (n=1), hyponatremia (n=2), and rash (n=2). No grade 4 or 5 toxicities were observed. 4 of 8 clear cell/sarcomatoid pts (50%) have died, 3 due to progressive disease and 1 of unrelated causes. DCE and DW MRI’s with direct surgical pathological correlation were available in 7 of these pts. The mean ADC DW MRI changes in the renal lesion of 4 longer term survivors (median survival = 43 months) was +.22 vs. –0.07 in the 3 short term survivors (median survival = 13 months). RECIST/WHO criteria did not correlate with response. Evaluation of lack of enhancement on DCE MRI and increase in ADC on DW MRI were seen and correlated with necrosis on pathologic specimens. Conclusions: Four weeks of neoS is associated with significant necrosis that correlates with DCE-MRI and DW-MRI. There may be a trend in survival with greater necrosis, suggesting a role for these imaging biomarkers to assess early benefits of therapy. Clinical trial information: NCT00727532.
Comorbidity and other predictors of survival in veterans with metastatic renal cell carcinoma (RCC).
Authors: Cho Michael , Wang Trent P , Gonzalez Melanie L. , Chang Victor T , Zhong Fengming , Srinivas Shanthi , Crump Barbara , Paz-Querubin Emma R , McPherson Monica , Blumenfrucht Marvin , Kasimis Basil
Published: March 2020

e15561

Background: Comorbidity as a prognostic marker has been reported in several solid tumors. We examined whether co-morbidity indices predict survival in Veterans with metastatic renal cell carcinoma (RCC) who were treated with signal transduction inhibitors. Methods: In an IRB-approved protocol, we reviewed the records of patients (Pts) diagnosed with RCC at a VA Medical Center from 1/1/2000 to 12/31/2011. Age, ECOG Performance Status (ECOG PS), Hemoglobin (Hgb), Albumin (Alb), Corrected Calcium (CCa), history of Nephrectomy, and histology (clear cell (CC) vs. non clear cell (NCC)) were abstracted. Co-morbidity was assessed with Charlson Comorbidity Index (CCI), and the Kaplan-Feinstein Index (KFI). We developed a survival model with age, ECOG PS, Hgb, Alb, CCa, history of nephrectomy, and histology. Co-morbidity indices were tested by determining if they were independent predictors of survival after inclusion in this model. Cox regression analyses were performed with SAS V9.2. Results: There were 24 Pts;6 (25%) are alive. The Median (M) age when seen at VA was 64 years (54-85). The M Hgb level was 12.1g/dL (6.7-16.5), Alb was 4.1g/dL (2.8-5.0), and CCa was 9.19mg/dL (7.9-12.5). The M CCI was 4.2 (1.4-12.0) and KFI was 2.0 (1-3). The M Survival was 823 days (24-3482). 17(68%) pts had clear cell carcinoma and 18(72%) had nephrectomies Median ECOG PS was one range(0-4). The median number of treatments was 2, range 1-7. Results of univariate analyses with co-morbidity indices were significant for age (p < ,029) and history of nephrectomy p< .068). There were no multivariate predictors of survival. Conclusions: In the univariate analysis, ECOG PS as well as Nephrectomy status were significant predictors for M survival. CCI and KFI did not predict M survival. In distinction to other solid tumor histologies where chemotherapy is used, KFI and CCI in RCC may not be associated with overall survival due to either RCC histology or use of signal transduction inhibitors as treatment. Confirmatory studies should be done in larger populations. This was supported by the New Jersey Commission for Cancer Research.
Renal cell carcinoma with a novel germ-line mutation in isocitrate dehydrogenase 1 (IDH1) and its functional study.
Authors: Takayama Tatsuya , Kitagawa Mitsuhiro , Takaoka Naohisa , Sugiyama Naoyuki , Igarashi Kaori , Miyazaki Miki , Sugiyama Takayuki , Kai Fumitake , Soga Tomoyoshi , Ozono Seiichiro
Published: March 2020

e15568

Background: Recently, omics study such as metabolome analysis and whole genome sequencing has been applied to various disorders. We predicted the dysfunction of isocitrate dehydrogenase 1 (IDH1) in renal cell carcinoma (RCC) using metabolome analysis and identified a novel mutation of IDH1. In addition, we examined its function. Methods: We determined the global-scale metabolome profiling of human RCC by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS), and compared the metabolite levels of tumors and paired normal tissues in 10 patients with RCC. We performed the genotyping of IDH1 and von Hippel-Lindau (VHL) gene. We also performed transfection experiments by using Lipofectamine and measured the enzymatic activity of IDH1 in RCC cell lines. All protocols were performed by the Institutional Review Board (IRB) of Hamamatsu University School of Medicine and Keio University. Informed consent was obtained from the patient in accordance with the IRB of Hamamatsu University School of Medicine. Results: The acceleration of glycolysis with low level of NADPH and citrate in one patient led to IDH1 dysfunction followed by identifying a novel missense mutation, V178I. In transfection experiment, the reductive activity of IDH1 variant (V178I) increased 2.5 times than that of IDH1 wild type while the oxidative activity of IDH1 variant oxidative activity was as well as that of IDH1 wild type. Furthermore, in the metabolome analysis using labeling glutamine, RCC cell lines deficient in the von Hippel-Lindau (VHL) protein preferentially use reductive glutamine metabolism. On the other hand, this patient with V178I mutation of IDH1 had no VHL mutation. Conclusions: Metabolome analysis led to the identification a novel IDH1 missense mutation in RCC. This mutation might be involved with acceleration of reductive reaction in tricarboxylic acid cycle. Metabolome analysis using CE-TOFMS could be a powerful tool for the global-scale exploration of disease-specific metabolism.
Inadequate data availability on clinical trial accrual and its effect on progress in cancer research.
Authors: Mitchell Aaron Philip , Hirsch Bradford Richard , Abernethy Amy Pickar
Published: March 2020

e15572

Background: Participant accrual is a critical benchmark in clinical research, predicting study completion and reflecting the perceived value of the clinical question and study designed to answer it. Timely accrual data can be used prospectively to inform the design of new clinical trials. Accrual statistics are available within research networks, such as the cancer cooperative groups, but comprehensive data reflecting the overall portfolio of cancer clinical trials are lacking. As a demonstration case, we tested the availability of accrual data across all recent renal cell carcinoma (RCC) studies. Methods: The database for the Aggregate Analysis of ClinicalTrials.gov (CTG) summarizes all trials registered between 10/2007-9/2010. 137 RCC trials were included, of which 108 focused on pharmacologic therapy. Accrual data on these trials were gathered from CTG, online surveys sent to principle investigators, trial coordinators, and/or industry sponsors, review of resulting publications, and follow up phone calls to non-responders. Results: 20 of 76 (26%) trials listing a government, academic, or cooperative group (GAC) sponsor responded to the survey vs 0 of 32 (0%) of those listing only industry (I) sponsors. Across all methods, accrual data were collected for 43 trials (40%), including 28 of 76 (37%) GAC trials and 15 of 32 (47%) I trials. 87% of GAC trials which were ongoing (open, actively recruiting, or of unknown status) vs 75% of I trials. 10 of 108 trials (9%) were closed prematurely. Conclusions: Despite extensive efforts (surveys, phone calls, CTG abstraction, publication searches), accurate accrual data remained inaccessible for 60% of the RCC trial cohort. While CTG reports trial results, ongoing accrual data are also critically needed. Poor access to accrual data will continue to limit attempts to develop a national summary of clinical trials metrics and to optimize the cancer clinical research portfolio. [Table: see text]
Efficacy and toxicity of sunitinib in renal insufficiency patients with metastatic renal cell carcinoma.
Authors: Kim Ki Hyang , Rha Sun Young , Kim Ho Young , Kim Hye Ryun , Sun Jong-Mu , Lim Ho Yeong , Lee Hyo Jin , Lee Suee , Bae Woo Kyun
Published: March 2020

e15573

Background: We investigated the efficacy and toxicity of sunitinib in renal insufficiency patients with metastatic renal cell carcinoma (mRCC). Methods: From Korean Renal Cell Cancer Registry (KRCCR, http://kcsg-rcc.or.kr), we searched renal insufficiency patients with mRCC treated with sunitinib as a first-line treatment between January 2008 and May 2012. The Crockcroft-Gault formula was used for calculation of glomerular filtration rate and selected patients with chronic renal failure not requiring dialysis. Patients characteristics, clinical outcomes, toxicities were evaluated. The patients were divided by 2 groups based on the National Kidney Foundation definition of renal impairment and overall survival (OS) and progression-free survival (PFS) were obtained. Results: From total 997 enrolled from KRCCR, 34 patients were evaluated. Patients characteristics included: median age 66 years, ECOG performance status of 0 and 1 were 90%, and median GFR 46.5 ml/min/1.73m2 (range, 21.1-59.5). The starting dose of sunitinib was 50 mg for 22 patients and 37.5 mg for 12 patients. A schedule of sunitinib was 4 weeks on-2 weeks off for 31 patients, 2 weeks on-2 weeks off for 1 patient and daily for 2 patients. Best response was partial response (N=8) or stable disease (N=12). The median OS and PFS was 26.3 (95% CI: 17.1-35.3) and 12.2 (95% CI: 10.2-13.2) months, respectively. Log rank analysis revealed that severity of renal impairment was significantly associated with PFS but not with OS. Most common adverse events (AEs) of non-hematologic toxicities were stomatitis, rash, general edema and fatigue. The most common grade ≥3 AEs were fatigue, neutropenia and thrombocytopenia. Conclusions: Renal insufficiency patients with metastatic RCC did not impact on the efficacy of sunitinib and did not increased toxicities. Clinicians should not hesitate to treat renal insufficiency patients with metastatic renal cell carcinoma.
Effect of targeted therapy on renal cell carcinoma with rapid progression.
Authors: Wu Shenhong , Ranpura Vishal Navnitray
Published: March 2020

e15578

Background: Seven targeted agents so far have been approved for the treatment of advanced renal cell carcinoma (RCC). However, it is not clear whether these agents are effective in patients with rapid progressive disease, which is characterized by progression within three months and associated with poor prognosis. Therefore, we conducted a systematic review and meta-analysis of published randomized controlled clinical trials (RCTs) to assess the effect of targeted therapy on rapid progressive RCC. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October, 2012 were searched to identify relevant studies. Rapid progression was defined as progressive disease or death within 3 months after the initiation of clinical trial. Eligible studies included prospective RCTs in which a targeted therapy was compared to a placebo or cytokine control in RCC patients. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated based on the heterogeneity of included studies. Results: A total of 4,628 patients (targeted therapy: 2,461, control: 2,167) with RCC from 10 RCTs were included for analysis. When compared to controls, the targeted therapy significantly reduced the overall risk of rapid progression (23.6%, 95% CI: 19.2-28.6% versus 54.5%, 95% CI: 44.6-64.1%) with an overall RR of 0.46 (95% CI: 0.38-0.54, P<0.001). The effect did not vary significantly with prior therapies (P=0.67), but varied with different prognostic groups (P=0.025). In addition, the effect varied significantly among different agents (p<0.001), with the highest reduction seen in patients treated with pazopanib (RR=0.27; 95% CI: 0.21-0.35). There was no significant difference between mTOR and VEGF inhibitors (P=0.25) in the risk reduction. Furthermore, the targeted therapy significantly reduced the risk of 3-month mortality (RR 0.58, P=0.002) from 10.0% (95% CI: 5.3-18.1%) to 5.5% (95% CI: 3.3-8.9%) in comparison with controls. Conclusions: The targeted therapy may significantly reduce the risk of rapid progression and early death in patients with renal cell carcinoma. Early application of these agents is recommended.
Meta-analysis of hematologic toxicities in patients with solid tumors treated with everolimus.
Authors: Funakoshi Tomohiro , Latif Asma , Galsky Matt D.
Published: March 2020

e15580

Background: Everolimus is an orally administered targeted agent that inhibits mammalian target of rapamycin (mTOR) signaling involved in tumor growth and proliferation. Hematologic toxicities associated with everolimus have been reported with a substantial variation in the incidences among clinical studies without a systematic attempt to synthesize these data. We performed a systemic review and meta-analysis of published clinical trials to evaluate the overall risk of everolimus-related hematologic toxicities. Methods: We searched Medline and the American Society of Clinical Oncology online database of meeting abstracts up to December 2012 for relevant clinical trials. Eligible studies included phase II and III trials in patients with solid tumors treated with everolimus that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia based on the CTCAE of the NCI. The relative risk (RR), summary incidence and 95% confidence intervals (CI) were calculated. Results: For the incidence analysis, we included a total of 1,090 patients from 14 studies (three phase III and 11phase II trials) considering only arms with everolimus as a single agent. The incidence of everolimus -associated all-grade and high-grade (Grade 3-4) hematologic toxicities were, respectively: neutropenia: 21.7% and 3.7%; thrombocytopenia: 36.0% and 4.7% and anemia: 61.2% and 4.4%. For the RR calculation, seven randomized trials with everolimus in only one of the arms in addition to similar therapy in both arms were available (five phase III and two phase II trials, representing 2,462 patients). Everolimus -treated patients had a significantly increased risk of all-grade neutropenia (RR = 2.24; 95% CI, 1.51–3.32), all-grade (RR = 9.19; 95% CI, 4.51–18.70) and high-grade (RR = 7.46; 95% CI, 2.58–21.61) thrombocytopenia and all-grade (RR = 1.58; 95% CI, 1.25–1.99) and high-grade (RR = 3.92; 95% CI, 1.46–10.52) anemia. RR of high-grade neutropenia was 1.40 (95% CI: 0.70-2.78; p=0.34). Conclusions: Everolimus is associated with a significant increase in the risk of developing all-grade and high-grade thrombocytopenia and anemia and all-grade neutropenia compared with control.
Brain metastases (BM) of nonseminomatous germ cell tumors (NSGCT): What population of patients should be screened?
Authors: Tryakin Alexey , Fedyanin Mikhail , Aleshin Vladimir , Mikhina Zoja , Zakharova Tatiana , Sergeev Urii , Garin Avgust , Tjulandin Sergei
Published: March 2020

e15583

Background: BM from NSGCT present in 5-15% of pts with metastatic disease. There is no uniform consensus what population of pts with NSGCT should be screened for BM. Methods: Among 1700 pts with metastatic GCT who were treated in our center from 1990 to 2009 we identified 20 (1.1%) pts with BM: 11 pts had BM at initial presentation. No pts with BM of seminoma were identified. The minimal f.-up time after the end of treatment was 24 months. None of 9 pts with BM at relapse had brain imaging initially and 6 (67%) had BM as the only site of relapse. Since 2005 we have started routine brain MRI for all new pts with hCG level above 50000 IU/l. BM were found in 4 (14%) of 28 those pts, incl. 3 pts with asymptomatic BM. Before 2005 there were 38 pts with hCG level above 50000 IU/l and BM were seen in only 3 (7,9%) pts, who had specific symptoms. For further analysis we combined pts with initially presented BM (n=11) and pts who had BM as the only site of relapse (n=6), because in later group BM were obviously missed before 1-st line of chemotherapy. Results: Factors associated with BM were multiple (n>3) pulmonary mets >2cm - all 17 pts, IGCCCG poor prognosis -13 (76%) pts, initial hCG > 50000 IU/l - 9(53%) pts. Among 43 pts with multiple pulmonary mets and hCG > 50000 IU/l 9 (21%) pts had BM: sensitivity 53%, specificity 93%, PPV 21%, NPV 98%. Screening of BM in this population would miss 47% of them. Among 142 pts with multiple pulmonary mets and intermediate or poor IGCCCG prognosis 17 (12%) pts had BM: sensitivity 100%, specificity 76%, PPV 12%, NPV 100%. Conclusions: Pts with elevated hCG level above 50000 IU/l and multiple (n>3) pulmonary mets >2cm have high incidence (21%) of BM. Brain imaging of pts with multiple (n>3) pulmonary mets >2cm and intermediate or poor IGCCCG prognosis is recommended.
Retrospective, correlative study of BRAF mutation V600E in testicular cancer patients.
Authors: Satpute Shailesh R. , Koster Roelof , Nathanson Katherine L. , Vaughn David J. , Albany Costantine , Einhorn Lawrence H. , Hanna Nasser H.
Published: March 2020

e15584

Background: Presence of BRAF V600E mutation forms the basis of a successful targeted therapy against malignant melanoma. While this mutation is also demonstrated in various other tumor types, its presence in germ cell tumor (GCT) is inconsistent across various studies. In one study, 9 out of 35 (26%) platinum-refractory GCTs were positive for BRAF V600E mutation (Honecker et al, JCO 2009 May 1; 27(13):2129-36). In the current study we tested tumor tissue of patients for BRAF V600E mutation in order to correlate it with known tumor subtypes and treatment outcomes. Methods: We obtained tumor specimen of 59 patients with GCT that were treated at either Indiana University or University of Pennsylvania from 2000 to 2011 and tested them for presence of BRAF V600E mutation by Sanger sequencing with exon 15 specific primers. Out of 59 tumors, 12 (20%) were seminomas and 47 (80%) were non-seminomas. 26 (44%) patients had no recurrence after first line cisplatin-based chemotherapy whereas 33 (56%) patients had either platinum-refractory disease or had a disease recurrence within 2 years of completing chemotherapy. Tumors from 10 patients contained only mature teratoma after chemotherapy. 31 (52%) patients were classified at the time of diagnosis as good risk, 8 (14%) patients as intermediate risk and 20 (34%) patients as poor risk according to international germ cell consensus classification. Results: We found that all 59 tumor tissue were wild-type or lacked BRAF V600E mutation. Appropriate positive and negative controls were used for the assay. Conclusions: BRAF V600E mutation is not a feature of GCT. In our study, we failed to observe any correlation of the mutation with tumor subtypes or with treatment outcomes. Based on this study, BRAF inhibiting drugs may not be beneficial in germ cell tumors.
Effect of CTCAE v4 grading of hypertension on reported toxicity in advanced cancer patients receiving vascular endothelial growth factor (VEGF)-targeting agents.
Authors: Akhtar Naveed Hassan , Singh Beerinder , Ocean Allyson J. , Karpenko Irene , Beltran Himisha , Popa Elizabeta C. , Nanus David M. , Shah Manish A. , Tagawa Scott T.
Published: March 2020

e15600

Background: The NCI Common Terminology Criteria for Adverse Events (CTCAE) system changed to version 4 in 2009, and several AE categories underwent changes in grading (Gr), including HTN. As many anti-neoplastic agents, particularly those targeting VEGF are associated with HTN, changing in the grading system may result in changes to maximum tolerated or recommended phase II doses in early dose-escalation studies or overall HTN AE reporting across all studies. Methods: We initially reviewed individual patient data of a multicenter phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC), which graded AE’s using CTCAE v3. Individual patient (pt) data was reviewed and HTN AE’s were re-graded using CTCAE v4 criteria for up to 12 cycles of therapy on study. A separate (confirmatory) data set in pts with metastatic colorectal cancer (CRC) treated on a phase IIIb study of regorafenib was subsequently analyzed. Results: In the RCC study, only 1 of 23 pts with complete source documents available had stable highest HTN Gr across both CTCAE versions. In the CRC study, 0 of 8 pts had stable Gr. Table 1 compares each individual’s highest CTCAE v3 versus v4 grading of HTN in each study. Across both studies, all pts had HTN AE’s using CTCAE v4. Only 1 pt maintained grading using both versions (Gr 3), with 30 (96.8%) changing grades. Four (12.9%) moved from Gr 0 to Gr 1, fifteen (48.4%) from Gr 0 to Gr 2, five (16.1%) from Gr 1 to Gr 2, one from Gr 1 to Gr 3, and six (19.4%) from Gr 2 to Gr 3. Conclusions: Re-classification of grading in this study demonstrates that only 3.2% maintained stable grading of HTN across systems, with 51.6% increasing by 2 grades. The change in AE reporting criteria has the potential to significantly impact results of clinical trials. This may be particularly important with VEGF-targeted agents, with emerging data pointing towards HTN as a pharmacodynamic marker in pts with RCC, and may affect dosing and AE reporting of other drugs with blood pressure effects. Clinical trial information: NCT00121251, NCT01538680. [Table: see text]
High-dose interleukin-2 therapy for metastatic renal cell carcinoma: A contemporary experience.
Authors: Aboumohamed Ahmed A. , Yarlagadda Naveen , Creighton Terrance , Mehedint Diana , Attwood Kristopher , Kauffman Eric , George Saby , Khushalani Nikhil I. , Pili Roberto , Schwaab Thomas
Published: March 2020

e15604

Background: Despite recent advances in targeted treatment options, high dose interleukin-2 (HDIL-2) remains an important therapeutic option for metastatic renal cell carcinoma (mRCC). We present a contemporary experience of HDIL-2 in a high-volume, National Cancer Institute (NCI)-designated cancer center. Methods: Patients with mRCC who received HDIL-2 monotherapy as a first- or second-line therapy during 2004-2011 were identified. Patients’ demographics, pathologic variables, renal function, time until start of HDIL-2 therapy, number of cycles given (1-3), best responses (complete response; CR, partial response; PR, stable disease; SD, and progressive disease; PD), and primary RCC treatment were analyzed. Progression free survival (PFS) and overall survival (OS) were determined. Results: Of 176 mRCC patients, 91 patients were treated with HDIL-2 (59 as a primary treatment). Median age was 51 years and 73.9% were males. Median Follow-up was 44.9 months. Majority (92%) of tumors showed clear cell histology, and 14.8% had impaired renal function (creatinine >1.5 mg/dL) prior to treatment. Patients with impaired initial renal function were more likely to get more treatment cycles (2-3) than those with adequate initial kidney function (92.3% vs.50.6%, respectively; p=0.002). Eighteen (20.5%) patients underwent cytoreductive nephrectomy. Lower tumor stage at diagnosis correlated with better treatment response (p=0.023), but with longer time from diagnosis to initiation of HDIL-2 (p=0.011). Prominent therapy complications included hypotension (67.4%), renal impairment (63%), impaired liver function (42.4%), and thrombocytopenia (31.5%). None needed hemodialysis for IL-2 induced renal toxicity, and all regained their pre-treatment baseline kidney functions after therapy. Four patients (4.5%) had CR, 11.4% had PR, and 31.8% had SD. Median PFS and OS were 8.6 and 35.5 months, respectively. Estimated 2-year OS rate was 60.6%. Conclusions: Incorporating HDIL-2 therapy in treatment strategies of patients with mRCC added to the patients’ survival in this contemporary series. HDIL-2 therapy appears to be well tolerated in patients with preexisting renal impairment with no long term renal toxicity.
A phase II trial of weekly docetaxel for second-line treatment of urothelial carcinoma.
Authors: Kim Young Saing , Choi Moon Ki , Hong Jung Yong , Maeng Chi Hoon , Lee Soonil , Hwang In Gyu , Lee Sang-Cheol , Sun Jong-Mu , Park Se Hoon , Lee Jeeyun , Lim Ho Yeong
Published: March 2020

e15613

Background: Despite high response rates (RRs) with first-line platinum-based chemotherapy in advanced urothelial carcinoma (UCC), treatment after first-line failure remains unclear. The present multi-center phase II trial evaluated the tolerability and efficacy of weekly docetaxel as second-line chemotherapy for UCC. Methods: Between Aug 2010 and Sep 2012, 31 patients with measurable UCC, progressive after one prior platinum-based chemotherapy for advanced disease, were treated with docetaxel 30 mg/m2 on days 1 and 8. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The primary endpoints were the RR, progression-free survival (PFS), and safety. To detect a 20% difference in RR (6% vs. 26%), 28 eligible patients were required. Results: All 31 patients were previously treated with gemcitabine/platinum and had Bellmunt risk of one or more. The patients’ median age was 64 years (range, 40 to 79) and 31 (100%) patients had an ECOG performance status of 1. A total of 106 (median, 2; range, 1 to 16) chemotherapy cycles were delivered. Although fatigue (13%) and anorexia (6%) were the most frequently observed grade 3 or 4 toxicities, safety profiles were generally mild and manageable. One patient developed prolonged thrombocytopenia which led to treatment discontinuation but was resolved thereafter. In an intent-to-treat analysis, two (6%) patients achieved objective response, which maintained for 3.0 to 7.8 months. Eight patients experienced disease stabilization, resulting in a disease control rate of 32%. The median PFS and overall survival were 1.4 (95% CI, 1.3 to 1.6) and 9.6 (95% CI, 7.8 to 11.4) months, respectively. Conclusions: Second-line chemotherapy with weekly docetaxel was well tolerated but demonstrated modest antitumor activity in patient with advanced UCC who had progression after first-line platinum-containing regimen and poor prognostic factors. Clinical trial information: NCT01711112.