bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-life treatment of patients with advanced or metastatic renal cell carcinoma in German oncology and urology outpatient centers (RCC-Registry).
Authors: Mueller L. , Goebell P. , Blumenstengel K. , Lueck A. , Koska M. , Marschner N.
Published: February 2017

367

Background: Until 2006, advanced or metastatic renal cell carcinoma (mRCC) patients were treated with immunomodulators such as interleukins and interferons. Multiple new targeted therapeutics, mainly signal transduction inhibitors, have been developed resulting in fundamental changes of therapeutic standards for patients with mRCC. In 2007, recruitment into the registry started in order to survey the treatment of mRCC patients, the course of disease and treatment as well as the therapeutic decision-making processes.

Methods: It is intended to enroll 1,000 mRCC patients and collect data for each case for a maximum of 3 years. Over 100 oncology and urology outpatient centers in Germany are participating. Inclusion Criteria: (1) patients with metastatic or locally advanced RCC requiring antineoplastic therapy, (2) start of first palliative therapy within 1 year before enrolment, (3) age at least 18 years, and (4) Informed written consent.

Results: By May 2010, 509 patients were enrolled. At the start of systemic therapy mean age were 66.2 years for male and 69.0 years for female patients, respectively. Patients have a Charlson Comorbidity Index of 1.0. More than 94% of patients had metastases at inclusion. 62.8% of the patients received sunitinib as first-line treatment, 12.0% received temsirolimus, 9.6% were treated with bevacizumab/interferon alpha, and 9.1% received sorafenib. Median duration determined using Kaplan-Meier analyses of first-line treatment with: sunitinib: 8.5 months (n=319), temsirolimus: 2.6 months (n=60), bevacizumab/interferon alpha: 4.6 months (n=49), and sorafenib: 6.7 months (n=45) whereby the duration of ongoing therapies was censored as the date of last documentation; thus the final duration might exceed the given values. After first-line treatment with sunitinib most of the patients received either sorafenib (12.4%, n=63) or temsirolimus (7.7%, n=39) in the second line.

Conclusions: The registry provides an overview of the current treatment of mRCC patients in German outpatient cancer centers and shows how fast the insights of clinical studies concerning treatment of mRCC patients are transferred into current medical practice.

[Table: see text]
Prognostic factors for response to systemic treatments carried out in patients with advanced renal carcinoma.
Authors: Muriel C. , Esteban E. , Martinez-Camblor P. , Astudillo A. , Crespo G. , Pardo P. , Izquierdo M. , Berros J. , Gutierrez E. , Lacave A. J.
Published: February 2017

369

Background: The analysis of predictive factors of response could help to select those patients with advanced renal cell carcinoma (RCC) who would be good candidates for systemic treatments

Methods: The expression of several biomarkers was retrospectively analysed by immunohistochemistry (IHC), as well as 2 analytical variables: thrombocytosis and neutrophilia, in 135 patients with advanced RCC treated with cytokines (CK) and/or biological agents and was correlated to the response.

Results: 67 patients were treated only with biological agents and 68 with CK (23 treated also with biological agents). Univariate statistical analysis: HIF-1alpha did not correlate significantly with the response to these drugs. The overexpression of ACIX was associated to a larger response (%) to biological agents such as sunitinib (65.9 vs. 16.7 p<0.001) or sorafenib (61.9 vs 0 p=0.007), and CK (22.6 vs. 0 p=0.038). PTEN showed a predictive value for response (%) to sunitinib (70.8 vs. 34.1 with PTEN negative p=0.005). p21 was associated to a lower response (%) with sunitinib (35.9 vs. 65.4 with p=0.025). Thrombocytosis was not significantly associated with the response (%) to biological agents, although it was associated to CK (0 vs. 20 without thrombocytosis p=0.017). Neutrophilia correlated with a smaller response to biological agents (29.6 vs. 57.5 without neutrophilia, p=0.045), although it did not associate with a response to CK. In the multivariate analysis, overexpression of ACIX was an independent predictor of a larger response to biological agents and CK with an OR of 8,773 (p<0.001).

Conclusions: Our findings prove the usefulness of ACIX to select patients with advanced RCC candidates to receive systemic treatment. PTEN and p21 could be important in the prediction of response to sunitinib. Thrombocytosis and neutrophilia appear to relate to the response to CK and biological agents respectively.

No significant financial relationships to disclose.
Evaluation of tumor-associated macrophages as a prognostic indicator in patients with papillary renal cell carcinoma.
Authors: Hutterer G. C. , Chromecki T. F. , Zigeuner R. , Klatte T. , Kampel-Kettner K. , Pummer K. , Remzi M. , Mannweiler S.
Published: February 2017

372

Background: Prognostic indicators in papillary renal cell carcinoma (PRCC) are not well defined. We evaluated the prognostic relevance of tumor-associated macrophages (TAM) in patients with PRCC.

Methods: PRCC specimens were re-evaluated by one blinded pathologist (SM), with respect to pT-classification (TNM 2002), nodal status, Fuhrman grade (I-IV), tumor size, subtype (type 1 or 2), tumor necrosis, and presence of TAM. Presence of TAM was associated with pathological parameters (chi-square and fisher's exact tests). Impact of TAM on cancer-specific survival (CSS) was assessed (Kaplan-Meier method and log-rank test). A multivariate regression analysis including pT-stage, grade, vascular invasion, necrosis, tumor size, papillary subtype and TAM was performed with respect to CSS.

Results: 177 patients operated for PRCC from 1984 to 2006, were evaluated. Presence of TAM was noted in 112/177 (63%) tumors and was significantly associated with favorable pathological parameters: low pT-classification (pT1a/b: 71/90, 79%; pT2: 14/31, 45%; pT3a/b: 27/56, 48%; p<0.001), node negative tumors (Nx/pN0: 111/170, 65% vs. pN1/2: 1/7, 14%; p=0.01), low grade (G1: 35/45, 78%; G2: 67/110, 61%; G3: 10/22, 45%; p=0.025), absence of vascular invasion (V0: 106/153, 69% vs. V1/2: 6/24, 25%; p<0.001), and papillary subtype (type 1: 64/87, 74% vs. 48/89, 54%; p=0.007), respectively. Median follow-up was 68.3 months. Five-year CSS probabilities for patients with TAM-positive tumors were 93.5%, compared with 72.5% in patients with TAM-negative tumors (p<0.001). Median survival was not reached in both groups. Multivariate analysis revealed node positive tumors (HR=2.4, 95%CI=1.1-5.0; p=0.025), distant metastases (HR=8.7, 95%CI=2.6-29.3; p<0.001), and tumor size (HR=1.2, 95%CI=1.0-1.3; p=0.03) as independent predictors of death from PRCC, whereas presence of TAM was independently associated with favorable outcome (HR=0.3, 95%CI=0.1-0.9, p=0.026).

Conclusions: Presence of TAM was independently associated with a favorable outcome in patients with PRCC and was shown to reduce the risk of death from cancer by 66%. Presence of TAM should therefore be part of routine pathology reporting in PRCC.

No significant financial relationships to disclose.
Neoadjuvant temsirolimus in high-risk renal cell carcinoma: Results from a single-center prospective study.
Authors: Sheikh A. A. , Gharajeh A. , Hotte S. J. , Pinthus J. H. , Kapoor A.
Published: February 2017

387

Background: The current first-line treatment for advanced renal cell carcinoma (RCC) includes targeted therapy with or without cytoreductive radical nephrectomy. There is a paucity of data as to the effectiveness of adjuvant and neoadjuvant treatment before radical nephrectomy for localized high-risk or advanced disease. We initiated a trial of neoadjuvant Temsirolimus before radical nephrectomy for locally advanced and metastatic RCC examining tumor response and survival.

Methods: Patients who presented with advanced RCC were offered enrolment into a prospective, single-centre, ethics approved trial with 12 weeks of temsirolimus before radical nephrectomy. Biopsy tissue was obtained at enrollment and at time of cytoreductive nephrectomy for diagnosis. Patients were administered 25 mg in temsirolimus on a weekly basis for 12 weeks, and then underwent radical nephrectomy. Computed tomography scans and biomarkers were obtained on enrolment, 6 weeks and 12 weeks (before nephrectomy). Ongoing outcome and survival data were analyzed.

Results: Eight patients were enrolled into the trial. Patient #1 (10-cm renal mass with bulky adenopathy T2N2M0) had no evidence of disease (NED) at 6 months post-nephrectomy. Patient #2 (9-cm renal mass, bulky adenopathy, pulmonary metastases T2N2M1) also had NED at 6 months postnephrectomy. Patients #3 and #4 experienced regression of the primary mass and have recently undergone uneventful surgery with follow-up pending. Patients #5 and #6 expired prior to the full course of therapy, but had diagnoses other than RCC. Patient #7 experienced disease progression, however, this patient's nephrectomy was delayed by 3 months due to an unrelated myocardial infarct. Patient #8 experienced adverse events.

Conclusions: Our findings suggest that neoadjuvant temsirolimus before radical nephrectomy for advanced RCC may improve disease regression post-surgery, and may lead to disease resolution in patients with low-volume disease. Randomized studies with longer term follow-up is necessary to assess overall progression-free survival and overall survival.

[Table: see text]
Fuhrman grade and concomitant bisphosphonates as additional prognostic factors in metastatic renal cell carcinoma with bone metastases treated with sunitinib.
Authors: Beuselinck B. L. , Medioni J. , Wolter P. , Blesius A. , Karadimou A. , Schöffski P. , Escudier B. J. , Zucman-Rossi J. , Paridaens R. , Oudard S.
Published: February 2017

388

Background: With a median progression-free survival(PFS) of 8.2 months (mo) (vs. 19.1 mo; p<0.0001) and overall survival (OS) of 19.5 mo (vs. 38.5 mo; p<0.0001), metastatic renal cell carcinoma (m-RCC) patients (pts) with bone metastases (BM) have a poorer outcome under sunitinib (SUN) than pts without BM (Beuselinck et al, Annals of Oncology 2010). The aim of this retrospective study was to determine additional prognostic factors in this poor risk subgroup of pts.

Methods: We collected data on classical prognostic factors for m-RCC, Fuhrman grade, number of BM, and bone-oriented therapy in the charts of 80 m-RCC pts with BM who started first-line SUN between 01/2005 and 12/2009 in 4 academic centers in Belgium and France. Univariate analysis was conducted using Maentel Hetzel test. Validation of these findings on a second series of m-RCC patients is ongoing. Multivariate analysis will be performed on the total series.

Results: In the total population, median PFS and OS were 9.8 and 20.6 mo. Pts with Fuhrman grade 4 tumors (MSKCC prognosis: intermediate 50%; poor 50%) had a PFS of 4.5 mo vs. 12.3 mo for Fuhrman grade 1-2-3 tumors (MSKCC prognosis: good 20%; intermediate 60%; poor 20%) (p=0.005). OS was 13.5 mo vs. 26.5 mo respectively (p=0.003). There was no difference in PFS and OS between pts with Fuhrman grade 1-2 and Fuhrman grade 3 tumors. The number of BM had no significant influence on PFS and OS. Whether or not radiation therapy and/or surgery had been applied to all BM before starting SUN was a factor without influence on PFS or OS. Concomitant bisphosphonates (BF) and SUN administration was analyzed on all the evaluable pts (24) treated at the University Hospitals Leuven. 14 pts (MSKCC prognosis: poor: 8; intermediate: 6) received concomitant BF. 10 pts (MSKCC prognosis: poor: 5; intermediate: 5) did not. Median PFS was 16.3 and 3.4 mo (p=0.03) and OS 18.1 and 13.9 mo respectively (not significant). Results of the validation series and multivariate analysis will be presented.

Conclusions: m-RCC pts combining BM and Fuhrman grade 4 tumors have a very poor outcome on SUN. Concomitant use of BF may be a strategy to improve PFS in pts with bone metastatic RCC.

No significant financial relationships to disclose.
The effect of bevacizumab on tumor response and primary resistance to systematic therapy.
Authors: Ranpura V. , Su X. , Wu S.
Published: February 2017

399

Background: The angiogenesis inhibitor bevacizumab in combination with chemotherapeutic agents or cytokines are used extensively in the treatment of metastatic tumors including renal cell carcinoma (RCC). Risk factors for the treatment response are not clear. We performed a systemic review and meta-analysis of published randomized controlled trials (RCT) to determine the effect of bevacizumab on tumor response to systematic therapy.

Methods: We searched databases from Pubmed, Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences up to May 2010 to identify relevant studies. Tumor response was defined according to RECIST criteria. Eligible studies include RCTs in which bevacizumab in combination with systematic therapy was compared with systematic therapy alone. Relative risk (RR), and 95% confidence intervals (CIs) were calculated using a random-effects or fixed-effects model based on heterogeneity of included studies.

Results: A total of 8,972 patients from 16 studies were included for analysis. Overall, bevacizumab significantly increased the response rate with an RR of 1.67 (95% CI: 1.41–1.84). The effect varied significantly with tumor types (p=0.007), with the highest seen in RCC (RR 2.17, 95% CI: 1.71–2.74), and the lowest seen in mesothelioma (RR 1.14, 95% CI: 0.89–1.44). No significant difference was found between bevacizumab at 2.5 and 5 mg/kg/week. Also, bevacizumab significantly reduced the risk of primary resistance to systematic therapy (RR 0.83, 95% CI: 0.70–0.99; p=0.04). The risk reduction varied significantly with tumor types (p=0.02), with the highest reduction seen in RCC (RR 0.76, 95% CI: 0.51–1.14) and colorectal cancer (RR 0.74, 95% CI: 0.51–1.09). Notably, bevacizumab significantly increased the risk of primary resistance to chemotherapy in mesothelioma (RR 1.34, 95% CI: 1.03–1.74). No significant correlation was found between the effect on response rates and progression-free survival (p=0.62) or overall survival (p=0.63).

Conclusions: Bevacizumab has a significant effect on tumor response and primary resistance to systematic therapy, particularly in RCC.

[Table: see text]
Validation of MSKCC-criteria in metastatic renal cancer patients treated with sorafenib or sunitinib.
Authors: Hoffmeister I. , Riesenbeck L. , Bierer S. , Koepke T. , Hertle L. , Thielen B. , Herrmann E.
Published: February 2017

401

Background: To validate the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria as a prognostic factor in patients with metastatic renal cell carcinoma (mRCC) treated with the tyrosine kinase inhibitors (TKIs) sorafenib (So) or sunitinib (Su).

Methods: Clinical and laboratory parameters from 83 patients with mRCC were investigated. All patients were treated at our institution between 2006 and 2009. Specifically, the MSKCC criteria (Karnofsky performance status <80%, time between diagnosis and treatment < 1 year, baseline anemia, elevated LDH > 1.5 times upper limit of normal, and elevated serum calcium) were evaluated as surrogate parameters for progression-free survival (PFS).

Results: 34 (41.0%) patients were treated as first-line, and 49 (59.0%) patients were treated as second-line treatments, respectively. In univariate analyses, a poor ECOG status was associated with an unfavorable progression-free survival (p<0.0001); similarly high risk MSKCC criteria correlated with a worse PFS (p=0.003). Furthermore, response to therapy was a surrogate parameter (p<0.0001). Albeit statistically not significant, prior nephrectomy (p=0.056), histologic subtype (p=0.052) as well as baseline anemia (p=0.079) tended to be associated with PFS. In multivariate analyses, only the ECOG status (ECOG 0/1 vs. ECOG 2, p=0.001) and best treatment response (p<0.001) were independent prognostic markers, but not MSKCC criteria.

Conclusions: In this patient cohort, MSKCC criteria did not show prognostic relevance in terms of PFS. The role of risk group stratification according to MSKCC in patients with mRCC and treatment with TKIs must be questioned.

No significant financial relationships to disclose.
Alkaline phosphatase (ALP) normalization and overall survival in patients with bone metastases from castration-resistant prostate cancer (CRPC) treated with radium-223.
Authors: Parker C. , O'Bryan-Tear C. G. , Bolstad B. , Lokna A. , Nilsson S.
Published: February 2017

49

Background: Radium-223 (Alpharadin) is a first-in-class alpha-pharmaceutical. It targets bone metastases with high-energy alpha-radiation of extremely short range that spares bone marrow. Radium-223 has a profound effect on serum markers of bone metabolism, including ALP, in patients with bone metastases from CRPC. In an exploratory analysis, we studied whether this effect is associated with a meaningful clinical benefit.

Methods: Patients with CRPC and bone metastases were treated in 2 randomized phase II studies. BC1-02 was a placebo-controlled study of radium-223 (50 kBq/kg) every 4 weeks for 12 weeks. BC1-04 evaluated radium-223 (25, 50, or 80 kBq/kg) every 6 weeks for 12 weeks. Baseline total ALP values > 128 U/L were considered elevated; those decreasing to below 128 U/L during treatment with radium-223 were defined as normalized, and those remaining above that value as non-normalized.

Results: In BC1-02, ALP normalization was seen in 12/26 (46%) patients treated with radium-223. Median survivals of those with and without ALP normalization were 102 weeks and 42 weeks, respectively (log-rank P < 0.001). In BC1-04, ALP normalization was seen in 25/75 (33%) cases: 5/29 (17%) in the 25 kBq/kg group, 10/25 (40%) with 50 kBq/kg, and 10/21 (48%) with 80 kBq/kg, indicating a dose-response relationship. Median survivals for the 25 patients with, and the 50 patients without, ALP normalization were 102 weeks and 58 weeks, respectively (log-rank P = 0.0086).

Conclusions: Inpatients with metastatic CRPC and bone metastases treated with radium-223, ALP normalization was associated with significantly better overall survival. These data support the rationale for the ongoing ALSYMPCA phase III trial of radium-223.

[Table: see text]
Capture and analysis of prostate cancer circulating tumor cells (CTCS) using geometrically enhanced differential immunocapture (GEDI).
Authors: Jodari M. , Loftus M. , Gleghorn J. , Gakhar G. , Pratt E. , Tagawa S. T. , Bander N. H. , Giannakakou P. , Kirby B. , Nanus D. M.
Published: February 2017

53

Background: EpCAM-based immunocapture of prostate cancer (PC) CTCs yields relatively low purity and specificity. We developed a geometrically enhanced differential immunocapture (GEDI) microfluidic device that incorporates flow dynamics and utilizes a mAb to prostate-specific membrane antigen (PSMA) to optimize isolation and analysis of CTCs from PC patients.

Methods: GEDI microfluidic silicon chips, fabricated using standard photolithography techniques, were functionalized by chemical cross-linking ending with a neutravidin terminated surface to which anti-PSMA biotinylated-mAb J591 was bound. C4-2 (PSMA+) and PC-3 (PSMA-) cells were used for chip optimization. 1 mL of peripheral blood from PC patients was flowed (1mL/hour) over functionalized chips. Captured cells were washed with PBS × 30 min, fixed with 3.7% formaldehyde, immunofluorescently stained for DAPI, androgen receptor (AR), tubulin and EpCAM and analyzed by high resolution point-scanning confocal microscopy. PSMA+, DAPI+, and CD45- cells were manually scored. RNA was extracted from unfixed captured CTCs using lysis buffer flowed thru the chip.

Results: ∼80% capture efficiency was achieved from 26 PSMA positive C4-2 cells spiked into 1 mL blood flowed through the GEDI chip. RNA extracted from 50 C4-2 cells in 1 mL blood flowed thru the chip detected a known AR point mutation by RT-PCR and Sanger sequencing. Immunofluorescence staining of PSMA+ cells captured on the chip detected changes in AR subcellular localization and microtubule structure following treatment with DHT or paclitaxel, respectively. 10 patients with metastatic PC were analyzed by CellSearch (range 0-201 cells/7.5 mL) and GEDI chip (range 35->1200 cells/mL) yielding a 7->350 fold enrichment using GEDI. Captured PC cells isolated from PC patient incubated in 50 nm paclitaxel (ex vivo) overnight demonstrated microtubule bundling, indicative of drug-target engagement.

Conclusions: PSMA based GEDI microfluidic CTC capture is highly specific and sensitive in capturing PSMA positive PC CTCs; and allows detailed CTC analysis including protein expression and subcellular localization, mutational analysis and drug sensitivity assessment.

[Table: see text]
Detection of prostate cancer with HistoScanning.
Authors: Epplen R. , van Erps T. , Thueer D. , Knuechel-Clarke R. , Heidenreich A.
Published: February 2017

55

Background: HistoScan is a tool for differentiation, visualization and quantification of changes in solid organ tissue. It is used in combination with transrectal ultrasound that transmits data to a computer program. Data is processed and suspicious areas shown. Our objective was to compare HistoScan with histopathology of radical prostate specimens and to determine sensitivity in detection regarding cancer volume and localization.

Methods: 52 patients who underwent radical prostatectomy HistoScan was performed one day preoperatively. Scan with the largest suspicious volume was used for evaluation. All prostatectomy specimens were processed according to the Stanford protocol. The prostate specimens were divided into a grid of 9 different areas. HistoScan findings were correlated with final pathology regarding localization and volume. A match was defined as well a positive lesion in HistoScan as in a correspondent histopathologically proven area. Results were analyzed regarding to T-stadium, Gleason Score (GS), PSA, tumor volume and volume of HistoScan lesions.

Results: Mean patient age was 63.6 years, mean PSA was 8.97 ng/ml, mean prostate volume was 45.4 ml and mean tumor volume was 4.1 ml. 27 patients (pts) had a pT2 tumour, 25 pT3 carcinoma. 4 pts had salvage prostatectomy. 6 pts had a final GS, 34 and 8 pts had GS 7 and GS ≥8 respectively. Sensitivitiy was 75% for detecting prostate cancer. 64% of the cases showed a good correlation for tumor volume. Results were identical for normal and salvage prostatectomy. Sensitivity was higher for T3 tumors than for pT2 tumors. HistoScan detected 50% of the GS 6 tumors, 74% of GS 7 and 100% of GS ≥8. HistoScan detected small tumors (<1 ml) in 60%, intermediate tumours (1-5 ml) and large tumours (>5 ml) in 87 and 82% respectively. Similar findings are seen regarding the volume of suspicious lesions in HistoScan. For small (≤ 0.5 ml), intermediate (0.5-2 ml) and large (>2ml) lesions, HistoScan correctly predicted localisation in 53%, 86% and 85% respectively.

Conclusions: HistoScan has a great potential in detection of significant prostate cancer. In particular extracapsular poor differentiated and large tumors show a high detection rate. However, larger prospective studies are needed to verify these preliminary results.

No significant financial relationships to disclose.
Novel image analysis tools for evaluating the androgen receptor in the prostate needle biopsy: Impact on future systems-based outcome models.
Authors: Fernandez G. , Ajemba P. , Khan F. , Bayer-Zubek V. , Liu Q. , Donovan M. J.
Published: February 2017

56

Background: A systems-based model was previously developed and validated to predict disease progression (DP) using pretreatment clinical data and standardized, robust prostate needle biopsy (PNB) tissue metrics. We sought to apply novel, advanced immunofluorescent (IF) image analysis methods to re-assess PNB androgen receptor (AR) and Ki67 expression profiles and identify cut-points useful for understanding and guiding therapeutic decision making.

Methods: Pretreatment clinical features and PNB H&E / IF images on 306 patients (91% cT1-T2b, 66% PSA</=10ng/mL; 49% Gleason biopsy score </=6) from the original study cohort were obtained. IF images were re-processed using a novel CK18 and DAPI algorithm to optimize segmentation of the tumor (epithelial) nuclear (TEN) and stromal compartments. The original threshold for determining TEN Ki67was retained. An enhanced image analysis approach was applied to calculate the normalized ratio of maximum AR levels in TEN to stromal nuclei. Feature performance was evaluated with the concordance index (CI); AR and Ki67 cut-point (CP) analysis and new multivariate models were completed.

Results: Increasing amounts of Ki67 and two new AR features reflecting different percentages of the maximum AR level in TEN were associated with a shorter time to DP (Ki67 CI0.37, AR-ratio 21, CI0.30 and AR-ratio 22, CI0.33). Several cut-points were identified including: Ki67 CP 0.04, hazard ratio (HR) of 3.1, p-value 0.0005 (sensitivity 64%, specificity 68%); ARratio-21 CP 0.90, HR 3.8, p-value 0.0001 (sensitivity 78%, specificity 73%) and ARratio-22 CP 0.87, HR 2.2, p-value 0.013 (sensitivity 68%, specificity 68%). A multivariate model for predicting DP consisted of 4 weighted features including the biopsy Gleason score, the ARratio-22, and two morphometric (H&E&IF) variables.

Conclusions: Novel image analysis methods to analyze biomarker attributes in PNB specimens confirm and enhance our understanding of AR and Ki67 in disease progression. Such approaches will become useful tools for finalizing biomarker cut-points, performing pharmacodynamic assessment and establishing parameters for guiding therapy.

[Table: see text]
Prognostic indicators of aggressive disease in patients with locally advanced or metastatic prostate cancer: A focus on neutrophil to lymphocyte and platelet to lymphocyte ratios.
Authors: Dabaja A. , Menon M. , Agarwal P.
Published: February 2017

62

Background: Prostate specific antigen (PSA) and Gleason Score (GS) are helpful in predicting aggressive disease. Recently, the neutrophil:lymphocyte ratio (NLR) and platlet:lymphocyte ratio (PLR) were identified as prognostic indicators in gastric cancer which has an inflammatory pathogenesis. We hypothesized that these indicators may be prognostic in prostate cancer which is also postulated to have an inflammatory mechanism of carcinogenesis. Our goal was to assess if NLR and PLR is predictive of aggressive prostate cancer, which will be measured by metastasis and overall survival in patients on hormonal therapy as treatment.

Methods: We performed a retrospective analysis of 246 patients that were being treated with hormone therapy for either locally advanced or metastatic disease, or who were not surgical candidates or refused surgery. A logistic regression model was used to analyze various prognostic factors including total GS, pre-biopsy PSA, perineural invasion, % of core biopsies positive, NLR, and PLR. Endpoints studied were overall survival and metastasis.

Results: The logistic regression showed only pre biopsy PSA as a predictor of metastasis (n=82). The increased risk when measured continuously was 0.6% increase in odds ratio (p<0.015). When PSA was measured categorically the % biopsy cores positive were predictive of increased risk of metastatic disease with a 2.9% increase in odds ratio (p<0.002). The % biopsy cores positive were predictive of a 3.7% increased odds ratio in cancer-specific mortality (p<0.002). These results were controlled for age, which gave a 7% increase in odds ratio of overall survival (p<0.049).

Conclusions: Despite the thought that prostate cancer has an inflammatory pathogenesis, no correlation was found between N:L and P:L ratios and overall survival or bone metastasis in patients on hormone therapy for locally advanced disease. There was a negative correlation between increased % positive biopsy cores a decreased risk of survival. Further investigation is necessary to investigate the role of NLR and PLR as prognostic indicators in organ confined prostate cancer.

No significant financial relationships to disclose.
Long-term (potential 10-year follow-up) toxicity after treatment for prostate cancer with either external beam radiation therapy, interstitial brachytherapy, or radical prostatectomy.
Authors: Hunter G. K. , Reddy C. A. , Angermeier K. , Ulchaker J. , Stephans K. L. , Tendulkar R. D. , Zippe C. , Kupelian P. , Klein E. A. , Ciezki J. P.
Published: February 2017

65

Background: To examine gastrointestinal (GI) and genitourinary (GU) toxicity profiles of patients treated in 1999 with external beam radiotherapy (RT), prostate interstitial brachytherapy (PI) or radical prostatectomy (RP).

Methods: The records of 483 patients treated in 1999 were retrospectively reviewed to evaluate toxicity profiles, with 24% of the patients treated with PI, 40% with RP, and 36% with RT. Late GI and GU morbidity profiles were specifically examined and both were graded according to the RTOG acute and late morbidity scoring criteria. Other factors examined were patient age, BMI, smoking history, and medical comorbidities including presence of diabetes mellitus (DM), peripheral vascular disease, and connective tissue disease. Due to the low event rate for late GU and GI toxicities, a competing risk regression (CRR) analysis was done with death as the competing event.

Results: See Table. Median follow-up time was 8.6 years (range 0.2-11.5). On CRR univariate analysis the presence of DM was associated with GU toxicity grade ≥2 (p=0.043, HR 2.35, 95% CI=1.03-5.39). DM remained significant on multivariate analysis (p=0.034, HR 2.44, 95% CI= 1.07-5.59). Since there were no events in the RP group, only the PI and RT patients were included in the CRR analysis for late GI toxicity Grade <=2. On univariate analysis, RT and DM were significantly associated with late GI toxicity. On multivariable analysis, both variables remained significant (RT: p=0.038, HR=4.71, 95%CI=1.09-20.3; DM: p=0.008, HR=3.81, 95%CI=1.42-10.2).

Conclusions: Late effects occur with all three treatment modalities. The presence of DM at the time of treatment was significantly associated with worse late GI and GU toxicity. RT was significantly associated with worse late GI toxicity compared to PI and RP.

[Table: see text]

No significant financial relationships to disclose.
Long-term QOL outcome after proton beam monotherapy for localized prostate cancer.
Authors: Coen J. , Paly J. J. , Weyman E. A. , Rodrigues A. , Shipley W. U. , Zietman A. L. , Efstathiou J. A. , Talcott J. A.
Published: February 2017

68

Background: High-dose conformal proton radiation for localized prostate cancer results in favorable clinical outcomes and low toxicity rates. Here, we report long-term quality of life (QOL) outcome for men treated with conformal protons.

Methods: Serial QOL questionnaires were administered to men who received proton radiation. Long-term questionnaires (minimum 2 years) were completed by 72 patients. Men were stratified into functional groups from their baseline questionnaires (normal, intermediate or poor function) for each symptom domain. Symptom scores were calculated at baseline and long-term follow-up and expressed as mean values. QOL changes were assessed overall and within functional groups in a paired fashion using the Student's t-test.

Results: The median age at treatment and follow-up were 66 years and 44 months, respectively. The median dose was 82 GyE (range 74-82 GyE). For all 72 patients, there were increased scores for incontinence (ID) (3.2 baseline vs. 9.9 long-term, p=<0.001), obstructive/irritative voiding (OID; 20 vs. 24, p=0.028), bowel (BD; 4.4 vs. 8.0, p=0.001) and sexual dysfunction (SD; 25 vs. 48, p<0.001). When stratified by functional category, more specific estimates were possible. For ID, only normal function was associated with a significant increased score (0 vs. 8.4 at baseline and long-term, p=<0.001); for OID, only the group with normal baseline function showed a significant increased score (12 vs. 17, p=0.01); similarly for BD, only men with normal function had a significant increased score (0 vs. 5.4, p<0.001). For SD, the score increased in men with normal (1.4 vs. 30, p<0.001) and intermediate function (17 vs. 46, p<0.001).

Conclusions: Patient reported outcomes are sensitive indicators of treatment related sequelae and here quantitate, for the first time, the long-term consequences of proton monotherapy for prostate cancer. Analysis by baseline functional category is a useful means of predicting long-term QOL scores for an individual patient. High-dose proton radiation was associated with small increases in bowel dysfunction, obstructive/irritative voiding dysfunction and incontinence. With long term follow-up, sexual dysfunction increased more than any other symptom domain.

No significant financial relationships to disclose.
Prostate cancer incidence and disease-specific survival in men participating in the ERSPC with an initial PSA less than 3.0 ng/mL.
Authors: Bul M. , van Leeuwen P. J. , Zhu X. , Schröder F. H. , Roobol M. J.
Published: February 2017

7

Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) applies a prostate- specific antigen (PSA) cut-off >3.0 ng/mL as an indication for biopsy. We analyzed the incidence and disease-specific mortality for prostate cancer (PC) within ERSPC Rotterdam for men with an initial PSA <3.0 ng/ml in a 15-year follow-up period.

Methods: From 1993-1999, a total of 42,376 men identified from population registries in the Rotterdam region (55-74 yrs) were randomized to a screening or control arm. During the first screening round 19,950 men were screened, with biopsies being initially recommended in case of abnormal DRE or PSA >4.0 ng/mL. From 1997 on, solely PSA >3.0 ng/mL was used. The screening interval was 4 yrs. A total of 15,758 men (79%) had an initial PSA <3.0 ng/mL. Follow-up was complete until January 2009.

Results: From 1993-2008, 915 PC cases were diagnosed in 15,758 men (5.8%, median age 62.3 yrs) with an initial PSA <3.0 ng/mL (733 screen detected and 182 interval detected). Median follow-up was 11 yrs. PC incidence increased significantly with higher initial PSA levels (Table). Aggressive PC (clinical stage >T2c, Gleason score >8, PSA >20 ng/mL, positive lymph nodes or metastases at diagnosis) was detected in 65/733 screen detected PC (8.9%) and 102/182 interval detected PC (56.0%). PC death occurred in 23 cases (5 screen detected and 18 interval detected) in the total population (0.15%), with increasing risk in men with higher initial PSA values.

Conclusions: The risk of (aggressive) PC and PC mortality in a screening population with initial PSA <3.0 ng/mL increases significantly with higher PSA levels. The risk of dying of PC is minor in men with initial PSA <1.0 ng/mL. Interval detected PC is more aggressive and has a substantial influence on PC specific mortality.

[Table: see text]

[Table: see text]
Is radiation therapy superior to conservative management in men with localized prostate cancer?
Authors: Lu-Yao G. L. , Kim S. , Moore D. , Shih W. , Lin Y. , DiPaola R. S. , Zietman A. L. , Yao S.
Published: February 2017

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Background: Radiation therapy is commonly employed for localized prostate cancer; however, there is little data regarding the comparative effectiveness of radiation therapy (RAD) vs. conservative management (CM).

Methods: We performed a population-based cohort study, using Medicare claims data linked to the Surveillance, Epidemiology, and End Results data, to evaluate outcomes in 42,039 men aged 65-85 years treated with either primary RAD or CM for T1-T2 prostate cancer diagnosed in 1992-2005. To overcome potential biases associated with unmeasured confounding variables, we used instrumental variable analysis (IVA), a pseudo-randomization technique that captures the randomness associated with geographic variations in the use of RAD, to control for overt and hidden confounders.

Results: The majority of patients (57%) had low-risk disease (Gleason score ≤7, PSA <10, and T stage ≤T2a), and RAD was commonly used (60%) with considerable geographic variations. With median age 74 years and median follow-up 119 months, higher RAD use was not associated with improved survival in low-risk patients (10-year disease-specific survival differed by −0.9%, 94.9% vs. 95.8% in the highest and lowest tertile RAD use areas respectively; 95% C.I. −.1 to 0.6%). Among high-risk patients (Gleason score >7 or PSA >20), highest tertile RAD areas showed a borderline improved (2.7%) 10-year disease-survival (83.9% vs. 81.2% in the highest and lowest tertile radiation use areas; 95% C.I. −1.1% to 7.0%). The results in the moderate-risk group were between that of the low- and high-risk group. Primary RAD did not reduce future ADT use (odds ratios 0.95 for low-risk, 1.02 for moderate-risk, and 1.07 for high-risk with corresponding P values of 0.50, 0.86, and 0.51, respectively).

Conclusions: In patients aged over 65 years old with low-risk prostate cancer, primary RAD is unlikely to improve 10-year disease-specific survival or prevent future ADT use. Weighing the potential risks and benefits of radiation therapy is critical for decision making.

No significant financial relationships to disclose.
Efficacy and rectal toxicity of hypofractionated radiation therapy with daily image guidance.
Authors: McDonald A. M. , Dobelbower M. C. , Kim R. Y. , Jacob R. , Bishop J. , Fiveash J. B.
Published: February 2017

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Background: To assess the biochemical control rates and long-term rectal side effect profile of hypofractionated image guided radiation therapy for prostate cancer. We hypothesize that daily CT-based image guidance will allow a higher dose per fraction to be safely administered, shortening the overall treatment time from 8 weeks to 4-5.5 weeks.

Methods: 160 patients were treated with image guided radiation therapy with or without adjuvant hormonal ablation between 2005 and 2009 for patients <= T3a N0 M0. Patients were classified into risk groups with 51 patients defined as low risk, 67 as intermediate risk, and 43 as high risk. Mean age was 70.2 years. All patients were treated with 60/67.6/70/70.2 Gy to the prostate divided into 20/26/28/27 fractions. 57% of patients received hormone therapy. Daily CT or fiducial-based image guidance was performed prior to each fraction. The median follow up was 34 months. Biochemical control was defined by the Phoenix definition. Rectal toxicity was graded by the CTCAE 4.0 scale. In general patients with rectal bleeding more than once per week were started on rectal steroids.

Results: 12/160 (7.5%) of patients had late grade 2 or worse rectal toxicity after radiation treatment. The Kaplan-Meier estimate for grade 2 rectal toxicity at 2 years was 6.9%. The crude rate of biochemical no evidence of disease was 96.3%. Kaplan Meier estimates for biochemical no evidence of disease at 3 and 5 years are 0.98/0.84, 0.97/0.97, and 1.0/0.67 for low, medium, and high-risk patients respectively. Log-rank analysis showed no statistically significant difference among the dosing regimens for toxicity-free survival (p=0.24).

Conclusions: With daily image guidance hypofractionated radiation therapy is clinically safe with moderate late rectal toxicity. Early follow-up suggests high efficacy. Ongoing and future randomized trials such as RTOG 0415 will be required to confirm these findings.

No significant financial relationships to disclose.
Two-year PSA outcomes after cesium prostate brachytherapy.
Authors: Smith R. , Jacobs B. L. , Beriwal S. , Benoit R. M.
Published: February 2017

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Background: Given the long natural history of prostate cancer, long term follow up is needed to definitively know the efficacy of a new treatment, in this case 131Cs brachytherapy. However, it is also important to report on short term outcomes to ensure that this treatment is on course to provide equivalent outcomes as compared to existing treatment options. This reports two year PSA outcomes in men undergoing prostate brachytherapy with cesium 131 at a single institution.

Methods: All patients who underwent prostate brachytherapy with 131Cs and had at least 24 months of follow up were included in this study. Results are reported for the total cohort and stratified by risk group as well as treatment received (monotherapy, combination therapy, or trimodal therapy). The Phoenix definition was used to define biochemical disease free survival (bDFS). Outcomes were analyzed using descriptive statistics.

Results: 115 patients underwent prostate brachytherapy with 131Cs and had at least 24 months of follow up. Fifty two (45.2%) patients were classified as low risk, 52 (45.2%) were intermediate risk, and 11 (9.6%) were high risk. Eighty one patients were treated with prostate brachytherapy as monotherapy, including six patients who received androgen-deprivation therapy (ADT) in combination with their brachytherapy. Twenty five patients received combination therapy, and 9 patients received trimodal therapy. Specifics of bDFS rates and PSA data are reported in the table. Of the 115 patients four had biochemical recurrence. Two patients died during the study period, both due to causes other than prostate cancer, and one patient was unwilling to obtain a PSA at the 24 month follow up time point.

Conclusions: The first 115 patients who have undergone prostate brachytherapy with 131Cs at our institution have a bDFS rate of 96.4% 24 months after their procedure. With the very important caveat that only short term results are reported, 131Cs appears to be on course to achieve results comparable to those achieved with iodine 125 (125I) and palladium 103 (103Pd).

[Table: see text]

No significant financial relationships to disclose.
Effect of lymph node harvest for squamous cell cancer of the esophagus on survival.
Authors: Deneve Jeremiah Lee , Weber Jill M. , Hoffe Sarah E. , Sridhar Ravi , Almhanna Khaldoun , Barthel James S. , Karl Richard C. , Meredith Kenneth
Published: February 2017

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Background: The optimal number of lymph nodes harvested remains controversial in patients with esophageal cancer. Pathologic response to neoadjuvant therapy (NT) has demonstrated improved survival. However, little is known regarding the impact of NT or nodal harvest in patients with squamous cell carcinoma (SCC) of the esophagus. We examined the extent of LN harvest and outcome in patients who underwent esophagectomy for SCC.

Methods: After IRB approval, using a comprehensive esophageal cancer database we identified patients who underwent esophagectomy between 1994-2011. Clinical and pathologic data were compared using Fisher’s exact and chi-square when appropriate while Kaplan-Meier estimates were utilized for survival analysis. Nodal strata were set at 12 (ST-1), 15 (ST-2), and 20 nodes (ST-3). Pathologic response to NT was defined as complete (pCR), partial (pPR), or non-response (pNR).

Results: We identified 76 patients who underwent esophagectomy for SCC between 1994-2011. The median age was 62.5 years (40-85 months) with median follow up of 18.5 months (1-157 months). 48 (63%) were male and 28 (37%) were female. Twenty-eight patients (37%) underwent primary esophagectomy alone (PE) while 48 (63%) patients were treated with NT. Extent of lymphadenectomy had no significant impact on overall survival (OS) or disease free survival (DFS) for the entire cohort ST-1 p=0.8 and p=0.9, ST-2 p=0.5 and p=0.4, and ST-3 p=0.5 and 0.4, respectively. Among the patients who received NT, pCR was observed in 28 (58%), pPR in 14 (29)%, and pNR in 6 (13)%. When examining the degree of pathologic response to treatment, extent of LN harvest had no significant impact on OS or DFS for patients who underwent esophagectomy after NT (p=ns across all strata).

Conclusions: The extent of LN harvest failed to demonstrate an overall or disease free survival benefit in patients with squamous cell carcinoma of the esophagus. Moreover, patients treated with NT also did not benefit from increased nodal resection irrespective of their pathologic response.
D-dimers as a tumor marker in GIST: Can it reduce the frequency of CT scanning in patients receiving palliative imatinib?
Authors: Seligmann Jenny F. , Hall Peter , Hamilton Patrick , Lord Simon Richard , Baxter Paul , Marples Maria , Stark Daniel P.
Published: February 2017

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Background: Treatment with palliative imatinib has improved outcomes in advanced GISTs, with a reported 2 year PFS of 50%. Guidelines suggest monitoring during imatinib by CT scan at 12 week intervals. There are no validated biomarkers to assist in disease evaluation. High d-dimer levels are associated with poor prognosis in several cancers and are predictive of disease progression during chemotherapy. In the diagnosis of venous thromboembolism, low D-dimer levels have a high negative predictive value (npv) for thrombosis. We investigated whether low d-dimers have a clinically useful npv for GIST progression.

Methods: We retrospectively identified all patients treated with palliative Imatinib for GIST in a single tertiary referral centre using a systematic search of an electronic clinical database. Every 12 weeks during treatment patients were assessed by clinical evaluation, CT and a d-dimer measurement (HemosIL HS assay). The prognostic value of d-dimers was assessed by Cox regression. The clinical utility of d-dimers as a biomarker for radiological progression (rPD) was evaluated using radio operator curve (ROC) analysis.

Results: 50 patients treated between Jan 2002 and June 2011 met criteria for inclusion. D-dimers were prognostic for progression free survival and overall survival, when analysed by level or over time (p <0.05). Over 460 clinical observations with CT and d-dimer were analysed. Scans demonstrating rPD were associated with higher d-dimer levels and a rising trend (p <0.05). D-dimer levels <1000 had a npv for rPD of 85%. An asymptomatic patient with a d-dimer level <1000 and a falling level over time was seen in 32% of observations, and had a npv for rPD of 92%.

Conclusions: D-dimers may have a useful role in disease monitoring for GIST patients treated with palliative imatinib, particularly as a negative predictor of progression. This may reduce the burden of CT scanning in a useful percentage of patients but will require further validation.