bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between plasma pazopanib concentration and incidence of adverse events in renal cell carcinoma.
Authors: Lin Y. , Ball H. A. , Suttle B. , Mehmud F. , Amado R. G. , Hutson T. E. , Pandite L. N.
Published: February 2017

345

Background: Pazopanib (P), an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit, is approved by the US FDA for the treatment of advanced renal cell cancer (mRCC). Exploratory analyses of data from a Ph II mRCC study (Hutson T, J Clin Oncol. 27, 2009:1) indicated that 70% of patients (pt) receiving 800mg once daily had a week (wk) 4 plasma P trough (Cmin) >20.6μ g/mL that is associated with improved efficacy (Suttle B, J Clin Oncol. 28, 2010:S3048). In this further analysis of the dataset, we investigated the relation between plasma P concentrations at wk 4 and clinically important adverse events (AE) reported within the first 12 wks of treatment.

Methods: The % of patients with hypertension (defined as ≥ 15mmHg - baseline on 3 occasions)- a recognized PD marker for this class of agents- or other AEs (CTC grades), occurring during the first 12 wks of treatment were calculated by wk4 Cmin quartiles (Q1-Q4: median and range).

Results: P concentrations at 4 wks and AE data were available for 205 out of 225 pts. The incidence of hypertension was 58% in Q1, increasing with concentration to 78% at Q4. The incidence of diarrhea, hair color change, ALT increase, HFS (marked increase), and stomatitis were concentration-dependent, with ≥ 2 fold increase from Q1 to Q4. The incidence of nausea, fatigue, vomiting, dysgeusia, and rash were variable or displayed a flat relationship with Cmin.

Conclusions: The incidence of some AEs, such as diarrhea, ALT, HFS (marked relation), and stomatitis increased with plasma Cmin while others did not. We suggest that concentration-dependent AEs are more likely to respond to P dose reduction and as such, provides support for development of a dose optimization strategy.

[Table: see text]

[Table: see text]
Functional and oncologic outcomes of nephron-sparing surgery (NSS) for patients with renal cell carcinoma (RCC) greater than 4 cm in diameter.
Authors: Piper C. , Richter S. , Brehmer B. , Pfister D. J. , Epplen R. , Heidenreich A.
Published: February 2017

347

Background: Organ preserving surgery represents the guideline recommended surgical treatment of choice for patients with small renal tumors ≤ 4cm in diameter. There are only few data in the literature with regard to the oncological and functional outcome of elective NSS in RCC larger than 4cm.

Methods: We retrospectively reviewed the charts of all patients who underwent elective NSS for RCC at our institution during 2004-2009. We identified 288 patients of whom 196 (68.1%) patients and 92(31.9%) patients underwent NSS for a tumor < 4cm (group 1) and a tumour ≥ 4cm (group 2), respectively. We analyzed tumor size, TNM-classification, OR time, surgical margins, complications, mortality, recurrences and metastases in both groups.

Results: We identified significant differences between group 1 and 2 for the following variables: mean tumor size (2.9 vs. 8.6cm, p = 0.03), necessity for warm ischemia (15.1% vs. 51%, p = 0.001), mean ischemia time (3.5 vs. 10.2 min, p = 0.002), need for endoluminal stenting due to involvement of the renal pelvis (0.5% vs. 24.2%, p = 0.001). Significantly less pT2 (12.7% vs. 29.7%, p = 0.03) and pT3 tumors (8.7% vs. 12%, p = 0.05) were identified in group 1 when compared to group 2. There were no significant differences with regard to mean OR time (61 vs. 74 min), positive surgical margins (1/192 vs. 1/92), hospital stay, and perioperative complications. There were no significant differences with regard to stage specific overall survival, cancer-specific survival and progression-free survival. There was no significant survival difference between NSS and radical nephrectomy.

Conclusions: NSS can be safely performed in RCC > 4 cm without increasing the frequency of treatment-associated complications or decreasing cancer-specific survival. NSS should represent the treatment of choice in all patients with RCC of 4-7cm in diameter if technically feasible.

No significant financial relationships to disclose.
Metastatic renal cell carcinoma treated with pazopanib after progression on other targeted agents: A single-institution experience.
Authors: Matrana M. R. , Atkinson B. J. , Corn P. G. , Jonasch E. , Tannir N. M.
Published: February 2017

351

Background: Pazopanib, a multityrosine kinase inhibitor (TKI), prolongs PFS compared to placebo in treatment-naive and cytokine refractory metastatic renal cell carcinoma (mRCC). No data has been reported about pazopanib salvage therapy after treatment with other targeted agents.

Methods: We retrospectively reviewed the records of 88 consecutive patients (pts) with mRCC (median age 62.7, M:F 63/25, 84% clear cell) who received salvage pazopanib between 11/09-8/10. All pts failed previous treatment with one or more targeted agents (median number of prior targeted agents was 2, range 1-5; median time on previous treatments was 632 days). 78% of pts had progressed on sunitinib, 40% on sorafenib, 20% on temsirolimus, 51% on everolimus, and 26% on bevacizumab. 26% received previous chemotherapy and 16% received previous cytokines in addition to targeted therapies. 58% failed both TKI/VEGF inhibitors and mTOR inhibitors. 57% had intermediate-risk disease and 43% had poor-risk disease by MSKCC criteria. All pts had follow-up at least every 3 months after initiating pazopanib.

Results: Median time to last follow-up was 114 days (range 30-278 days). 42% continued pazopanib at last follow- up. 25% had partial response (PR) by treating physician assessment. 50% failing 1-2 previous targeted therapies remained on pazopanib at last follow-up, compared to 27% of those failing more than 2 targeted therapies (p=0.04). 56% of pts with intermediate-risk disease by MSKCC criteria continued pazopanib at follow-up compared to 27% with poor-risk disease (p=0.002). 42% of those failing 1 prior targeted therapy achieved PR compared to 18% failing >1 prior targeted therapy (p=0.02). 35% discontinued pazopanib due to progressive disease (PD) (median time to PD 71 days, range 36-198 days), 10% discontinued due to adverse drug events, and 10% died of PD on treatment. There were no treatment related deaths.

Conclusions: In this retrospective study, pazopanib demonstrated clinically relevant activity in mRCC following PD with other targeted therapies. Mature survival data will be provided with final presentation.

No significant financial relationships to disclose.
Treatment (trx) patterns of angiogenesis inhibitors in patients (pts) with metastatic renal cell carcinoma (mRCC) in Ireland.
Authors: McDermott R. S. , Donnellan P. P. , McCaffery J. , Sarda S. P. , Korves C. , Luka A. , Wei R. , Neary M. , Hanley R. , Duh M. S.
Published: February 2017

383

Background: This study evaluated rates of trx modifications and reasons for these changes among pts treated with angiogenesis inhibitors in Irish clinical practice.

Methods: Data from medical records were retrospectively reviewed at 3 large oncology centers in Ireland for mRCC pts who were ≥ 18 years and received sunitinib (SU) (n=54), sorafenib (n=9), bevacizumab (n=6), or temsirolimus (n=7) as first-line trx from 1/1/2005 to 8/31/2010. Proportions of pts with trx discontinuation (d/c), interruption, or dose change, and reasons for modifications and time to modifications were determined.

Results: Due to small sample sizes in other groups, only results for SU are summarized. 1.9% of pts had prior cytokine therapy. Median first-line trx duration for SU was 8.7 months (mo), while median progression-free survival was 13.8 mo. 87% of patients treated with first-line SU experienced adverse events (AEs); 18.5% experienced grade 3/4 AEs. AEs led to trx modifications in 42.6% of pts. 94.4% of pts started trx on 50 mg QD 4/2 dosing; 33.3% of them were dose reduced to 37.5 mg QD 4/2 with median time to reduction 2.7 mo. Among pts who discontinued trx, 31.6% discontinued within 18 weeks (w) (15.8% within 0-6 w, 7.9% in 7-12 w, and 7.9% in 13-18 w). Among pts who discontinued trx within 18 w, 66.7% discontinued due to AEs.

Conclusions: Over three-quarters of SU pts experienced trx modifications, more than half due to AEs. About 24% of txt discontinuations occurred within the first two cycles. This real-world practice study suggests that treatment tolerability is a challenge for physicians in the clinical care of mRCC pts.

[Table: see text]

[Table: see text]
GAPDH, YWHAZ, and RRN18S as control reference genes for gene expression studies on renal cell carcinoma (RCC) formaldehyde-fixed paraffin-embedded (FFPE) tissue samples.
Authors: Medina Villaamil V. , Vazquez-Estevez S. , Campos B. , Leon Mateos L. , Fírvida J. L. , Ramos M. , Afonso F. J. , Fernández Calvo O. , Valladares Ayerbes M. , Antón Aparicio L. M.
Published: February 2017

389

Background: It is mandatory to have a control reference gen (RG) to correctly measure gene expression by real-time quantitative PCR (qPCR). The purpose of this study was to test a panel of 12 RGs (Human Endogenous Control Gene Panel, tataabiocenter) in order to select and validate the most appropriate control genes for expression studies on FFPE RCC tissues.

Methods: qPCR followed by Normfinder and geNorm-based analysis was employed (GenEx Standard). The study was performed on 9 selected RCC tumor samples with different local stage (T1, T2 and T3). The most representative RCC histologies were also collected; clear-cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC) and cromophobe renal cell carcinoma (cRCC). A commercial pool (Biochain) of 5 cases of normal kidney was analyzed too. All samples were measured in triplicate. Expression levels of RGs: GAPDH, TUBB, PPIA, ACTB, YWHAZ, RRN18S, B2M, UBC, TBP, RPLP, GUSB and HPRT1 were measured by qPCR on a Light Cycler 480 (Roche) utilizing Light Cycler 480 SYBR Green I Master (Roche).

Results: The analysis of experimental data showed that RRN18S is the most stable gene found in our FFEP RCC samples followed by GUSB and TBP. In contrast, ACTB was found to be the least stable gene between our samples. GAPDH together with YWHAZ was showed as the pair of genes introducing the least systematic error into data normalization (M-value < 1) needed to conduct expression gene studies further.

Conclusions: These data suggest that GAPDH, YWHAZ and RRN18S are the most suitable RGs for gene expression profile studies in FFEP RCC. Standardization of RGs will help us to compare results from translational studies on RCC FFPE samples genes profiling.

No significant financial relationships to disclose.
Correlation of percent of core biopsies positive for prostate cancer and biochemical outcome following I-125 prostate brachytherapy or external beam radiation.
Authors: Tendulkar R. D. , Stephans K. L. , Reddy C. A. , Martires K. , Patel A. R. , Raj D. , Lowes D. , Geng T. , Klein E. A. , Ciezki J. P.
Published: February 2017

40

Background: The percentage of positive cores (PPC) on biopsy for prostate cancer has been identified as a predictor of outcome following definitive local treatment. We aim to identify whether this observation holds true for a modern cohort of patients (pts) treated at Cleveland Clinic with permanent prostate brachytherapy (PB) or external beam radiation therapy (EBRT).

Methods: We retrospectively reviewed pathology reports of pts treated with either PB or EBRT from our IRB-approved prospective prostate cancer registry. No pts underwent both PB and EBRT. The number of biopsy cores sampled, number of cores positive for prostate cancer, and maximum length of any core positive for prostate cancer were collected. Cox proportional hazards regression was used to analyze biochemical relapse free survival (bRFS) using the nadir + 2 ng/ml definition.

Results: We identified 1253 PB and 879 EBRT pts with complete pathology and clinical information. Among PB pts, 46% were low risk, 40% intermediate risk, and 14% high risk, while 78% had <50% PPC, and 22% had >=50% PPC. The 5-year bRFS for PB was 92.0% for <50% PPC, vs. 83.1% for >=50% PPC (HR 2.1, p=0.0005). For PB pts, significant predictors of bRFS on univariate analysis included: PPC, clinical T stage, PSA, biopsy Gleason score, androgen deprivation, and frequency of PSA testing. On multivariate analysis, only PPC, biopsy Gleason score, and PSA frequency remained significant predictors following PB. Among EBRT pts, 11% were low risk, 36% intermediate risk, and 53% high risk, while 55% had <50% PPC, and 45% had >=50% PPC. The 5-year bRFS for EBRT was 85.6% for <50% PPC, vs. 77.1% for >=50% PPC (HR 1.8, p<0.0001). For EBRT pts, significant predictors of bRFS on univariate analysis included: PPC, clinical T stage, PSA, biopsy Gleason score, androgen deprivation, EBRT dose, and frequency of PSA testing. On multivariate analysis, only PPC, biopsy Gleason score, and PSA frequency remained significant predictors following EBRT.

Conclusions: Following PB or EBRT, the percent of positive cores for prostate cancer was a significant predictor of bRFS on multivariate analysis, more so than conventional predictors such as T stage and PSA.

No significant financial relationships to disclose.
Long-term therapy with sunitinib and sorafenib in patients with metastasizing renal cell carcinoma.
Authors: Richter S. , Piper C. , Pfister D. A. , Brehmer B. , Heidenreich A.
Published: February 2017

407

Background: Multitargeted tyrosine kinase inhibitors (MTKIs) constitute the established therapy in patients with metastasizing renal cell carcinoma. There are only few data concerning efficiency and safety, the reasons for a longterm response with good tolerability under MTKIs is still unknown.

Methods: We retrospectively analyzed the data of patients (pts.) under long-term therapy (>1 year) with sorafenib or sunitinib. Localization of metastases, number of cycles, sequence of therapy, treatment-associated toxicities, and frequency of dose reductions were our main focus of interest.

Results: 15 pts. (14 male, one female) with an mean age of 66,33 (44-81) years, were treated with 19,86 (12-35) cycles of sorafenib or sunitinib. 14/15 pts. underwent radical nephrectomy before the treatment. Localization of metastasis were as follows: pulmonary (9/15), hepatic (4/15), nodal (8/15), osseous (3/15), and pancreatic (2/15). In four pts. two or more organs were affected, in six pts. only one organ. As a first-line therapy nine pts. received sunitinib for 20.67 (12-35) cycles and one patient sorafenib for 44 cycles. For second line therapy two pts. were treated with sunitinib for 13 (12-14) cycles and three pts. with sorafenib for 23.33 (18-28) cycles. In five pts. a dose reduction of 25-50% was necessary due to significant treatment associated side effects, afterwards toxicities were tolerable under long term therapy (grade 1 in 10 pts.).

Conclusions: The results show, that longterm therapy with sunitinib or sorafenib is tolerable and efficacious independent on previous treatment. Prognostic factors concerning longterm response and low toxicity profile at a molecular biological level are still unknown, further investigations are of importance and are currently performed at our institution.

No significant financial relationships to disclose.
MicroRNAs as emerging biomarkers for micrometastasis detection in genitourinary tumors.
Authors: Medina Villaamil V. , Santamarina Caínzos I. , Aparicio Gallego G. , Quindós Varela M. , Dopico Vázquez D. , Antolín Novoa S. , García Campelo R. , Reboredo M. , Valladares Ayerbes M. , Antón Aparicio L. M.
Published: February 2017

52

Background: MicroRNAs regulate numerous aspects of normal and pathological cellular processes, including cancer. Detection of circulating tumor cells (CTC) may provide diagnostic and prognostic information in genitourinary (GU) tumors. miRNAs may also be considered as potential therapeutic targets when overexpression is associated to pathogenic effect. miRNAs may constitute a promising new class of cancer biomarkers for CTC detection. The aim of this work is identify miRNAs potentially useful for CTC detection in blood samples from patients with GU tumors: bladder, prostate and renal tumors.

Methods: miRGator, miRBase, smiRNAdb, GeneHUB-GEPIS, microRNA.org and miRNAMap free databases were used in order to identify miRNAs as biomarkers for CTC detection. In silico data were used to identify miRNAs highly expressed in GU tumors, but absent in hematopoietic-derived sources. RNA enriched in miRNAs was isolated from: GU tumors (bladder: HT1376, HT1197; prostate: VCaP, LNCaP and renal: ACHN, A704) and hematopoietic cell lines, GU tumor tissues (N= 6) and healthy blood samples (N= 19). mirVana miRNA and RiboPure Blood isolation kits were used. Using qRT-PCR miRNAs tumor-related were amplified.

Results: Bioinformatic analysis included tissue-specific and oncogenic miRNAs and showed that mir-31, mir-136, mir-133a, mir-145, mir-187, mir-200a, mir-200b, mir-200c, mir-368 and hsa-let-7c levels were up-regulated in tumor tissues from patients with advanced GU tumors. For instance, relative expression of mir-31 was 6-timeshigher in bladder cell lines than in normal peripheral blood, mir-200c was 104-times higher in renal tumor tissue than in normal peripheral blood and finally hsa-let-7c was 3-times higher in prostate tumor tissue than in healthy blood samples.

Conclusions: These results suggest that this bioinformatic approach is an useful high-throughout method to identified GU tumors-associated miRNAs. The selected miRNAs should be further evaluated for their potential as markers for CTC detection, prognosis and therapeutic outcome. This work was supported by Grants PI07/0477 from Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III.

No significant financial relationships to disclose.
Androgen pathway constitutional polymorphism predictors of progression-free and overall survivals in advanced castrate-resistant prostate cancer (CRPC) patients treated with ketoconazole (KC).
Authors: Davis T. L. , Jung J. , Carr K. A. , Philips S. , Mohammadi Y. , Campbell M. T. , Li L. , Sweeney C. , Skaar T. C. , Hahn N. M.
Published: February 2017

54

Background: Recent trials have highlighted the clinical utility of second-line hormonal therapies for CRPC. KC, an oral inhibitor of CYP3A4 and CYP17, is commonly used in this setting. Germline SNPs in genes critical to hormone synthesis, transport, metabolism, binding sites, and degradation may contribute to variability in outcomes observed in KC treated CRPC pts.

Methods: Between 1/07 and 10/08, all PCa pts seen in the Indiana University Simon Cancer Center oncology clinics were approached for recruitment to the Prostate Cancer Genetic Risk Evaluation of SNPs Study (PROGRESS). Participants completed a demographic and clinical questionnaire and provided a peripheral blood sample. Only pts with initiated on KC were included in this analysis. Germline DNA was analyzed for SNP genotyping on a 128-SNP chip using a TaqMan OpenArray GT Kit. The chip included genes critical to hormone signaling, transport, and elimination pathways with minor allele frequencies > 5%. Pts were followed for progression-free survival (PFS) and overall survival (OS) endpoints. Univariable analyses were performed to identify significant associations between SNP genotype, clinical parameters, and PFS and OS outcomes.

Results: Between January 2007 and October 2008, 39 pts with CRPC initiated on KC therapy enrolled. Demographics included: age (median) – 70 yrs, prostate specific antigen (PSA) (median) – 13.0 ng/ml, PSA doubling time (median) – 2.9 months, metastatic –85%, ECOG PS 0– 74%. Age < 70 was associated with shorter PFS (p=0.010) and age > 70 was associated with shorter OS (p=0.030). SNPs significantly associated with PFS and OS are summarized in the table.

Conclusions: Interpatient differences in hormonal pathway germline SNPs may contribute to variability in clinical outcomes in pts treated with KC.

[Table: see text]

No significant financial relationships to disclose.
Use of serum and tissue biomarker analysis embedded in a phase II clinical trial of cytarabine in castration-refractory prostate cancer to investigate prostate cancer biology.
Authors: Niraula S. , Emmeneger U. , Adams L. , Tannock I. , Sridhar S. S. , Knox J. J. , Day J. R. , Manthe J. , Groskopf J. , Joshua A. M.
Published: February 2017

59

Background: Other than the androgen receptor, the TMPRSS2-ERG genomic aberrations in prostate cancer provide the first recent opportunity to target therapy in castration refractory prostate cancer (CRPC). We initiated a phase II clinical trial of cytarabine in docetaxel refractory CRPC on the basis of microarray, in vitro and case report evidence that cytarabine may be particularly effective in men harbouring abnormalities of the ERG oncogenes. Embedded in this clinical trial was the first use of blood mRNA levels of prostate cancer related genes as biomarkers of response and prognosis.

Methods: Patients with docetaxel refractory progressive CRPC received intravenous cytarabine at doses between 1g/m2-0.25 g/m2 q3 weekly. Responses were defined according to PCWG2C. 10 patients were enrolled between June 2007 and January 2010. TMPRSS2:ERG, PSA and PCA3 mRNA copies in whole blood collected with PAXgene tubes at the beginning of each cycle and at trial termination were quantified using transcription-mediated amplification assays. The prototype TMPRSS2:ERG assay detects the gene fusion isoform TMPRSS2 exon1 to ERG exon4.

Results: No patients demonstrated a serum PSA response (PCWG2C). The average number of cycles administered was 2.6. Significant toxicities including grade 3-4 thrombocytopenia (2) and grade 3-4 neutropenia (3). These toxicities necessitated several dose reductions in the protocol, however most patients were removed from trial for serum PSA progression alone. PCA3 and PSA mRNAs were detectable in 8/10 and 9/10 cases, respectively; there was no correlation between serum PSA and PCA3 or PSA mRNA copy levels in blood. Testing for TMPRSS2:ERG in blood was able to predict the presence or absence of the TMPRSS2-ERG rearrangement in 9/10 cases when compared to 3 colour FISH carried out on baseline biopsies/ prostatectomies (2/10 positive for Exon 4:Exon 1 deletion).

Conclusions: Cytarabine administation is ineffective in docetaxel refractory CRPC. Blood mRNA levels of prostate cancer genes reveal novel aspects of prostate cancer biology and have implications for the understanding of circulating tumour cells.

[Table: see text]
Identification of gene copy number and whole-genome methylation changes associated with lethal metastatic castration-resistant prostate cancer (CRPC).
Authors: Friedlander T. W. , Roy R. , Tomlins S. A. , Kobayashi Y. , Rubin M. A. , Pienta K. J. , Chinnaiyan A. , Small E. J. , Ryan C. J. , Paris P.
Published: February 2017

6

Background: Metastatic CRPC undergoes significant genomic evolution compared to primary, localized disease. Multiple genetic mechanisms contribute to this evolution including changes in gene copy number as well as and changes in CpG island methylation. In this study, copy number and methylation status of metastatic CRPC tissue obtained at autopsy were assessed by high-resolution array comparative genomic hybridization (aCGH) and whole genome methylation microarray profiling.

Methods: Array CGH was performed on DNA isolated from metastatic CRPC samples obtained from the University of Michigan Rapid Autopsy Program, using the Agilent Human Genome 244K CGH Microarray. A total of 15 samples comprising 7 metastatic liver implants and 8 soft tissue metastases were analyzed with DNA Analytics 4.0 software. Expression of genes identified as commonly amplified or deleted was assessed in a confirmatory fashion using existing Agilent 4×44 Expression Array data. The Illumina Infinium HumanMethylation27 BeadChip was used to determine whole genome methylation status.

Results: A total of 79 amplified and 419 deleted genes common to >66% of samples were identified. There was significant correlation (p<0.05) of gene copy number to the mRNA level for 9 of the amplified and 76 of the deleted genes, including amplification/overexpression of AR and deletion/underexpression of the tumor suppressors PTEN and RB. While copy number was normal for the androgen synthesis genes CYP17A1, HSD17B3, HSD17B4, and HSD3B2, methylation analysis indicates their upregulation in the majority of samples, suggesting an alternative mechanism of intratumoral hormone production. There was promoter hypermethylation and gene deletion of RB1 in >85% of samples, suggesting that inactivation of this tumor suppressor through multiple pathways is critical to tumor cell survival.

Conclusions: This is the first known study examining both gene copy number and whole genome CpG island methylation status in metastatic CRPC. Integration of this data allows for identification of specific genes or pathways that confer a selective growth advantage to prostate cancer cells harboring those changes.

No significant financial relationships to disclose.
High dose rate brachytherapy as a single 15 Gy fraction combined with hypofractionated external beam radiotherapy for intermediate-risk prostate cancer.
Authors: Morton G. , Loblaw D. A. , Chung H. T.
Published: February 2017

66

Background: High dose rate (HDR) brachytherapy for prostate cancer is commonly given in multiple fractions combined with external beam radiotherapy (EBRT) over 5 weeks. We report results of a phase II clinical trial of single fraction HDR combined with hypofractionated EBRT over 3 weeks.

Methods: Eligible patients had T1 or T2 carcinoma of the prostate with a PSA < 20 and Gleason score of 7 or less, without use of androgen deprivation. The trial accrued 125 patients with a median PSA of 6.8 ng/ml; 93% had Gleason 7. Single 15 Gy HDR was delivered to the prostate, followed 2-weeks later by EBRT to 37.5 Gy in 15 fractions. Patients were followed for toxicity (CTCAE v 3.0), health related quality of life (EPIC), urinary symptoms (IPSS), and clinical and biochemical control.

Results: Median follow-up is 3 years (range: 1-4.5 years), with no biochemical failures. Median PSA at 3 years is 0.24 ng/ml. One of 38 biopsies at 2 years had persistent cancer. Two patients (1.6%) had acute grade 3 urinary toxicity, and median IPSS score returned to within 2 points of baseline by 3 months. The prevalence of grade 2 rectal and urinary toxicity at 2 years was 2% and 25%, respectively. Mean EPIC urinary and bowel domain scores decreased in the first 2 years, but returned to within 5 points of baseline at 3 years. Mean sexual function scores declined over the first 4 years although sexual bother scores returned to baseline at 3 years. On multivariate analysis, baseline IPSS score (p=0.0125), V100 (p=0.0002) and V200 (p=0.0141) were associated with acute grade 2 urinary toxicity. Decline in EPIC urinary quality of life domain was associated with HDR dose to 10% of urethra (p=0.0168), with a threshold of 120%. Decline in sexual scores was associated with smaller prostates and high baseline erectile functioning.

Conclusions: Single fraction 15 Gy HDR combined with hypofractionated external beam radiotherapy is a well tolerated and effective treatment for intermediate risk prostate cancer.

No significant financial relationships to disclose.
High-dose radiotherapy with or without androgen-deprivation therapy for intermediate-risk prostate cancer: Cancer control and toxicity.
Authors: Edelman S. , Rossi P. J. , Cooper S. , Jani A. B.
Published: February 2017

67

Background: Randomized studies show an improvement in biochemical failure-free survival (BFFS) and overall survival (OS) with the addition of androgen therapy (ADT) to external-beam radiotherapy (EBRT) for high-risk prostate cancer (PC). However, the role of ADT in intermediate risk PC in the current dose-escalation era remains poorly defined, as studies evaluating ADT in this group have included high-risk patients or did not use dose-escalation. Our goal was to evaluate the impact of ADT on cancer control and toxicity in intermediate-risk PC.

Methods: From a multi-institutional IRB-approved database of 850 pts, we identified 251 intermediate risk PC patients (defined as ≥ T2b or PSA > 10 or Gleason score [GS] of 7, with none of the following: ≥ T3, PSA > 20, GS ≥ 8, positive nodes, distant metastases) treated with EBRT to a dose of ≥70 Gy (no brachytherapy or prostatectomy). Eighty-seven men received ADT; 164 did not. BFFS (Phoenix definition) and OS survival curves for ADT vs no-ADT arms were compared with the log rank test. Univariate and multivariate analyses of major demographic, disease and treatment factors were performed, as were chi-square analyses of genitourinary (GU) and gastrointestinal (GI) toxicity.

Results: Median follow up was 47 mo. Mean dose [ADT vs no-ADT] was 76.8 Gy vs 76.2 Gy (p=0.41; range: 70.0-81.0 Gy). The ADT group had a higher mean PSA (12.0 vs 8.9, p<0.001), proportion of ≥ T2b (22 vs 11%, p<0.01) and proportion of pelvic XRT use (49 vs 22%, p<0.001) than the no-ADT group, but the groups were well-balanced by age, race, GS, EBRT dose and intensity-modulated radiotherapy (IMRT) use. For ADT vs no-ADT, 5-yr BFFS was 80% vs 76% (p=0.17) and 5-yr OS was 84% vs 76% (p=0.82). On multivariate analysis, only ADT (p=0.006) and GS (p=0.006) were significantly associated with BFFS, and only PSA (p=0.028) and IMRT use (p=0.011) reached significance for OS. There were no significant differences in acute or late GU or GI toxicity.

Conclusions: While RTOG 0815 is exploring this study question in a randomized setting, our study suggests that the addition of ADT to dose-escalated EBRT may improve BFFS, but without a demonstrated OS benefit, and is not associated with additional EBRT-related GI or GU toxicity.

No significant financial relationships to disclose.
Adjuvant high-dose intensity-modulated radiotherapy following radical prostatectomy: Updated 5-year results.
Authors: Ost P. , De Potter B. , Beerens A. , Lumen N. , Fonteyne V. , De Meerleer G.
Published: February 2017

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Background: Approximately 25% of patients treated with immediate post-prostatectomy (adjuvant) radiotherapy will develop a biochemical failure within 5 years after radiotherapy when doses of 60-64 Gy are used. We wanted to report on the safety and biochemical outcome of adjuvant intensity-modulated radiotherapy (AIMRT) with a median dose of 74 Gy.

Methods: Between 1999 and 2008, 104 patients underwent a radical prostatectomy followed by AIMRT +/− androgen deprivation (AD). Indications for AIMRT were capsule perforation, seminal vesicle invasion and/or positive surgical margins at prostatectomy specimen. All patients were irradiated at a single tertiary academic centre. AD was initiated in 65% of the patients on the basis of seminal vesicles invasion, pre-prostatectomy PSA > 20ng/mL, Gleason score ≥ 4+3 or personal preference of the referring urologist. A median dose of 74 Gy was prescribed to the planning target volume using IMRT in all patients. AD consisted out of a LHRH analogue for 6 months. The Kaplan-Meier method was used to estimate biochemical relapse-free survival (bRFS). Univariate and multivariate analysis were used to examine the influence of patient- and treatment-related factors on bRFS.

Results: The median follow-up was 5 years. Late toxicity: no patients developed grade 3 gastrointestinal (GI) toxicity. Grade 2 GI toxicity was seen in 8%. Seven patients (7%) and 24 (23%) developed grade 3 and 2 genitourinary (GU) toxicity, respectively. An urethral stricture was observed in 8 patients (8%). The 3- and 5-year actuarial bRFS was 91% and 85%, respectively. On univariate analysis bRFS rates was reduced with seminal vesicle invasion (p < 0.04) or Gleason score ≥ 4+3 (p < 0.02) or negative margins (p < 0.001). AD and preoperative PSA levels did not influence bRFS. None of the variables remained significant on multivariate analysis.Eight patients had a distant clinical relapse (pelvic lymph nodes: 3, bone metastases: 3 and 2 patients had both). Seven patients died (3 prostate cancer related deaths).

Conclusions: Adjuvant high-dose IMRT after prostatectomy is safe. Five-year bRFS is excellent.

No significant financial relationships to disclose.
A matched-pair analysis of dose-escalated adaptive image-guided radiotherapy (IGRT) versus pelvic irradiation with brachytherapy boost for intermediate- and high-risk prostate cancer.
Authors: Shah C. , Kestin L. L. , Ghilezan M. , Vicini F. A. , Gustafson G. S. , Brabbins D. , Wallace M. , Marvin K. , Ye H. , Martinez A.
Published: February 2017

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Background: The purpose of this study was to compare clinical outcomes in a cohort of intermediate- and high-risk prostate cancer patients treated with either dose-escalated adaptive IGRT or pelvic external beam RT with high-dose rate brachytherapy boost (EBRT+HDR).

Methods: 1,520 patients with clinical stage T1-T3 N0 M0 prostate cancer were treated with either CT-based offline adaptive IGRT (n=1,037) or EBRT+HDR, n=438) at William Beaumont Hospital. For IGRT, the CTV included the prostate and proximal seminal vesicles only. Median dose (minimum to cl-PTV) delivered via 3D conformal RT or intensity-modulated RT was 75.6 Gy (range: 73.8-79.2 Gy). For EBRT+HDR, the whole pelvis was treated to 46 Gy + 2 HDR implants with a median of 10.5 Gy (8.75-11.5 Gy) per implant. 208 patients from each group were matched based on criteria of pretreatment PSA ± 4 ng/mL, same Gleason score, T stage ± 2 sublevels, and use of neoadjuvant androgen deprivation therapy (ADT).

Results: Mean follow-up was 5.1 years for IGRT vs 7.0 years for EBRT+HDR. Mean pretreatment PSA was 9 for both groups. Mean Gleason was 7 for both groups. EBRT+HDR patients were younger (67 vs 71 years, p<0.01) with a higher percentage of positive biopsy cores (51% vs 39%, p<0.01). Intermediate risk patients comprised 78% and 76% for IGRT and EBRT+HDR, respectively (p=0.56). 42% in each treatment group received neoadjuvant or concurrent ADT. 5-year biochemical control (BC) based on the Phoenix definition was 91% for IGRT vs 87% for EBRT+HDR (p=0.60). For intermediate-risk, 5-year BC was 94% vs 87% (p=0.71) and was 86% vs 86% (p=0.83) for high-risk patients. No significant differences were noted between the 2 groups for local recurrence, distant metastasis, clinical failure, overall survival, and cause-specific survival.

Conclusions: In this matched-pair analysis of 416 patients, treatment of intermediate and high-risk prostate cancer with either offline adaptive IGRT or EBRT+HDR yielded excellent clinical outcomes without significant differences. The omission of pelvic radiotherapy in the IGRT patients did not appear to be associated with poorer clinical outcomes with modern high-dose RT.

No significant financial relationships to disclose.
Long-term outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2C-T3B).
Authors: Al-zahrani A. A. , Autran Gomez A. , Williams A. , Bauman G. , Izawa J. , Chin J.
Published: February 2017

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Background: Our primary objective is to assess and compare the survival outcomes between cryoablation (CRYO) and external beam radiation therapy (EBRT) in locally advanced prostate cancer.

Methods: This is a single institution, retrospective study. Our institution ethics board had approved this study. Patients were initially recruited for the trial between 1999 and 2002. The inclusion criteria for the trial were patients with cT2c–cT3b prostate cancer, PSA < 25ng/ml, with negative metastatic evaluation on CT and bone scan. Patients with evidence of metastasis, prior pelvic radiotherapy or hormone therapy, prostate volume > 75 ml or American Society of Anesthesiology Risk class > 3 were excluded. The biochemical failure was based on the Phoenix criteria (PSA nadir + 2ng/dl). Patients were subjected for regular trans-rectal ultrasound and biopsy until 24 months of follow-up (at 3, 6, 12, 18, 24 months for CRYO and at 18, 24 months for EBRT) and then as clinically indicated. Biochemical disease-free survival (bDFS), disease-specific survival (DSS) and overall survival (OS) were analyzed with Kaplan-Meier curve.

Results: Sixty-two patients completed the trial with a median follow-up of 105.2 (± 35.8) months. Preoperative demographic and clinicopathological characteristics of both groups were comparable. All patients received neoadjuvant hormonal therapy for 3 months prior and continued for 3 months after the procedures. The prostate volume before the therapy was smaller in the CRYO group (31.3 ml vs 40.9 ml; p≤0.01). There was greater reduction in the prostate volume in the CRYO group after the intervention (–54% vs 34%; p≤0.01).Three patients in the cryotherapy arm and 2 patients in the radiotherapy arm were crossed over to the other modality at the time of biochemical or biopsy proven progression. The DSS and the OS were comparable between both groups. The 8-year bDFS rate was significant lower in the CRYO group (17.4% vs 59.1%; p=0.01).

Conclusions: This randomized trial showed that CRYO was suboptimal in attaining bDFS at 8 years in patients with locally advanced prostate cancer (cT3). Other recent randomized trial showed favorable outcome with CRYO for localized prostate cancer.

No significant financial relationships to disclose.
Three-dimensional visualization of stranded source migration following prostate brachytherapy.
Authors: Daniel S. E. , Aref A. , Rabbani C. , Taylor R. , Campbell T. , Shamsa F. , Chuba P. J.
Published: February 2017

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Background: The use of radioactive seeds embedded in absorbable vicryl suture material has emerged as one preferred method for prostate cancer brachytherapy. However, it is unclear how strand displacement affects post-implant dosimetry. Our objective was to use CT imaging and 3D reconstruction to determine strand displacement between day zero and day 30 and to assess the dosimetric consequences of strand displacement.

Methods: Between March 2006 and December 2009 there were 86 prostate brachytherapy patients with day zero and day 30 post-plan imaging. There was a mean of 18.24 strands per implant, 9.81 loose seeds per implant, and 69.08 total seeds per implant. Substantial strand displacement was identified by inspection. Migrated strands were identified on day zero and day 30 scans and the distance of displacement was measured using 3D fusion software.

Results: Of 1550 strands placed, 23 were found to show substantial migration revealed by 3D imaging. These displacements occurred in 21 of the 86 cases. The estimated distance of strand displacement ranged from 0.5 cm to 2.5 cm with an average movement of 1.5 cm. The exact distance of strand displacement ranged from 0.31 m to 3.44 cm, with mean movement of 2.75 cm.

Conclusions: 3D imaging reveals unexpected spatial instability in stranded brachytherapy sources. Significant movement may be expected to occur in approximately 1.48% of stranded sources and 24.42% of cases. Factors which predict for the migration of sources remain relatively undefined. Minimal dosimetric effects from strand displacement appear to be offset by resolution of prostate edema.

[Table: see text]

No significant financial relationships to disclose.
The impact of comorbidity on survival among men with localized prostate cancer.
Authors: Lu-Yao G. L. , Moore D. , Shih W. , Lin Y. , Li H. , Albertsen P. C.
Published: February 2017

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Background: To provide patients and clinicians more accurate estimates of co-morbidity specific survival stratified by patient age, tumor stage and tumor grade.

Methods: We conducted a ten year competing risk analysis of 19,639 men age 66 years and older identified by the Surveillance, Epidemiology and End Results (SEER) program linked to Medicare program files. All men were diagnosed with localized prostate cancer and received no surgery or radiation within 180 days of diagnosis. The analysis was stratified by tumor grade and stage and by age and co-morbidity at diagnosis classified using the Charlson co-morbidity index. Underlying causes of death were obtained from SEER.

Results: During the first ten years following diagnosis men with moderately and poorly differentiated prostate cancer were more likely to die from causes other than their disease. For men age 66-74 years with stage T1c Gleason score 5-7 disease at diagnosis, ten year overall mortality rates and prostate cancer specific rates were 28.8%, 50.5%, 83.1% and 4.8%, 2.0%, 5.3% respectively for men with Charlson scores 0, 1 and > 2. For men age 66-74 years with T1c Gleason score 8-10 disease at diagnosis, the corresponding rates were 55.0%, 52.0%, 64.3% and 25.7%, 20.2%, 13.7% respectively for men with Charlson scores 0, 1, > 2. Death from competing medical hazards was roughly comparable for men with stage T2 disease and higher for all men over age 75.

Conclusions: Patients and clinicians should consider using co-morbidity specific data to estimate the threat posed by localized prostate cancer.

No significant financial relationships to disclose.
Dose escalation with high-dose 3D-conformal radiotherapy (HD-3D-CRT) or low-dose 3D-conformal radiotherapy plus HDR brachytherapy (LD-3D-CRT+HDR-B) for intermediate- or high-risk prostate cancer: Higher PSA control with lower toxicity.
Authors: Guix B. , Bartrina J. , Tello J. , Lacorte T. , Henriquez I. , Sole J. , Guix I. , Galdon G. , Espino M.
Published: February 2017

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Background: To report early and late toxicity and preliminary biochemical outcome in in a prospective serie of 445 patients with intermediate- or high-risk clinically localized prostate cancer treated with either HD-3D-CRT or with LD-3D-CRT+HDR-B.

Methods: Between 12/1999 and 10/2005, 445 patients (pts) with PSA >10, Gleason score > 6 and/or T2b-T3 N0 M0 prostate cancer entered the study. Pts were prospevtively assigned to one of the two treatment groups: 76 Gy HD-3D-CRT to the prostate in 38 fractions (group 1; 223 patients) or 46 Gy LD-3D-CRT+ 16 Gy HDR-B given in 2 fractions of 8 Gy (group 2, 222 patients), limiting the maximum rectal dose to 85% of the prescribed dose. Both groups were well balanced taking into account patient’s as well as tumors’ characteristics. Toxicities were scored by the EORTC /RTOG morbidity grading scales. Special attention to local, regional or distant recurrence, survival, late effects, PSA and testosterone levels and quality of life was done.

Results: All pts completed treatment. None pts included in the group 1 or 2 experienced grade 3 rectal toxicity. 28 pts of group 1 (12.5%) and 6 pts of group 2 (2.7%) developed grade 2 rectal toxicity (rectal bleeding or urgency). 15 pts in group 1 (6.7%) and 3 pts in group 2 (1.3%) developed grade 1 rectal bleeding (less than 2 times/week). In group 1 and 2, 81.8%and 95,9% of pts were free from rectal reactions respectively (p<0.005). Free from failure survival at 5-year was 82.3% and 98.1% respectively (p<0.05)

Conclusions: High-dose 3D-EBRT + HDR brachytherapy was a safe and effective method of escalating the dose to the prostate without increasing the risk of late effects. Acute as well as late rectal complications were significantly reduced with the combined treatment, compared with what was observed with high-dose conventional, 3D-conformal radiotherapy. Short-term PSA control rates tends to be better with in the HDR-boosted patients as spected by higher effective dose.

No significant financial relationships to disclose.
Stereotactic body radiotherapy for low-risk prostate cancer: Five-year outcomes.
Authors: Freeman D. , King C. R.
Published: February 2017

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Background: Hypofractionated, stereotactic body radiotherapy (SBRT) is an emerging treatment approach for prostate cancer. We present the outcomes for low-risk prostate cancer patients with a median follow-up of 5 years after SBRT.

Methods: Between Dec. 2003 and Dec. 2005, a pooled cohort of 41 consecutive patients from Stanford, CA and Naples, FL received SBRT with CyberKnife for clinically localized, low-risk prostate cancer. Prescribed dose was 35–36.25 Gy in five fractions. No patient received hormone therapy. Kaplan-Meier biochemical progression-free survival (defined using the Phoenix method) and RTOG toxicity outcomes were assessed.

Results: At a median follow-up of 5 years the biochemical progression-free survival was 93% (95% CI = 84.7% to 100%). Acute side effects resolved within 1–3 months of treatment completion. There were no grade 4 toxicities. No late grade 3 rectal toxicity and only one late grade 3 genitourinary toxicity occurred following repeated urologic instrumentation.

Conclusions: Five-year results of SBRT for localized prostate cancer demonstrate the effectiveness and safety of shorter courses of high dose per fraction radiation delivered with SBRT technique. Ongoing clinical trials are expected to further support this experience.

[Table: see text]
Hyperthermic intraperitoneal chemotherapy following gastrectomy for the prevention of carcinomatosis in advanced gastric cancer: Nonrandomized phase II prospective trial.
Authors: Murata Satoshi , Naito Hiroyuki , Yamamoto Hiroshi , Yamaguchi Tsuyoshi , Miyake Tohru , Mekata Eiji , Shimizu Tomoharu , Shiomi Hisanori , Naka Shigeyuki , Sonoda Hiromichi , Mori Tsuyoshi , Akabori Hiroya , Kawai Yuki , Cho Hirotomi , Kubota Yoshihiro , Umeda Tomoko , Endo Yoshihiro , Abe Hajime , Kurumi Yoshimasa , Tani Tohru
Published: February 2017

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Background: About half of patients with serosa-invasive gastric cancer develop peritoneal recurrence and die of this disease even if curative resections performed. This prospective phase II study was performed to assess the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) with three anticancer drugs in patients with curative resection of clinically T3 or T4 serosa-invasive advanced gastric cancer.

Methods: Patients age 75 years or younger with curative resection of clinically T3 or T4 advanced gastric cancer were eligible for this nonrandomized phase II trial. After the curative resection of gastric cancer with D2 lymph node dissection, HIPEC was carried out for 30 minutes with 50mg of CDDP, 10mg of MMC, and 1000mg of 5-FU in 5 L saline maintained at 42-43C°. Patients were given an adjuvant S-1 treatment after surgery. Primary endpoint of this study was overall survival. Second end points included safety and recurrence rate.

Results: A total of 50 patients were eligible between January 2002 and December 2010. Pathologically, 12 patients had sub-serosal invasion (pT2(ss)), 35 patients had serosal invasion (pT3), and 3 patients had adjacent organ invasion (pT4). Median follow-up period was 52 months (12-104 months). Overall 5-year survival rate in all eligible patients was 89.9%. Overall 5-year survival rate in patients with stage IB (n=4), stage II (n=12), stage IIIA (n=18), or stage IIIB (n=16) was 100%, 100%, 90.9%, or 76.2%, respectively. Only one patient (2.0%) had peritoneal recurrences. Four patients (8.0%) with pN2 had lymphatic recurrences. A total of 13 patients had postoperative complications such as minor pancreatic fistula (Grade A) (10.0%), abdominal abscess (4.0%), leakage of the anastomosis (8.0%), and pneumonia (6.0%). All patients recovered without any surgical interventions. None of patients needed for the treatment in the Intensive Care Units after HIPEC.

Conclusions: Intra-operative HIPEC with three anticancer drugs following curative resection of advanced gastric cancer improves overall survival with an inhibition of peritoneal recurrence and an acceptable morbidity.