bluuebunny/crossref_metadata_2025 huggingface dataset:
Interim results of a phase II study of the mTOR inhibitor everolimus in patients with pretreated metastatic gastric and esophageal adenocarcinoma.
Authors: Wainberg Zev A. , Patel Ravi , DiCarlo Brian , Park David J , Kass Frederic C. , Liem Andre K. D. , Wang He-jing , Martinez Diego , Hecht J. Randolph
Published: February 2017

80

Background: There is increased evidence that cancers of the upper GI tract are comprised of distinct epidemiological and molecular entities that may respond differently to anti-cancer therapy in Asian patients compared to North American patients. Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) showed clinical promise in a phase II study in Japanese patients with pre-treated metastatic gastric cancer with a disease control rate of 56% (Doi et al, JCO, 2010). This study evaluates the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US population.

Methods: Patients with advanced upper GI adenocarcinomas who experienced disease progression despite 1-2 prior regimens were treated with everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR; CR+PR+SD). Secondary end points included progression free survival (PFS), toxicity, overall survival (OS) and translational correlatives of the mTOR pathway.

Results: Of the 40 patients enrolled to date, 19 have gastric, 7 have esophagus and 14 have tumors from the GEJ. 32 patients are evaluable to date: median age of 59 (range 36-79), all patients had an ECOG of 0 or 1; 11 (34%) received 1 prior regimen and 21 (64%) received 2 prior regimens. We observed 0 responses with 44% of evaluable patients having stable disease. Median overall survival was 5.6 months (95% CI: 3.2-7.6) and PFS was 1.8 months (95% CI: 1.6-2.2). 89% of all adverse events were grade 1-2, and 11% were grade 3-4. Grade 3-4 related adverse events include: fatigue (24%), thrombocytopenia (22%), anemia (9%). Updated results of translational correlatives with the mTOR pathway will be presented.

Conclusions: We did not achieve the same degree of overall survival or disease control as in the Japanese study which may reflect differences in the locations of the primary tumor or underlying geographic variation. However, OS is significantly better than best supportive care reported in a recent randomized European trial (Thuss-Patience PC et al, Eur J Cancer 2011). Results of the randomized Phase III trial of everolimus vs best supportive care in this patient population are pending.
Changing national trends and survival in stage IV gastric cancer.
Authors: Leung Anna M. , Chiu Connie G. , Hari Danielle M. , Sim Myung-Shin , Bilchik Anton J.
Published: February 2017

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Background: With more effective systemic chemotherapy, the role for palliative gastrectomy in patients with Stage IV gastric cancer has been questioned.

Methods: Using the National Cancer Data Base we identified 29,655 patients with Stage IV gastric cancer over a 14 year period (1994-2008). Patient demographics, tumor related features, and treatments were analyzed. Overall survival rates were examined using log-rank test power analysis.

Results: There was a decrease in surgical resection from 31.2% in 2000 to 22% in 2008 (p<0.0001), a decrease in radiation from 20% in 2000 to 18.5% in 2008 (p= 0.0009), and an increase in systemic therapy from 45.5% in 2000 to 55.1% in 2008 (p<0.001). There were no differences in gender, age, or histology, but there was a decreasing trend of Caucasians diagnosed (p<0.0001). Survival rates decreased significantly over time p<0.05 (see table below).

Conclusions: Over the past 14 years there has been an increase in the use of systemic chemotherapy and a reduction in palliative gastrectomy for stage IV gastric cancer. The negative impact on survival suggests that treatment pathways be re-evaluated.

[Table: see text]
Nomograms for prognostication of patients with esophageal and gastroesophageal carcinoma undergoing definitive chemoradiotherapy.
Authors: Suzuki Akihiro , Xiao Lianchun , Hayashi Yuki , Blum Mariela Anabel , Welsh James , Lin Steven H. , Lee Jeffrey H , Bhutani Manoop S. , Weston Brian , Maru Dipen , Rice David C. , Hofstetter Wayne Lewis , Erasmus Jeremy J. , Swisher Stephen , Ajani Jaffer A.
Published: February 2017

82

Background: Level-1 evidence for definitive chemoradiotherapy (bimodality therapy or BM therapy) has been established for patients with esophageal and gastroesophageal junction cancers (EGEJC) who otherwise do not qualify for surgery; however, tools to estimate individual patient’s prognosis are unavailable. We used a number of clinical pre-treatment and post-treatment parameters to establish two nomograms (for overall survival [OS] and relapse-free survival [RFS]).

Methods: From 2002 through 2010, 257 consecutive patients with EGJEC who received BM therapy and had pre- and post-treatment positron emission tomography (PET) and post-treatment endoscopic biopsies among other assessments were analyzed from a prospectively maintained database. Standard statistical methods were used to generate the nomograms.

Results: The median follow -up time was 39.2 months (95% confidence interval [CI], 35.7 – 50.1). None of 257 patients underwent surgery. Persistent or recurrent cancer was documented in 187 (72.8%) patients. The estimated median survival duration for all 257 patients was 21.1 months (95% CI, 18.9-27.1) and median RFS duration was 11.6 months (95% CI, 9.43-15.0). The estimated OS and RFS rates at 3 years were 37.3% (95% CI, 31.2%-44.7%) and 25.1% (95% CI, 19.9%-31.6%), respectively. After BM therapy, 155 (60.3%) patients achieved a clinical complete response (cCR). In the multivariate analyses, initial standardized uptake value maximum and cCR were independent prognostic variables for OS (P=0.038, P<0.001). Nomogram concordance indices of 0.70 for OS and 0.77 for RFS were established by 200 bootstrap resampling for each of the two outcomes.

Conclusions: Our data suggest that in patients with EGEJC, pre- and post-treatment clinical parameters contribute to the establishment of OS and RFS prognostic nomograms. Upon validated, these nomograms could prove useful in the clinic to individualize therapy.
Prognostic significance of lymphadenectomy in patients with esophageal cancer receiving neoadjuvant chemoradiation.
Authors: Vijapura Charmi , Shridhar Ravi , Weber Jill M. , Hoffe Sarah E. , Deneve Jeremiah Lee , Barthel James S. , Karl Richard C. , Meredith Ken , Almhanna Khaldoun
Published: February 2017

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Background: The optimal number of lymph nodes that should be harvested in esophageal cancer patients remains to be defined, particularly in patients that receive neoadjuvant therapies. We investigated the impact of nodal resection and survival in esophageal cancer patients treated with neoadjuvant chemoradiation (NT).

Methods: Using our comprehensive esophageal cancer database we identified patients treated with NT followed by esophagectomy between 2000-2011. Clinical and pathologic data were compared using Fisher’s exact and chi-square while, Kaplan Meier estimates were used for survival analysis. Overall (OS) and disease-free survival (DFS) were compared with varying numbers of lymph nodes resected <10 and ≥10 (ST-1), <12 and ≥12 (ST-2), and <15 and ≥15 (ST-3). Multivariate analysis was analyzed by the Cox proportional hazard model.

Results: We identified 358 patients treated with NT and esophagectomy with a median follow-up of 18.5 months (range, 0-116 months). There was no survival benefit demonstrated for patients with increased lymph nodes removed during their surgery (ST-1 OS p=0.400, DFS p=0.8727; ST-2 OS p=0.6833, DFS p=0.6092; ST-3 OS p=0.1798, DFS p=0.4028). Patients were further stratified by pathologic response to NT and nodal harvest. There were no differences in OS or DFS in patients with increased nodal harvest when analyzed by complete (pCR) (ST-1 OS p=0.7278, DFS p=0.3602; ST-2 OS p=0.6182, DFS p=0.3592; ST-3 OS p=0.4489, DFS p=0.6976), partial (pPR) (ST-1 OS p=0.3762, DFS p=0.5061; ST-2 OS p=0.8036, DFS p=0.6497; ST-3 OS p=0.0890, DFS p=0.3364), or non response (pNR) (ST-1 OS p=0.6825, DFS p=0.7161; ST-2 OS p=0.7084, DFS p=0.8351; ST-3 OS p=0.5002, DFS p=0.7314) to NT. Multivariate analysis demonstrated that age (p=0.028), t-stage (p=0.006), pPR (p=0.025), and pNR (p<0.0005) to NT were all independent predictors of mortality.

Conclusions: In our experience, the number of lymph nodes resected was not predictive for overall or disease free survival in esophageal cancer patients treated with NT. In addition, extended lymph node resection did not improve survival for those with residual disease.
Adenocarcinomas of the esophagogastric junction: How does surgeon’s assessment influence the fate of patients?
Authors: Bogoevski Dean , Mina Sormeh , Kutup Asad , Bockhorn Maximilian , Reeh Matthias , Rösch Thomas , Izbicki Jakob Robert
Published: February 2017

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Background: Due to controversial staging systems, classifying tumors of the esophagogastric junction (EGJ) and the choice of the following surgical therapy remains a delicate affair.

Methods: In this study the impact of the preoperative surgical-clinical assessment concerning assorting tumors of the EGJ was evaluated in correlation to the patient’s outcome. We analyzed clinicopathological data from 92 patients who were pre- and intraoperatively classified as distal esophageal cancer (Type I) and thus underwent esophagectomy with gastric tube reconstruction and who afterwards (final histology) in part turned out to be cardia/gastric cancers (Type II).

Results: Patients with Type II cancers showed significantly more frequent lymphonodal metastasis (p=0.022) and higher recurrence rates (p=0.01), especially distant metastatic recurrence (p=0.03). Cancer-related death was also significantly higher (p=0.002) and recurrence-free survival was significantly shorter (median: 22 vs. 57 months, p=0.027). Also the thoracoabdominal approach (TA) had a favourable influence on patients’ outcome compared to the transhiatal approach (TH).

Conclusions: The correct preoperative assessment of tumors of the EGJ and the appropriate surgical therapy are crucial for the outcome of the patient. Those patients with Type II cancers might experience a survival benefit by undergoing radical combined esophago (-hemi)gastrectomy with colon interposition.
Safety and oncologic outcomes of robotic-assisted esophagogastrectomy.
Authors: De La Fuente Sebastian G. , Weber Jill M. , Hoffe Sarah E. , Shridhar Ravi , Almhanna Khaldoun , Karl Richard C. , Meredith Kenneth
Published: February 2017

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Background: The introduction of robotic systems to surgical oncology has allowed improved visualization with more precise manipulation of tissues. In esophageal cancer patients, this is crucial since most patients undergo neoadjuvant therapy (NT) prior to surgical resection. We report our initial experience in patients undergoing robotic-assisted Ivor-Lewis esophagogastrectomy (RAIL) for oncologic purposes at a large-referral center.

Methods: A retrospective review of all consecutive patients undergoing RAIL from 2010-2011 was performed. Basic demographics such as age, gender, and body mass index (BMI) were recorded. Oncologic outcomes include tumor type, location, NT, post-operative tumor margins, and nodal harvest. Immediate 30-day postoperative complications were also recorded.

Results: We identified 50 patients who under went RAIL with median age of 66 (42-82 years). The mean BMI was 28.6 ± 0.7, 67% of patients received NT and 54% had an ASA classification of 3. The mean and median number of lymph nodes retrieved during surgery was 20 ± 1.4 and 18.5 (8-63) respectively. R0 resections were achieved in all patients. The mean estimated blood loss was 146 ± 15 ml and there were no conversions to an open procedure. Postoperative complications occurred in 13 (26 %) of patients. Complications included atrial fibrillation 5 (10%), pneumonia 5 (10%), anastamotic leak 1 (2%), conduit staple line leak 1(2%), and chylous thorax 2 (4%). There were no wound infections documented. The median ICU stay and length of hospitalization (LOH) were 2 and 9 days respectively. Total mean operating time calculated from time of skin incision to wound closure was 453 ± 13 minutes. The mean operative time significantly decreased over time (first 23 cases 479 min vs. second 23 cases 428 min, p<0.05). Similarly the frequency of complications decreased significantly after 28 cases: 10 (35%) vs. 3 (13%) p=0.04. There were no in hospital mortalities.

Conclusions: We demonstrated that RAIL for esophageal cancer can be performed safely with acceptable oncologic outcomes. RAIL may be associated with fewer complications after a learning curve, and shorter ICU stay and LOH.
Perioperative chemotherapy for upper gastrointestinal cancer: Correlation between response to treatment and outcome.
Authors: Alcindor Thierry , Ferri Lorenzo , Ades Steven , Andalib Amin , Al-Baimani Khalid , Hickeson Marc , Artho Giovanni , Chasen Martin Robert , Marcus Victoria , Thirlwell Michael P.
Published: February 2017

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Background: Perioperative chemotherapy improves outcomes of surgery for upper GI cancer. Some patients have rapid recurrence. We hypothesized that any type of response to chemotherapy would predict better disease-free survival (DFS).

Methods: From May 2007 to Sep 2009, 43 patients with operable adenocarcinoma of the esophagus, stomach or gastroesophageal junction went on a multicenter phase II trial. 3 cycles of docetaxel/cisplatin/5FU were given pre and post surgery. We compared DFS between responders and nonresponders after 3 cycles. Clinical response was defined as improvement of ≥ 2 points on a dysphagia score (0: normal swallowing, to 4: total obstruction), metabolic response as ≥ 35% reduction of maximum SUV by PET scan. Lack of nodal involvement or significant histologic regression (less than 50% viable tumor) was considered pathologic response. Log-rank test was used for univariate analysis, Cox regression model for multivariate analysis. All p values are double sided, median follow-up from surgery is 808 days.

Results: Clinical response data for 29/40 patients: 26 responses (90%). Median DFS was 405 days for clinical responders vs. 210 days for nonresponders (p= 0.018). Metabolic response data for 28/40 patients : 22 responses (70%). Median DFS was 276 days in metabolic nonresponders, and has not been reached in responders (p = 0.009). 14 patients had no nodal involvement at resection (N0) and had longer DFS (median not reached) than the 26 with N+, who had median DFS of 562 days (p = 0.045). A nonsignificant trend (p = 0.192) was seen in favor of the 20 with significant tumor regression (DFS 565 days) compared to the 20se without it (median DFS not reached). All results were supported by multivariate analysis.

Conclusions: These preliminary results indicate that clinical, metabolic and pathologic responses may be individually predictive of longer DFS in patients receiving perioperative chemotherapy for upper GI adenocarcinoma. This requires confirmation in larger datasets. The optimal management of nonresponders is unclear at present. Acknowledgements: Biostatistics Unit (McGill University Health Centre) and Cedars Cancer Institute (Henry R Shibata Fellowship to Dr Alcindor).
Validation of a panel of cell-cycle progression genes for improved risk stratification in a contemporary radical prostatectomy cohort.
Authors: Cooperberg Matthew R. , Simko Jeffrey , Cowan Janet E. , Reid Julia E. , Bhatnagar Satish , Gutin Alexander , Lanchbury Jerry S. , Stone Steven , Carroll Peter
Published: February 2017

10

Background: Using clinical parameters, prostate cancers can be risk-stratified to aid treatment decisions. However, novel biomarkers are needed to predict tumor behavior more accurately. We aimed to validate the ability of a previously described 46-gene expression panel consisting of 31 cell-cycle progression (CCP) genes and 15 “housekeeping” genes to predict recurrence in a contemporary cohort of men undergoing radical prostatectomy (RP).

Methods: Patients undergoing RP at UCSF since 1994 with ≥5 years of follow-up were included. RNA was extracted from archival RP tissue, and CCP score was calculated as average expression of the 31 CCP genes. Recurrence was defined as 2 PSAs ≥0.2 ng/ml or any salvage treatment at least 6 months after surgery. CCP score association with recurrence was assessed in univariate survival analysis and adjusted for PSA at diagnosis, pathologic Gleason score, margin status, extracapsular extension, seminal vesicle invasion, lymph node invasion. These variables were considered as separate covariates and as measured by the validated CAPRA-S score.

Results: 413 men were included, 82 recurred. Most had low- to intermediate-risk pathology (mean CAPRA-S 2.1 ± 1.8). CCP scores ranged from -1.62 to 2.16; the mean was -0.28 ± 0.63. CCP score was associated with recurrence, HR 2.1 per CCP score unit (95% CI 1.6-2.9), p<0.0001. With adjustment for pathologic variables, patient age, and year of surgery, HR was 2.0 per CCP score unit (1.4-2.9), p<0.0001; and with adjustment for CAPRA-S score, the HR was 1.7 per CCP score unit (1.3-2.3), p<0.001. By likelihood ratio testing, adding the CCP score to the CAPRA-S improved accuracy significantly (LR χ2 11.4, p<0.0001). Based on Kaplan-Meier analysis, CCP score adds useful discrimination to both the overall cohort and for patients with clinically low-risk disease (CAPRA-S score 0-2).

Conclusions: In a contemporary post-RP cohort, the CCP score was validated to have significant prognostic accuracy even when controlling for clinical and pathologic data. The score has potential to substantially improve accuracy of risk-stratification, and lead to better decision-making with respect to timing and intensity of treatment.
Differential response of prostate cancer cells to ionizing radiation: The RB status.
Authors: Den Robert Benjamin , Ciment Steve , Sharma Ankur , Mellert Hestia , McMahon Steven , Dicker Adam , Knudsen Karen E.
Published: February 2017

106

Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation and loss of RB has been observed in 25-30% of prostate cancers. We have previously shown that RB loss results in a castrate resistant phenotype, however the consequences of RB status with regard to radiation response are unknown. We hypothesized that RB loss would downregulate the G1-S cell cycle checkpoint arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to ionizing radiation.

Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts.

Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in both hormone sensitive and castrate resistant cell lines (p<0.05). Cell death was not mediated through increased apoptosis nor was perturbations in cell cycle noted. However, loss of RB effected DNA repair as measured by gamma H2AX staining as well as cellular senescence. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05).

Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. The underlying mechanism appears to be related to DNA damage repair and cellular senescence.
Value of prostate MRI in determining appropriate candidates for active surveillance.
Authors: Margolis Daniel , Tan Nelly , Natarajan Shyam , Chamie Karim , Finley David , Reiter Robert Evan , Huang Jiaoti , Raman Steven
Published: February 2017

109

Background: The objective was to measure the added benefit of multi-parametric endorectal coil prostate MRI (eMRI) to traditional active (AS) criteria in delineating men with more advanced disease.

Methods: We performed a retrospective study of 115 men who underwent robot-assisted laparoscopic prostatectomy (RALP) for their CaP with whole-mount pathological evaluation. All men underwent eMRI for surgical planning—including T2 weighted, diffusion-weighted (DWI), dynamic contrast-enhanced (DCE), and MR Spectroscopy—between July 2008 and March 2011. We examined the diagnostics of Epstein’s criteria (E-AS) for clinically insignificant CaP or in combination with MR parameters (eMRI-AS criteria) in predicting more advanced disease. E-AS criteria included Gleason score (GS) 3+3=6, <3 biopsy cores positive, PSA <10, ≤50% maximum % of cancer in any one core. The addition of apparent diffusion coefficient >0.85x10-3 mm2/sec, Ktrans<0.5 Hz, Kep>1.5 Hz, and normal MRSI defined the eMRI-AS cohort. Outcomes were stratified into low vs. high surgical risk. Low-risk disease was defined as having pT2, GS <3+4 with tumor size <1.5 cm, and negative surgical margins (SM). Conversely, higher-risk disease included men with GS ≥4+3, positive SM, ≥pT3 or those with GS 3+4 with tumor size ≥1.5 cm.

Results: We identified 104 who met our inclusion criteria. We excluded 11 (9%) men due to post-biopsy hemorrhage (n=4), failed DCE (n=4), poor DWI (n=2), and two-year delay between MRI and RALP (n=1). Mean age was 60.6 years. Thirty-seven men (35%) satisfied E-AS, while 25 men (24%) satisfied eMRI-AS. On whole-mount sectioning 49 (47%) men were low surgical risk. E-AS to detect low surgical risk revealed a sensitivity, specificity, false positive, false negative and AUC of 67%, 73%, 33%, 27%, and 70%, respectively. eMRI-AS performance parameters were: 62.8%, 94.4%, 37%, 5% and 78%—significantly different than E-AS (p=0.04).

Conclusions: eMRI-AS outperformed Epstein-AS in identifying poor candidates from going onto AS. If patients were identified as AS candidates based on traditional criteria, we found that 27% actually had higher risk disease; whereas the addition of eMRI reduced this number to 5%.
TMPRSS2-ERG status and biochemical recurrence following radiotherapy for intermediate-risk prostate cancer.
Authors: Dal Pra Alan , Warde Fiona , Ishkanian Adrian Shea , Meng Alice , Malloff Chad , Lam Wan , Sykes Jenna , Pintile Melania , Squire Jeremy , van der Kwast Theo , Evans Andrew , Milosevic Michael , Bristow Robert Glen
Published: February 2017

11

Background: Approximately 50% of prostate cancers (PC) contain TMPRSS2-ERG gene fusions leading to ERG overexpression. Pre-clinical data suggest that these fusions are due to altered DNA double-strand break repair status which could have therapeutic ramification for the use of radiotherapy (RT) and PARP inhibitors. The aim of this study was to correlate TMPRSS2-ERG status to biochemical failure following clinical induction of DNA breaks in the form of image-guided radiotherapy (IGRT) in intermediate-risk PC.

Methods: Pre-treatment biopsies from two separate cohorts of intermediate-risk PC patients (T1/T2, GS < 8, PSA < 20ng/ml) were analyzed: 1) 126 patients assessed by array Comparative Genomic Hybridization (aCGH) for TMPRSS2:ERG fusion; and 2) 121 patients assessed by tissue microarray (TMA) for ERG expression by immunohistochemistry (IHC). All patients received IGRT with a median dose of 79.8 Gy (60-79.8 Gy). TMPRSS2:ERG status was correlated to Gleason score, T stage, initial PSA and biochemical-free relapse rate (bFRR; Phoenix definition: nadir + 2ng/ml).

Results: At a median follow-up time of 6.36 years, the biochemical relapse event rate was 37% and 18% in the aCGH and IHC cohorts, respectively. ERG expression by IHC was found in 49.6% of the 121 PC. TMPRSS2-ERG status was not correlated to increased Gleason score, pre-treatment PSA or T stage. On multivariate analyses in models containing clinical factors, TMPRSS2:ERG status (either using aCGH or IHC) was not prognostic for biochemical outcome (ERG expression: HR=0.78, 95% CI: 0.33-1.85; p= 0.568; TMPRSS2-ERG fusion: HR=0.71, 95% CI: 0.35-1.41; p=0.326).

Conclusions: In two separate cohorts, TMPRSS2-ERG status was not prognostic for bRFR after IGRT. Although a trend was observed, these clinical data do not support the hypothesis that these cancers have DNA repair defects that render them significantly more radiosensitive when compared to other PC. Further clinical trials are required to understand the utility of TMPRSS2:ERG status and response to DNA damaging agents, including that of PARP inhibitors. The trans-Canadian PROFIT trial is completing accrual of close to 1200 patients allowing for TMPRSS2:ERG studies in a larger RT cohort.
Association of concurrent AURKA and MYCN amplification in primary prostate adenocarcinoma with the development of lethal neuroendocrine prostate cancer (NEPC).
Authors: Beltran Himisha , Park Kyung , Tagawa Scott T. , Macdonald Theresa , Nanus David M. , Mosquera Juan Miguel , Rubin Mark A.
Published: February 2017

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Background: NEPC is an aggressive variant of prostate cancer that most commonly arises from prostate adenocarcinoma (PCA), with likely clonal origin. There is currently no effective therapy with most patients surviving < 1 yr. Recent work identified overexpression and amplification of Aurora kinase A (AURKA) and N-myc (MYCN) in metastatic NEPC, evidence that they cooperate to directly induce a NE phenotype in PCA, and are targetable with Aurora kinase inhibitor therapy (AKI) (Beltran et al). NEPC xenografts demonstrate dramatic and preferential sensitivity to AKI therapy with complete reversal of NE marker expression. We evaluated primary prostate tumors of patients that later developed lethal NEPC for presence of AURKA and MYCN alterations.

Methods: 226 primary PCA tumors were evaluated, of which 57 tumors were from patients with NEPC. 22 benign prostate and 57 metastatic NE carcinomas from prostate (38) or other primary site were also evaluated. Histology, immunohistochemistry (IHC), Fluorescence In Situ Hybridization (FISH) were performed and correlated with clinical variables (ie, Gleason, PSA, OS).

Results: AURKA and concurrent MYCN amplification were identified by FISH in 75% of primary PCA of patients with NEPC (> 95% cells). In contrast, in an unselected PCA cohort, AURKA and MYCN amplifications were identified in 5% of 169 cases. These results are independent of NE marker expression by IHC. In only one case did MYCN gain occur in absence of AURKA amplification. When metastatic NEPC was compared to primary PCA in same patient, there was 100% concordance of AURKA and MYCN amplification. In prostate tumors with mixed features, there was 94% concordance between NEPC and PCA. 0% benign prostate and 40% metastatic NEPC harbored AURKA and MYCN amplifications.

Conclusions: AURKA and MYCN amplification occurs early and are nearly always concurrent despite separate chromosomes. Their presence in primary PCA identifies patients predisposed to the development of an aggressive lethal NEPC variant. These patients may benefit from early intervention with AKI therapy. Therefore, AURKA and MYCN amplification may be new prognostic and predictive biomarkers.
Treating people right: Who goes untreated with systemic therapy for metastatic prostate cancer (mPC)?
Authors: Perlroth Daniella J. , Thompson Stephen F. , Mozaffari Essy , Luna Yesenia , Goldman Dana P. , Lakdawalla Darius N.
Published: February 2017

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Background: We investigated the use of systemic therapies (androgen deprivation therapy and chemotherapy) for men with mPC in the community, comparing those treated and untreated.

Methods: 8,295 men diagnosed with mPC at presentation from the 2000-05 Surveillance, Epidemiology, and End Results (SEER) database were linked to Medicare claims. We excluded those diagnosed with other primary malignancies, disenrolling from Medicare Parts A or B (n=3,293), or who died within 1 month of diagnosis (n=468), leaving 4,534 patients. Treatment, service use and comorbidities were measured in Medicare claims, demographic and clinical data in SEER. We compared characteristics of patients by treatment group using univariate and logistic regression to estimate the predicted probability of receiving systemic therapies for black and nonblack patients. Differences across hospital service areas (HSAs) were computed, using logistic regression to adjust for demographic and clinical characteristics.

Results: 3,657 patients (80.7%) received systemic therapy and 877 (19.3%) did not. Mean time to systemic treatment was 2.5 months. Follow up was 28.8 months for the treated, 19.2 months for the untreated. Among the treated, 20.4% received ADT and chemotherapy, 78.3% ADT only and 1.3% chemo only. Untreated patients were statistically older (78.6 versus 77.3 years), less likely to be married (48% versus 61%), and more likely residents of lower income areas and black race (26% versus 13%). The two groups scored similarly on a comorbidity index (0.51 versus 0.43). The model predicted a 66% probability of receiving systemic treatment for blacks versus 82% for whites, controlling for other factors. Systemic treatment use varied across regions from 62% to 94%. There was an 8-14% greater likelihood of receiving systemic treatment for men living in above versus below median regions.

Conclusions: One in 5 men with mPC in this sample survived long enough to be treated systemically, yet was not. Untreated men with mPC are more likely to be black, unmarried and reside in low income areas, raising concerns for equal access to treatment. Some regions are better at initiating systemic treatment for men with mPC than others.
Evaluating the effect of tobacco on prostate cancer outcomes with VEGF-targeted therapy.
Authors: Harzstark Andrea Lynne , Halabi Susan , Kelly William Kevin , Morris Michael J. , Febbo Phillip G. , Small Eric Jay
Published: February 2017

129

Background: Docetaxel/prednisone (DP) plus bevacizumab (B) demonstrated a superior progression-free survival (PFS) but did not prolong overall survival (OS) in comparison to DP monotherapy in CALGB 90401, a study of 1,050 patients with metastatic castration-resistant prostate cancer (CRPC) who had not received prior chemotherapy for metastatic disease. Tobacco use increases VEGF levels, suggesting the benefit of bevacizumab may be greater in patients who use tobacco.

Methods: The association of tobacco usage and OS was evaluated. Patient-reported history of tobacco usage was prospectively collected for patients on CALGB 90401. Within each smoking status group, the log-rank test was used to compare the survival time between the two treatment arms. The proportional hazards model was used to test for smoking by treatment interaction predicting OS.

Results: Of 865 patients with available smoking history, 21%, 30% and 49% were current, former, and never smokers. As summarized in the table below, there was a non-statistically significant improvement in OS for current smokers treated on the DP+B arm compared to the DP arm. However, treatment-by-smoking interaction was not statistically significant in predicting OS (p=0.299).

Conclusions: There was a trend toward an improvement in OS for current smokers treated with DP+B. The accuracy of patient-reported smoking status will be confirmed with serum cotinine levels in a pilot study. The effect of tobacco use on cancer outcomes with VEGF targeted therapy will be evaluated in other malignancies.
Use of elevated baseline IL-8, CCL-2, and TNFα to predict for shorter overall survival (OS) in men with metastatic prostate cancer initiating androgen-deprivation therapy (ADT).
Authors: Sharma Jaya , Gray Kathryn P. , Nakabayashi Mari , Petrozziello Gillian , Evan Carolyn , Fichorova Raina , Kantoff Philip W. , Sweeney Christopher
Published: February 2017

13

Background: Inflammation associated chemokines and cytokines have been shown in preclinical models to lead to the induction of castration resistance. We assessed whether higher blood cytokines and chemokines were associated with shorter time to CRPC and OS in patients initiating ADT for metastatic prostate cancer.

Methods: A retrospective analysis of inflammatory markers including IL1β, IL-6, IL-8, TNFα and CCL-2 was undertaken in men initiating ADT for metastatic prostate cancer. Proteins were measured using multiplex electrochemiluminescence assays. The analytical cohort of 122 patients included a prospective trial (50 patients) and chart review (72 patients). A multivariate COX model was used to investigate the relationship between serum markers of inflammation and time to CRPC and OS. The covariates were age at time of ADT, ECOG score, race, baseline PSA, and extent of disease.

Results: At time of initiating ADT, the median age of the cohort was 67 years, median PSA was 27.4, 82% had an ECOG PS of 0, 62% had extensive metastatic disease and 91% were Caucasian. Median OS was 42.2 months. The median (med) baseline levels for IL8 was 9.3pg/ml, TNFα was 2.4 pg/ml and CCL-2 was 507.5 pg/ml. As detailed below, patients with elevated IL-8, TNFα and CCL-2 had a significantly shorter OS and showed a non-significant shorter time to CRPC.

Conclusions: In men with metastatic prostate cancer starting ADT, higher serum inflammatory markers are associated with poorer OS. This correlative data suggests that anti-inflammatory strategies which improved ADT efficacy in preclinical models may be relevant to the clinical setting.

[Table: see text]
Multidisciplinary care and pursuit of active surveillance in low-risk prostate cancer.
Authors: Aizer Ayal , Paly Jonathan J. , Zietman Anthony L. , D'Amico Anthony Victor , Nguyen Paul Linh , Beard Clair , Rao Sandhya K , Kaplan Irving D. , Hirsch Michelle S. , Wu Chin-Lee , Efstathiou Jason Alexander
Published: February 2017

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Background: Factors associated with pursuit of active surveillance in men with low-risk prostate cancer are not well-delineated.

Methods: 701 patients with low-risk prostate cancer (clinical stage < T2b, Gleason score < 7, and PSA < 10 ng/mL), treated in 2009 at three tertiary care centers affiliated with the same medical school and within the same health care system were identified. All patients were evaluated by one or more urological, radiation, and/or medical oncologists specializing in genitourinary malignancies, either sequentially at independent appointments with differing dates/locations, or concurrently at a multidisciplinary genitourinary oncology clinic in which all three specialists evaluated the patient jointly during a single visit. Pre-treatment and treatment-related variables were recorded. Logistic regression was performed to identify demographic and clinical factors associated with the employment of active surveillance.

Results: Forty three percent of patients referred to a multidisciplinary clinic underwent active surveillance, as opposed to 22% of patients seen by individual practitioners (p<.001). On multivariate logistic regression, older age (OR 1.09 (per year), p <.001), increased comorbidities (OR 1.41 (per unit increase in Charlson score), p=.01), unmarried social status (OR 1.76, p=.04), a smaller percentage of positive cores (OR 0.92 (per percent core increase), p<.001), and referral to a multidisciplinary clinic (OR 2.22, p<.01) were all significantly associated with pursuit of active surveillance. The number of physicians or specialities seen in consultation was not significantly associated with pursuit of active surveillance.

Conclusions: Older age, increased comorbidities, unmarried social status, and a smaller percentage of positive cores are associated with pursuit of active surveillance. Notably, referral to a multidisciplinary genitourinary oncology clinic significantly increases rates of active surveillance in men with low-risk prostate cancer, implying that the multidisciplinary clinic itself, and not merely the number or type of physicians seen, is important to the shared decision making process for a patient to elect active surveillance.
Image-guided proton therapy for low- and intermediate-risk prostate cancer: Three-year results of two prospective trials.
Authors: Henderson Randal H. , Hoppe Bradford S. , Nichols Romaine Charles , Mendenhall William M , Marcus Robert B , Su Zhong , Williams Christopher R , Li Zuofeng , Morris Christopher G. , Mendenhall Nancy Price
Published: February 2017

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Background: To report outcomes in two prospective proton therapy (PT) trials for localized prostate cancer.

Methods: From 2006 to 2007, 171 low- and intermediate-risk prostate cancer patients were treated with PT on prospective trials. Low-risk patients (N=89) were treated on PR01 with 78 CGE/39 fractions to the prostate. Intermediate-risk patients (N=82) were treated on PR02, a dose-escalation trial, with 78-82 CGE to the prostate and proximal seminal vesicles. Based on organ-constraint goals, 57 (69%), 13 (16%), and 12 (15%) PR02 patients received 82 CGE, 80 CGE, and 78 CGE, respectively. Toxicity was scored by CTCAE v3 and biochemical failure defined as nadir + 2 ng/mL.

Results: The proportions of PR01 and 02 patients alive with no evidence of disease are 83 (93%) and 73 (89%); alive with disease, 1 (1%) and 1 (1%); and dead of intercurrent disease, 5 (6%) and 8 (10%), respectively. Only 2 patients had disease progression, both isolated pelvic-node recurrences. No patient died of prostate cancer or recurred locally. Grade (GR) 3 genitourinary (GU) and gastrointestinal (GI) complications occurred in 2 of 101 (2%), 0 of 13, and 4 of 57 (7%) patients receiving 78, 80, and 82 CGE, respectively. GR 3 GU toxicity occurred in 1 PR01 and 3 PR02 patients, including hematuria in 1 PR01 patient on anticoagulation; posttreatment TURP in 2 who had pretreatment (pre-tx) TURP; and dysuria in 1 with severe chronic pre-tx prostatitis. Multivariate analysis (MVA) of protocol, dose, age, prostate volume, pre-tx IPSS, pre-tx medical or surgical GU symptom management (SM), anticoagulation, and bladder wall V70 or V30 showed only pre-tx SM (P< .0001) and age (P =.007) to be associated with GR2+ toxicity. GR 3 GI toxicity occurred in 2 PR02 patients, including rectal bleeding in a patient on anticoagulation, and rectal bleeding and proctitis in a patient on anticoagulation who had a transrectal prostate biopsy. MVA of protocol, age, dose, anticoagulation, and rectal wall V70 or rectum V30 showed only rectal wall V70 (.045) and rectum V30 (.027) to be associated with GR 2+ rectal bleeding and proctitis.

Conclusions: PT may provide sufficiently reduced toxicity to permit further dose intensification and/or concomitant chemotherapy.
Pretreatment serum biomarkers and clinical outcome in the phase II trial of zibotentan (endothelin A receptor antagonist) in metastatic CRPC.
Authors: Shelkey Julia , Bisen Ajit , Leitzel Kim , Ali Suhail M. , Carney Walter P. , Lipton Allan
Published: February 2017

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Background: Three angiogenesis-related serum biomarkers [TIMP-1 (tissue inhibitor of metalloproteinase-1), CA IX (carbonic anhydrase 9), and VEGF] and PSA were correlated with outcome in the phase II zibotentan [endothelin A (ETA) receptor inhibitor] trial in metastatic CRPC.

Methods: Pretreatment serum samples were available from 206 of 312 patients enrolled in the multicenter phase II trial evaluating zibotentan in patients with metastatic CRPC and bone metastases who were pain free or mildly symptomatic for pain, with a 1:1:1 randomization to zibotentan 10mg, 15mg, or placebo. The CA IX, TIMP-1, and VEGF ELISAs were from WILEX Inc./Oncogene Science, Cambridge, MA. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling.

Results: In the final efficacy report, there were no statistical differences in PFS, but a trend for OS improvement was observed in the zibotentan arms compared with placebo: 15 mg (HR 0.76; 80% CI 0.61–0.94; p= 0.103) and 10 mg (HR 0.83; 80% CI 0.67–1.02; p= 0.254) (James et al, BJUI 106L966-973, 2010). In the retrospective serum biomarker analysis (206 patients), there were no apparent differences for PFS with any of the 3 novel biomarkers in the whole population, or within treatment arms. For OS in the whole population, patients with higher serum TIMP (> median) had reduced OS (17.5 mos), compared with patients who had lower serum TIMP-1 (< median) (28.4 mos). Within treatment arms, patients with higher serum CA IX (> median) treated with zibotentan had increased OS in both the 10 mg arm (median 28.4 mos), and the 15 mg arm (median 25.7 mos) compared with those in the placebo arm (median 15.4 mos). In a Cox model, including serum biomarkers and bisphosphonate use, for PFS only PSA was significant (p< 0.0001); for OS only PSA (p< 0.0001) and TIMP-1 (p< 0.002) were significant.

Conclusions: Higher pretreatment serum CA IX (a marker of hypoxia) may identify a cohort of metastatic CRPC patients more sensitive to zibotentan treatment, and higher serum TIMP-1 may identify patients at risk for reduced overall survival. These serum biomarkers deserve further study in larger ETA receptor inhibitor trials.
Clinical outcomes after transperineal template-guided prostate biopsy.
Authors: Hsi Richard A. , Moeller Randall James , Mitchell Marc , Bildsten Scott , Kozlowski Paul , Porter Christopher R.
Published: February 2017

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Background: To assess clinical outcomes after transperineal template-guided prostate biopsy (TTPB) including detection rates, pathologic features, clinical relevance and morbidity.

Methods: Forty eight men underwent TTPB. All patients had at least one (range 1–4) prior negative transrectal ultrasound-guided (TRUS) prostate biopsy and no prostate cancer diagnosis. The mean pre-biopsy PSA of the entire group was 13.1 ng/ml (range 4.5–46.4). The mean number of cores sampled was 24.7 (range 22–28).

Results: The rate of prostate cancer detection was 52% (25/48). Clinically significant prostate cancer, defined as intermediate (n=9) and high (n=11) risk disease using D’Amico criteria, was found in 80% (20/25) of positive biopsy cases. Seventy-two percent of all positive biopsy cores were anatomically located in the anterior or anterolateral positions within the prostate. Urinary retention requiring catheterization after the procedure developed in 6% (3/48) of patients. No patients developed rectal or infectious complications after TTPB.

Conclusions: TTPB is a well tolerated procedure resulting in a significant rate of cancer detection. Biopsies were frequently found to be positive in the anterior half of the prostate. Clinically significant disease was found in a high percentage of patients.
Stepwise examination of prostate clinical trials participation to reduce accrual barriers.
Authors: Olatoye Dare , Carducci Michael Anthony , Kanarek Norma
Published: February 2017

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Background: Adequate and representative enrollment in therapeutic clinical trials is important to an NCI cancer center. Clinical trial participation is a string of 6 sequential patient and physician decisions beginning with an available therapeutic trial to enrollment in the trial. Opportunities for participation may be lost at any one of these steps. The objective of this study was to calculate transitional probabilities that measure patient, especially minority patient, accrual to clinical trials at the Sidney Kimmel Comprehensive Cancer Center and to describe the barriers for those dropping out at each step.

Methods: Records for “first visit” medical oncology patients seen by three SKCCC physicians from January to April 2010 were abstracted. Prostate cancer case reports from the hospital cancer registry and a medical record review provided age, race, Hispanic ethnicity, place of residence, tumor characteristics, and prior treatment history. At each transition step, we calculated the proportion of patients who remained enrollable.

Results: Overall, prostate cancer clinical trial participation was 17% (16/94). Minority accrual was similar to Caucasian accrual at 19% and 17% , respectively. Retention at each step of trial participation was highest for “discussed” (98%), “enrolled” (94%), “eligibility” for available trials (79%), and “consented” (71%). Two bottlenecks were qualitatively identified: “trial availability” (65%) and “patient interest” (51%). Forty-two percent of those for whom there was no trial available were older than 70 years and 33% were patients with rising PSA after local therapy and hormone-naïve. The “patient interest” step was shaped primarily by disinterest due to distance to SKCCC (83%).

Conclusions: For prostate cancer patients, recruitment to medical oncology clinical trials is robust. Minority patients however are only 17% of all patients seen and half drop out when no trial is available and half of those remaining judged distance to be a problem (hence, no interest). This study approach has clarified which factors are likely to be barriers to participation and is likely useful to making adjustments that can reduce identified barriers by adding to trial portfolio as an example.
Phase I trial of cabazitaxel plus cisplatin in patients with advanced solid tumors.
Authors: Lockhart Albert C. , Sundaram Shankar , Sarantopoulos John , Mita Monica M. , Lane Alex R. , Moseley Jennifer L. , Dedieu Jean-Francois , Stash Diane , Zhi Xin , Mazuir Florent , Mita Alain C.
Published: February 2017

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Background: Cabazitaxel (Cbz) is a novel taxane with broad in vivo efficacy in taxane-sensitive and -resistant tumors. Clinical activity of Cbz was confirmed in the Phase III TROPIC trial ( NCT00417079 ); Cbz significantly improved overall survival compared with mitoxantrone in patients (pts) with metastatic castration-resistant prostate cancer whose disease had progressed during or after a prior docetaxel-containing regimen. Therapeutic synergism of Cbz/cisplatin (Cis) has been demonstrated in tumor-bearing mice.

Methods: The primary objective in part 1 of this Phase I study ( NCT00925743 ) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives were safety, pharmacokinetics (PK) and efficacy. The primary objective of part 2 was to determine the antitumor activity at the MTD. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1, with confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation with a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1.

Results: Pts (N = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). 2 of 6 evaluable pts experienced a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed. Eighteen pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all Grade/Grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of Grade 3–4 neutropenia was 78% and 1 pt had febrile neutropenia. No PK interactions between Cbz and Cis were observed. Stable disease was seen in 11 pts. No objective responses were reported.

Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with that of a platinum/taxane combination. No PK interactions were seen. Further investigations into the combined treatment combination are planned.