bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of positron emission tomography and preoperative CA19-9 in patients treated on a prospective phase II trial of neoadjuvant therapy and surgery.
Authors: Barnes Chad , Aldakkak Mohammed , Christians Kathleen K. , Tolat Parag , Ritch Paul S. , George Ben , Hall William Adrian , Erickson Beth , Evans Douglas B. , Tsai Susan
Published: September 2018

e15766

Background: The role of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging of pancreatic cancer (PC) has not been well defined. We evaluated the prognostic value of FDG-PET imaging in patients with localized PC enrolled in a prospective trial of personalized molecular-directed neoadjuvant therapy. Methods: Pretreatment FDG-PET was classified as high or low based on a standardized uptake value (SUV) cutpoint of 7.2 (population median). Carbohydrate antigen 19-9 (CA19-9) was measured after the completion of neoadjuvant therapy (preoperative) and classified as normal (≤35 U/mL) or elevated. Results: Pretreatment FDG-PET imaging was performed on 100 consecutive patients; SUV was high in 50 and low in 50. Preoperative CA19-9 values were available in 99 of 100 patients; 54 (55%) were elevated and 45 (45%) were normal. Of the 100 patients, 81 completed neoadjuvant therapy and surgery, and 19 were not resected. Among the 81 resected patients, SUV was high in 37 (46%) and low in 44 (54%); preoperative CA19-9 was elevated in 40 (49%) and normal in 41 (51%). The median overall survival (OS) for all patients was 39 months; 45 months for who completed all intended neoadjuvant therapy and surgery and 9 months for patients who were not resected. The median OS for patients with normal CA19-9/low SUV, normal CA19-9/high SUV, elevated CA19-9/low SUV, and elevated CA19-9/high SUV were not reached, 35, 24, and 18 months, respectively (p = 0.0001). Conclusions: Pretreatment FDG-PET avidity and preoperative CA19-9 are important prognostic markers and may be used to estimate the anticipated benefit of surgery; information of immediate clinical significance for both treatment sequencing and the application of surgery to patients who are frequently of advanced age or high-risk.
Extended neoadjuvant chemotherapy (CT) in borderline resectable pancreatic cancer (BRPC): Updated results.
Authors: Kanji Zaheer S. , Rocha Flavio G , Edwards Alicia M , Mandelson Margaret T. , Lin Bruce S. , Kozarek Richard A. , Rose J. Bart B. , Biehl Thomas R , Alseidi Adnan , Helton Scott , Picozzi Vincent J.
Published: September 2018

e15771

Background: Optimum therapy (Rx) for BRPC is unknown. Since 2008, we have used neoadjuvant Rx with extended course chemotherapy (CT) but not routine neoadjuvant chemoradiation (CRT). Initial results were presented in 2013 (Rose et.al. J Clin Oncolabstr 4043). We present updated findings here. Methods: Patients (pts) were prospectively identified in our institutional PC database. Inclusion criteria: 1) bx-proven PC; 2) radiographic staging per AHPBA/NCCN criteria; 3) no prior Rx; 4) negative staging laparoscopy whenever feasible; 5) all neoadjuvant Rx at our institution, 6) followup ≥ 24 weeks (wks) from initial Rx . Unless disease progression or Rx intolerance noted, pts received gemcitabine/docetaxel (G/D) as neoadjuvant CT x 24 weeks . At that time, all pts felt likely to achieve R0 resection offered surgery; other pts offered 5FU –based CRT if medically fit. Results evaluated by "intent to treat". Results: Among 129 pts, characteristics include median age 66 yrs (range 33-88 yrs), ECOG PS 0/1/2+ 86/36/7, 97%/43% venous /arterial involvement. 78% (101/129) pts completed ≥80% intended CT; 38% (6/16) pts age > 80 and /or ECOG 2+ (p < 0.01) 51% (66/129) pts were resected (44 R0, 22 R1 ≤ 1 mm margin ). 49% (63/129) pts were not (24 disease progression, 17 surgeon decision (anatomy/safety), 11 Rx toxicity/ comorbidity, 6 unresectable at surgery, 5 pt withdrawal). 45% (31/66) and 23% (16/66) resected pts received postop CRT/CT respectively. Median f/u is 47 months (mo). 58% (38/66) resected pts recurred: 18% (12/66) local, 41% (27/66) systemic. For resected pts, median PFS is 25.0 (95% CI: 16.2-32.7) mo, median OS is 37.6 (95% CI: 27.4-58.5) mo. 5-yr OS is 28% ( 95% CI :14-44%). Median OS for non-resected pts is 13.1 (95% CI 10.9-16.9) mo .Median OS for all pts is 22.1 (95% CI: 18.7-28.4) mo. Conclusions: 1.Our series is distinctive with respect to size, use of laparoscopic staging and neoadjuvant G/D CT as standards,and median f/u 2. Pt selection is key; e.g.approach suboptimal for pts > 80 yrs/ ECOG PS 2+ 3. Reported OS compares favorably with other BRPC and de novo resectable PC cooperative group results 4. Detailed analysis of our study (e.g. prognostic factors) will aid future clinical research in BRPC.
Prospective genomic/transcriptomic profiling of advanced pancreatic ductal adenocarcinoma (PDAC) for personalized therapy: Feasibility and preliminary results from the COMPASS study (NCT02750657).
Authors: Aung Kyaw Lwin , Fischer Sandra , Denroche Rob , Jang Gun Ho , Dodd Anna , Creighton Sean , Chadwick Dianne , Timms Lee , O'Kane Grainne M. , Albaba Hamzeh , Southwood Bernadette M. , Ghai Sangeet , Moore Malcolm J. , Miller Jessica , Notta Faiyaz , Wilson Julie , Hedley David W. , Dhani Neesha C. , Gallinger Steven , Knox Jennifer J.
Published: September 2018

e15776

Background: Prospective characterization of advanced PDAC using whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) may identify patients (pts) who will benefit from a personalized treatment strategy. The feasibility of this approach has not previously been established in PDAC. Methods: Advanced PDAC pts with ECOG PS 0-1 and accessible metastatic or primary tumors, were recruited. A fresh tumor sample for WGS and WTS was obtained by percutaneous biopsy and a reference whole blood sample for germline DNA analysis collected before starting 1st line palliative chemotherapy. Tumor biospecimens were enriched by laser capture microdissection before genomic analysis. The primary endpoint was feasibility (to report WGS results within 56 days in 40 of the first 50 recruited pts.) with a plan to accrue 200 pts. Results: From Dec 2015 – Jan 2017, 42 pts with advanced PDAC safely underwent tumor biopsy (32 liver, 1 omentum, 1 adrenal, 8 primary tumor). Adequate tumor biospecimens were obtained in all but one pt. The median number of tissue cores was 5 (range 3-6). The median post-enrichment tumor cellularity was 77% (range 37-93). WGS was successful for all samples analyzed. In 41 of 42 pts (97.6%), WGS was feasible and results were reported within 56 days (Median 37 days; range 19 to 52 days) meeting the primary endpoint. Potentially actionable somatic genetic aberrations were found in 12 pts (29%) involving ARID1A (N = 4), PIK3CA (N = 1), PDGFRB (N = 1), ERBB4 (N = 1), ATM (N = 2), CDK4 (N = 1) and CDK6 (N = 2). One pt with a germline BRCA2 mutation and another with somatic DSBR mutation signature achieved partial response with FOLFIRINOX (FFX). WTS results were available for 35 pts (85%). Of those, 19 were evaluable for FFX response. Eight of 9 pts (88%) with ‘classic’ signature and 4 of 10 pts (40%) with ‘basal like’ signature had tumor shrinkage with FFX (P = 0.08). Conclusions: Prospective comprehensive genomic profiling of advanced PDAC is feasible with an acceptable turnaround time. Approximately 30% of advanced PDAC pts have targetable genomic signatures and aberrations. RNA signature may predict FFX response.
Updated results of a phase II study of gemcitabine, erlotinib, and S-1 in patients with advanced pancreatic cancer.
Authors: Han Boram , Kim Hyeong Su , Choi Dae Ro , Shim Byoung Yong , Lee Kyung Hee , Kim Jin Won , Kim Jung Han , Kim Jung Hoon , Kim Ho Young , Song Hunho , Park Choong Kee , Moon Sung Hoon , Kim Jong Hyeok , Jeon Jang Yong , Lee Jung Woo , Zang Dae Young
Published: September 2018

e15778

Background: Gemcitabine-based chemotherapy is considered as a standard front-line treatment for patients with advanced pancreatic cancer. Although addition of erlotinib or S-1 to gemcitabine has yielded better outcomes, it has showed just modest improvement in survival. To overcome this limitation, we evaluated the efficacy and safety of the combination of gemcitabine, erlotinib, and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically proven locally advanced, recurrent or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine at 1,000 mg/m2 was administered intravenously on day 1, and 8, erlotinib at 100 mg/day was administered on days 1-21, and S-1 at 60 mg/m2 was administered on days 1-14 every 21 days and continued to maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2was permitted from second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1–8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusions: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer. Clinical trial information: NCT01693419.
Nab-paclitaxel plus S-1 as first-line treatment in patients with advanced pancreatic adenocarcinoma.
Authors: Shi Yan , Yan Huan , Han Quanli , Nie Yongkang , Lv Yao , Wang Zhikuan , Dai Guanghai
Published: September 2018

e15788

Background: Nab-paclitaxel plus gemcitabine and FOLFIRINOX showed survival advantage comparing to gemcitabine monotherapy in metastatic pancreatic cancer (PAC). However, the objective response rates (ORR) were about 30% and still unmet clinical expectation. S-1 is an oral fluoropyrimidine derivative showed comparable and superior clinical benefit in treatment of unresectable and postoperative PAC comparing to gemcitabine. Since nab-paclitaxel and S-1 provided additional clinical benefits in PAC, we conducted a single-arm, phase II trial to investigate the efficacy and safety of nab-paclitaxel plus S-1 as first-line treatment in patients with locally advanced and metastatic PAC. Methods: Nab-paclitaxel was given at 120 mg/m2 intravenously on day 1 and 8, in combination with S-1 which was orally administered (80-120 mg/d according to the body surface area) on day 1-14 of each 21-day cycle, for 6 cycles. The primary endpoint was ORR, secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: Sixty patients including 5 locally advanced and 55 metastatic PAC received a median of 4 cycles (range from 2 to 6). The ORR by either blinded independent review or investigator assessment was 50.0% (Table). Median PFS and OS were 5.7 months (95%CI, 4.9 to 6.6 m) and 9.3 months (95%CI, 8.3 to 10.3 m), respectively. The most common adverse events were neutropenia, sensory neuropathy, and nausea/vomiting. Grade 3 and 4 neutropenia were 22.3% and 11.7%, grade 3 sensory neuropathy was 5%. The patients with grade 3 and 4 neutropenia, and those with biochemical response (50% reduction of CA19-9) achieved better ORR (75% and 76.7%, respectively). Of 52 patients with elevated CA19-9 at baseline, 32 patients (61.5%) had biochemical response showed a better median OS than those without the biochemical response (15.9 m versus 5.7 m, P=0.029). Conclusions: Nab-paclitaxel plus S-1 showed encouraging ORR and being tolerated. Future phase III randomized clinical trial in advanced PAC is warranted. Clinical trial information: NCT02124317. [Table: see text]
Real world treatment utilization and outcomes of patients with metastatic bladder cancer by cisplatin eligibility in U.S. community oncology practice.
Authors: Flannery Kyle , Black-Shinn Jenny , Boyd Marley , Kamat Ashish M.
Published: September 2018

e16016

Background: Cisplatin(cis)-based therapy is standard first-line (1L) treatment for patients (pts) with metastatic bladder cancer (mBC). Many pts are cis-ineligible mostly due to reduced renal function (creatinine clearance (CrCl) < 60) or ECOG PS of 2 or greater (ECOG2+). Methods: We retrospectively identified mBC pts treated from Jan 2010 – June 2014 fromelectronic health records of McKesson Specialty Health/US Oncology, with follow-up through July 2016. Cis-ineligibility was identified using a consensus-based algorithm (pts with CrCl < 60 and/or ECOG2+ classified cis-ineligible). Results: 1155 pts received 1L treatment; median age 72 yrs (range 26-90+). The most common 1L regimens were cis/gemcitabine (gem) (26.8%), carboplatin (carbo)/gem (26.5%), carbo/paclitaxel (8.9%), and gem alone (8.3%). Among all pts, 55.2% were cis-ineligible. Cis-ineligible pts were older (mean 74.4 yrs vs 66.5 yrs; p < 0.0001). 48.7% of eligible pts did not receive cis, and 25.4% of cis-ineligible pts received cis-based therapy. Interestingly, among 1L cis/gem pts, 34.5 % had CrCl < 60 and 11.5% had ECOG2+. Median (95% CI) overall survival (OS) was affected by cis-eligibility and by 1L cis receipt as follows: eligible/received cis, 17.6 mos (15.1-23.6); eligible/no cis, 14.6 mos (11.5-16.7); ineligible/received cis, 13.4 mos (10.6-16.8); ineligible/no cis, 9.5 mos (8.2-11.4); (p < 0.0001). Conclusions: To date, this is the largest reported cohort of real-world mBC pts. Both cis-eligibility classification and 1L cis receipt were associated with longer OS, and both were approximately equivalent and additive in their magnitude of effect. Most pts were cis-ineligible; nonetheless, cis was used in one fourth of all cis-ineligible pts despite their classification. Cis-ineligible pts have high unmet medical need given their inferior survival.
Concurrent chemoradiotherapy (CRT) for bladder cancer: Practice patterns and outcomes in the general population.
Authors: Ghate Ketan , Brennan Kelly , Karim Safiya , Mackillop William J. , Booth Christopher M.
Published: September 2018

e16025

Background: Clinical trials have shown that CRT improves survival compared to RT alone in muscle invasive bladder cancer. We describe uptake of CRT and outcomes in routine practice. Methods: Electronic treatment records were linked to the population-based Ontario Cancer Registry to identify all patients treated with curative intent RT for bladder cancer in Ontario 1999-2013. Practice patterns were described in three eras: 1999-2003, 2004-2008, 2009-2013. Modified Poisson regression was used to analyze factors associated with use of CRT. Cox model and propensity score analysis were used to explore the association between CRT and overall (OS) and cancer-specific survival (CSS). Results: 1398 patients underwent curative intent RT during 1999-2013; median age was 79 and 75% (1050/1398) were male. Use of CRT increased over time: 33% (135/409) in 1999-2003, 35% (170/482) in 2004-2008, 46% (232/507) in 2009-2013 (p < 0.001). Among the 80% (431/537) of CRT cases with available drug details, the most common regimens were single-agent Cisplatin (57%, 245/431), single-agent Carboplatin (31%, 133/431) and 5-FU/Mitomycin (4%, 19/431). Factors associated with CRT include younger age (p < 0.001), male sex (p = 0.027), and lower co-morbidity (p < 0.001). There were large regional differences in use of CRT (range 14% to 85%, p < 0.001). Five year OS, CSS, and cystectomy-free survival rates among CRT cases were 34% (95%CI 30%-39%), 45% (95%CI 40%-50%), and 30% (95%CI 26%-34%). On adjusted analyses CRT was associated with superior survival compared to RT alone (OS HR 0.68, 95%CI 0.60-0.70; CSS HR 0.64, 95%CI 0.54-0.76). These results were consistent on propensity score analysis. There was a non-significant trend towards improved survival among all treated cases in 2009-2013 compared to 1999-2003 irrespective of chemotherapy delivery (OS HR 0.86, 95%CI 0.74-1.01; CSS HR 0.82, 95%CI 0.67-1.01). Conclusions: Although there has been substantial uptake of CRT in routine practice, utilization rates vary widely by region. CRT is associated with superior survival compared to RT alone and its uptake corresponded to a temporal trend towards improved survival among all treated cases in the general population.
Targeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 expressing bladder cancer using combination photoimmunotherapy (PIT).
Authors: Siddiqui Mohammad rashid , Railkar Reema S. , Sanford Thomas , Choyke Peter L. , Kobayashi Hisataka , Agarwal Piyush K.
Published: September 2018

e16026

Background: Bladder cancer (BC) is heterogeneous, expressing various cell surface targets, such as EGFR and Her2. Photoimmunotherapy (PIT) involves antibodies (Abs) conjugated to a photoabsorber (PA), IR Dye 700Dx, and then activated by Near infra-red light (NIR) to specifically target tumors. Our lab has previously shown that tumors expressing high levels of EGFR can be efficiently targeted with PIT. However, PIT is less effective when a tumor lacks “overwhelming” expression of a single target. Here, we present a novel, combinatorial PIT approach for such tumors expressing EGFR and Her2, using Panitumumab-IR700 (PanIR700) and Trastuzumumab-IR700 (TraIR700) antibodies, respectively. Methods: BC cell lines were analyzed for expression of EGFR and Her2 using flow cytometery. Concurrent and optimal binding of both PA-labeled Abs were determined using flow cytometery. NIR LD50 of multiple treatment regimens were determined to analyze in vitro efficacy of combination PIT. Results: The SW780 and RT112 cell lines showed low to moderate expression of EGFR and Her2. The EGFR expression was 143 fold higher in SW780 and 83 fold higher in RT112 over the isotype control. The Her2 expression was 42 fold higher in SW780 and 27 fold higher in RT112 over the isotype control. Hence, the ratio of cell surface EGFR to Her2 expression in both cell lines was about 3:1. For SW780, NIR LD50 was 28.66 J/cm2 for the combination PIT compared to 71.55 J/cm2 for the PanIR700 alone therapy. The NIR LD50 for RT112 was 14.66 J/cm2 for the combination PIT, with LD50 for PanIR700 alone therapy indeterminate from insufficient cell death. In both cases, the LD50 for TraIR700 alone therapy could not be determined from lack of sufficient cell death. Conclusions: PIT is a new targeted treatment for bladder cancer that can be effectively used either locally or for metastatic lesions accessible by the NIR light. We demonstrate a novel and promising approach to treating BC by selectively inducing cell death in BC cell lines with low to moderate expression of cell surface markers of EGFR and Her2 using combination PIT. This will be further evaluated in a xenograft model.
Potential underuse of repeat resection among patients with high-grade non-muscle invasive bladder cancer.
Authors: Check Devon , Aaronson David S. , Lee Valerie S. , Nielsen Matthew , Tang Li , Kushi Lawrence H. , Kwan Marilyn L.
Published: September 2018

e16028

Background: For patients diagnosed with non-muscle invasive bladder cancer (NMIBC), guidelines recommend that those with high-grade (HG) T1 disease and potentially those with lower risk HG Ta disease receive a repeat resection within six weeks of initial resection. For these patients, repeat resection has diagnostic, prognostic, and therapeutic value and is critical for informing treatment decision-making, and ultimately optimizing outcomes. Current rates of repeat resection in practice are unknown. Methods: We conducted a retrospective analysis of patients diagnosed with HG T1 and HG Ta NMIBC between 1/1/2015 and 3/1/2016 using cancer registry-linked electronic medical record data. Our analysis included 118 patients with HG T1 disease and 114 patients with HG Ta disease who did not undergo a cystectomy. We used modified Poisson regression with clustered standard errors to assess the associations of patients’ clinical and socio-demographic characteristics and providers’ characteristics with patients’ receipt of repeat resection. We present adjusted risk ratios (aRR) and 95% confidence intervals (CI). Results: 40% of HG patients (55% of T1 patients; 24% of Ta patients) underwent repeat resection, with no differences in receipt by patient age, gender, race, or comorbidity burden. In addition to HG T1 (vs. HG Ta) disease (aRR: 2.20, 95% CI: 1.53-3.22), higher census-tract median household income was associated with increased likelihood of repeat resection (aRR highest vs. lowest income quartile: 1.42, 95% CI: 1.08-2.23). At the treating urologist level, more time in practice was negatively associated with likelihood of repeat resection receipt (aRR highest vs. lowest quartile of number of years in practice: 0.56, 95% CI: 0.41-0.77). Conclusions: Our data suggest that a large proportion of potentially eligible HG patients did not undergo a repeat resection, and that variation in practice is driven by patients’ social characteristics and treating urologist characteristics. Further research is needed to understand whether the variation observed reflects a quality improvement need versus patient-centered decision-making that accounts for preferences and treatment eligibility.
Systemic immune-inflammation index is prognostic in testicular germ cell tumors with PD-L1 expressing tumor infiltrating lymphocytes.
Authors: Chovanec Michal , Cierna Zuzana , Miskovska Vera , Machalekova Katarina , Kalavska Katarina , Rejlekova Katarina , Svetlovska Daniela , Macak Dusan , Spanik Stanislav , Kajo Karol , Babal Pavel , Mardiak Jozef , Mego Michal
Published: September 2018

e16042

Background: Systemic immune-inflammation index (SII) and programmed death-ligand 1 (PD-L1) are prognostic in various types of malignancies. Recently we have shown a prognostic value of PD-L1 expression on tumor cells and tumor infiltrating lymphocytes (TILs) in testicular germ cell tumors (GCT). This study aimed to evaluate prognostic role of SII in a GCT population of patients expressing PD-L1 on TILs. Methods: SII was calculated using platelet (P), neutrophil (N) and lymphocyte (L) counts measured prior to chemotherapy (SII = P x N/L). SII was calculated in our discovery set of 216 patients with GCT treated at National Cancer Institute and St. Elisabeths' Cancer Institute between 1999 and 2015. A model with median obtained from the discovery data was tested in an independent validation set of 181 patients that were included in a retrospective study evaluating PD-L1 on TILs in GCT. PD-L1 on TILs was detected by immunohistochemistry and scored semiquantitatively by weighted histoscore method. SII was dichotomized into low and high categories based on median value. Results: Low SII ( < 1003) was found in 133 patients (73.5%) as opposed to 48 patients (26.5%) with high SII (≥ 1003). Ten (5.5%) and 171 patients (94.5%) from the validaton set had low (HS < 150) and high (HS ≥ 160) expression of PD-L1 on TILs, respectively. Discovery group of patients with high SII had significantly shorter PFS (HR = 4.48, 95% CI 2.44 – 8.23, p = 0.0000) and OS (HR = 6.10 95% CI 3.11 – 11.95, p = 0.0000) opposite to patients with low SII. PFS from validation set confirmed shorter PFS (HR = 3.03, 95% CI 3.86 – 7.46, p = 0.0062) and OS (HR = 6.49 95% CI 2.10 – 20.03, p = 0.0001) in patients with high versus low SII. A combined prognostic value of PD-L1 TILs and SII uncovered three prognostic groups. The best prognosis was observed in patients with low SII and high PD-L1 on TILs, the worst prognosis was seen in patients with high SII and low PD-L1 on TILs. Patients with SII and PD-L1 on TILs both values high or low had intermediate prognosis. Conclusions: SII was prognostic in our patients with GCT independently of international germ cell cancer collaborative group criteria, suggesting involvement of immune mechanisms in the behavior of GCT.
Audiograms and hearing loss before and after cisplatin-based chemotherapy (CBCT) in testicular cancer survivors (TCS).
Authors: Haugnes Hege Sagstuen , Stenklev Niels Christian , Brydoy Marianne , Wilsgaard Tom , Laukli Einar , Fossa Sophie D.
Published: September 2018

e16047

Background: 80% of TCS were reported to have a hearing loss based on post-CBCT audiograms (American Speech-Language-Hearing Association (ASHA) definition; Frisina et al, JCO 2016:34) Methods: 46 TCS treated with CBCT 1980-1994 with audiograms (0.25-8 kHz) pre chemotherapy (PRE) and at a survey (SURV) after median 10 years were included (cases). Audiograms at SURV from 46 age-matched TCS without CBCT were included as controls. Linear regression was performed to evaluate predictors for change in hearing threshold level (HTL) from PRE to SURV. Mean HTL for both ears exceeding 20 dB at any frequency 0.25-8 kHz were classified as a hearing loss (ASHA definition). We also applied the WHO definition of hearing loss, present if the average HTL threshold for the four frequencies 0.5, 1, 2 and 4 kHz exceeded 20 dB (M4 definition). At SURV, self-reported hearing loss was assessed by a questionnaire (categorized as “a little”, “quite a bit” and “very much” vs. “not at all”). Results: Age and PRE HTL was associated with change in HTL for most frequencies. Cisplatin dose was significantly associated with change in HTL for the frequencies 2 to 8 kHz, with a gradually greater change in HTL and lower p-value with increasing frequencies. For the 8 kHz frequency, each 100 mg increase in cumulative cisplatin dose was associated with a deterioration of 3.6 dB (p < .001). According to ASHA, the prevalence of a hearing loss among cases was 33% PRE, 70% at SURV, and 65% among controls at SURV (cases vs. controls, p = .66). According to M4, the prevalence of hearing loss among cases was 6.5% PRE, 13% at SURV, and 2.2% among controls at SURV (cases vs. controls, p = 0.05). Overall 29% of cases, and 33% of controls (p = .70) reported some degree of hearing impairment at SURV, of whom only 6.5% of cases reported more than “a little”. Self-reported hearing loss was not associated with hearing loss according to ASHA (p = .20), but was associated with the M4 definition (p = .02). Conclusions: Cisplatin is associated with a moderate hearing loss particularly at higher frequencies. Ageing is important for hearing loss regardless of treatment. The ASHA definition of hearing loss overestimates the hearing problem and should not be used as a clinical tool.
Activity of second line axitinib in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib: Results from SAX Italian real world trial.
Authors: Rossetti Sabrina , Romano Francesco Jacopo , D'Aniello Carmine , Cavaliere Carla , Pisconti Salvatore , Iovane Gelsomina , Berretta Massimiliano , Marchetti Paolo , Crispo Anna , Piscitelli Raffaele , Muto Paolo , Maiolino Piera , Perdonà Sisto , Botti Gerardo , Facchini Gaetano ,   SAX Study Group
Published: September 2018

e16054

Background: Axitinib, a selective tyrosine kinase inhibitor (TKI), is currently approved for the treatment of mRCC after failure of prior treatment with sunitinib or cytokine, according to AXIS trial results. The best sequence hasn’t been established: both axitinib and everolimus (a mTOR inhibitor) are viable therapeutic options, although recently immunotherapy agents entered this setting. This Italian multi-institutional retrospective analysis evaluated outcomes of Axitinib in exclusive sequence after sunitinib in second line treatment of mRCC Methods: Medical records of 148 patients treated with Axitinib from 21 Italian Oncology Centers were retrospectively assessed: PFS, OS, ORR DCR, and safety profile of axitinib were primary endpoints. Results: Median PFS and OS were 7.14 and 15.5 months, respectively. Overall, axitinib at standard schedule of 5 mg bid, was well tolerated, with no grade 4 toxicity event. Most common adverse events were hypertension (26% of the cases), fatigue (50 %), hypothyroidism (18%). At univariate analysis, when patients were stratified by Heng score, mPFS was 5.8, 7.0 and 9.0 months according to poor, intermediate and favourable risk group, respectively. When stratified by median duration of prior sunitinib therapy (≥ 13,1 mo vs < 13,1 mo), there was a statistically significant difference in PFS with 8.8 vs 6.3 months, respectively. Disease control rate (DCR) to previous sunitinib treatment was associated to longer PFS with axitinib ( 8.0 months vs4.0 months). The sequence sunitinib-axitinib was well tolerated, with a mOS of 41 months. At multivariate analysis, prognostic factors for progression were gender (p-value = 0,006), DCR to axitinib (p < 0,0001) and to previous sunitinib (p = 0,041); DCR to axitinib (p = < 0,0001), nephrectomy (p = 0,002) and Heng score (p = 0,025) independently affected overall survival. Conclusions: The preliminary SAX results in the real world population are consistent with available literature. The study confirms that Axitinib is effective and safe in routine clinical practice, and its efficacy seems to be greater in patients who most benefited from first-line sunitinib.
Can dynamic changes in prognostic markers predict survival in patients receiving VEGF-targeted therapy in clear cell renal cell carcinoma?
Authors: Shepherd Scott Thomas Colville , Hall Peter , Brown Janet Elizabeth , Larkin James M. G. , Jones Robert J. , Ralph Christy , Hawkins Robert E. , Chowdhury Simon , Boleti Ekaterini , Bahl Amit , Fife Kate , Webb Andrew , Crabb Simon J. , Geldart Thomas R. , Dunlop Joanna , McLaren Duncan , Ackerman Charlotte , Beltran Luis , Nathan Paul D. , Powles Thomas
Published: September 2018

e16061

Background: Markers of the systemic inflammatory response have prognostic value in ccRCC prior to starting treatment. Dynamic changes during therapy and their role in predicting prognosis are not well characterised. Methods: A retrospective analysis was conducted of a randomised, double-blind phase II study evaluating cediranib vs cediranib and saracatinib in patients with relapsed metastatic ccRCC (COSAK). Haemoglobin (Hb), neutrophil count (N0) platelet count (Plt), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were recorded at randomisation, 8-weeks and progression (PD). Change in mean values at each time point were compared. Baseline prognostic values for overall survival (OS) were assessed using Cox regression. Absolute changes in parameters were calculated at 8 weeks and PD, patients were grouped around the upper or lower quartile. Prognostic value of dynamic changes was assessed at 8 weeks and PD using the Kaplan-Meier method. Results: 138 patients were assessed; median OS was 12.0 months (IQR 8.1-15.6 months). Outcomes in the combination arm were similar to single agent arm (HR 1.28 (1.00–1.63)). On multivariate analysis at baseline, MSKCC score (0/1-2/≥3) (HR 2.52 (1.60 -3.96)), CRP ( < 10/≥10mg/L) (HR 1.72 (1.04 – 2.86)) and N0 ( < 7.5/≥7.5x109) (HR 2.38 (1.43 – 3.96)) were independent predictors of OS. Mean CRP was significantly different at baseline, 8 weeks and PD (64.9, 42.3 and 85.7 mg/L respectively, p < 0.001). Mean N0 count at baseline was 5.3 x109/L and was significantly higher 6.3x 109/L at PD (p < 0.001). Mean Hb at baseline, 8 weeks and PD was 11.5, 13.0 and 12.9g/L respectively (P < 0.001). A rise in CRP or N0 at 8 weeks was predictive of poor outcome ((HR 1.62 (1.10-2.56) and (HR 1.77 (1.19-2.61) respectively). A fall in Hb was predictive of poor outcome at 8 weeks (HR 1.75 (1.18-2.60)) and PD (HR 1.80 (1.20-2.76)). Conclusions: Dynamic changes occur in prognostic markers in patients receiving VEGF-targeted therapy in ccRCC and may predict OS.
Clinical outcomes according to ethnicity in patients with metastatic renal cell carcinoma (mRCC) treated with VEGF-targeted therapy (TT).
Authors: Bosse Dominick , Xie Wanling , Wells Connor , Lalani Aly-Khan A. , Donskov Frede , Bent Alisha , Sim Hao-Wen , Beuselinck Benoit , Bamias Aristotelis , Porta Camillo , Vaishampayan Ulka N. , Pal Sumanta K. , Agarwal Neeraj , Srinivas Sandy , Rini Brian I. , Alva Ajjai Shivaram , Wood Lori , Kapoor Anil , Choueiri Toni K. , Heng Daniel Yick Chin
Published: September 2018

e16065

Background: Discrepancies in clinical outcomes between different ethnic groups are well known in cancer patients. Differences in mRCC patients receiving VEGF-TT are less well characterized. We thought to report on baseline characteristics and treatment outcomes in African-Americans (AA) and Hispanic patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Methods: Caucasians, AA and Hispanics with mRCC treated with 1stline VEGF-TT were identified from the IMDC. We created 2 matched cohorts: 1) AA vs. Caucasians and 2) Hispanics vs. Caucasians, both matched for age (<50; 50-59; 60-69; <70-year-old), gender, years of treatment (2003-07; 2008-12; 2013-16) and geography (Canada, USA, Europe). Weighted Cox and logistic regressions were used to compare OS, time-to-treatment failure (TTF) and best response, adjusted for nephrectomy status, IMDC risk groups, number of metastatic sites (1 v. >1) and histology (clear-cell vs. else). Results: 73 AA and 71 Hispanics met eligibility criteria and were matched with 1236 and 901 eligible Caucasians, respectively. AA had more non-clear cell histology (26% v. 11%), time from diagnosis to therapy<1 year (67% v. 55%) and anemia (75% v. 54%) vs. Caucasians. Differences were not significant for Hispanics. Clinical outcomes are presented in Table. Conclusions: Adjusted for clinical prognostic factors, Hispanics with mRCC have statistically shorter TTF and survival than Caucasians. AA had a trend toward shorter TTF (not significant) but similar survival than Caucasians. Underlying genetic/biological differences, along with potential cultural variations, may impact survival in Hispanic mRCC patients. [Table: see text]
Efficacy and safety of sunitinib and everolimus as front-line treatment for nonclear cell RCC: A pooled-analysis from randomized trials.
Authors: Messina Carlo , Messina Marco
Published: September 2018

e16069

Background: Non-clear Renal cell carcinoma (non-ccRCC) accounts for about 25% of all RCC and generally is responsible for a poorer outcome in metastatic setting. Optimal treatment for patients with metastatic non-ccRCC has not been established yet; therefore Sunitinib and Everolimus still represent two feasible options as frontline therapy, given the results reported from single-arm trials and expanded access studies. Hence, we provided a pooled analysis from prospective randomized trials to evaluate the benefit and risks of these therapies for patients with metastatic-non-ccRCC. Methods: A systematic search of literature was carried out using Medline, Embase, ESMO and ASCO library with no data restriction up to December 2016, to identify relevant studies on this topic. Eligible studies had to fulfill the following criteria: randomized prospective trial comparing the efficacy of Sunitninb and Everolimus as first line therapy in patients with m-non-ccRCC. Studies excluded: non-randomized prospective trials, subgroup analysis data deriving from randomized prospective trials carried out on metastatic ccRCC population. No language restriction was applied. Data were pooled using RevMan 5.3 software. Results: The literature search identified 29 potential titles and abstracts of whom only 2, recruiting a total of 176 metastatic-non ccRCC patients (Sunitinib: 84, Everolimus: 92), fulfilled our eligible criteria and were included in the pooled analysis. A trend towards better outcome in terms of PFS and OS was reported among patients with non-cc RCC enrolled in Sunitinib arm. Sunitinib vs Everolimus: PFS [HR]:0,83 [0,38-1,78]; OS [HR]: 0,67 [0,37-1,21]. Moreover Sunitinib was associated with more Grade 3-4 adverse events HR: 3.06 [1,60-5,84]. Conclusions: This pooled analysis reported a trend towards favoring Sunitinib versus Everolimus for the first line treatment of patients with metastatic non-ccRCC, although statistical significance was not reached. Sutent was associated with more Grade 3-4 toxicieties. Further prospective randomized phase III trials are required to clarify the better therapeutic option for this subset of patients.
Prognostic value of BAP1 expression in clear cell renal cell carcinoma with inferior vena cava tumor thrombosis.
Authors: Oka Suguru , Inoshita Naoko , Miura Yuji , Oki Ryosuke , Miyama Yu , Nagamoto Shoichi , Ogawa Kohei , Sakaguchi Kazushige , Kondoh Chihiro , Kurosawa Kazuhiro , Urakami Shinji , Takano Toshimi , Okaneya Toshikazu
Published: September 2018

e16080

Background: Renal cell carcinoma (RCC) is characterized by a propensity for extension into the renal vein and inferior vena cava (IVC), and affected patients have a poor prognosis. BAP1 mutation, which occurs in about 15% of patients with clear cell RCC (ccRCC), also predicts a poor prognosis. The aim of this study was to elucidate the association between BAP1 expression and clinicopathologic outcomes in patients with ccRCC with an IVC tumor thrombus. Methods: Thirty-nine patients with ccRCC with an IVC tumor thrombus who underwent radical nephrectomy and tumor thrombectomy at our institution from 1999 to 2010 were retrospectively evaluated. Immunohistochemical analyses were performed for the expression of BAP1, and the associations between the expression of BAP1 and clinical outcomes were assessed. Survival analyses were performed using the Kaplan–Meier method and log-rank test. Multivariate analyses of the associations between overall survival (OS) and clinical variables were performed using a Cox proportional hazard model. For all analyses, P < 0.05 was considered statistically significant. Results: The median follow-up time was 58.8 months (range, 2–130 months). The median age was 66 years (range, 37–80 years). Four patients (10.3%) had lung metastasis at the initial diagnosis. The primary tumor was right-sided in 27 (69.2%) patients and left-sided in 12 (30.8%). The IVC tumor thrombus extended above and below the diaphragm in 11 (28.2%) and 28 (71.8%) patients, respectively. The KPS score was > 80 in 23 patients (59.0%). BAP1 expression was positive in 26 (67.0%) cases and negative in 13 (33.0%). BAP1-negative tumors were associated with a significantly shorter OS than BAP1-positive tumors (median OS, 42.0 vs. 81.5 months, respectively; P = 0.019). The median disease-free survival in BAP1-negative and -positive tumors was 10.0 and 19.0 months, respectively (P = 0.019). Multivariate analysis showed that only a BAP1-negative status was significantly associated with shorter OS (P = 0.026). Conclusions: A BAP1-negative tumor status was significantly associated with a poor prognosis in patients with ccRCC with an IVC tumor thrombus who underwent radical nephrectomy and tumor thrombectomy.
Outcomes of metastatic adrenocortical carcinoma (ACC): A 16-year single institutional experience.
Authors: Owen Dwight Hall , Patel Sandipkumar , Phay John E , Shirley Lawrence Andrew , Kirschner Lawrence S , Schmidt Carl Richard , Abdel-Misih Sherif , Brock Pamela , Wei Lai , Shah Manisha H. , Konda Bhavana
Published: September 2018

e16088

Background: ACC is a rare malignancy with limited data to guide management of metastatic disease. Prior research regarding survival has focused on pts with locoregional disease, but has not offered insight into the management and outcomes of pts with metastatic disease. Methods: We retrospectively reviewed patients (pts) with metastatic ACC who were treated with systemic therapy between January 2000 and October 2016 at The Ohio State University Comprehensive Cancer Center. Kaplan-Meier and Cox proportional hazards regression models were used for survival analysis. Results: A total of 18 pts received systemic therapy for distant metastatic disease. Median age at diagnosis was 51 (range 31 – 72). Median overall survival (OS) from time of diagnosis of ACC was 15.5 months (95% CI 4.8 – 28.2), and from time of systemic treatment (ST) was 7.1 months (95% CI 3.3 – 26). A germline variant of uncertain significance in MSH2 (c.138C > G) was identified in one patient. Baseline FDG-PET scans were obtained in 11/18 pts, and demonstrated avidity in all patients. Maximum SUV ranged from 4.1 to 47.6, with a median of 15. First line therapy was etoposide, doxorubicin, cisplatin, and mitotane (EDPM) in 13/18 pts and clinical trial with IMC-A12 (IGF-1 receptor antibody) in four pts. Median duration of first line therapy was 1.8 months (95% CI 0.9 – 2.8). Survival was not statistically different for patients receiving EDPM as first or second line therapy (median OS 23.3 vs 12.0 months, p = 0.96). Additional lines of therapy included EDPM, IMC-A12, AT-101, mifepristone, OSI-906 (IGF-1R inhibitor), and nivolumab. Median lines of therapy given were 2. The presence of bone metastases (p = 0.69) or lung metastases (p = 0.21) at the time of initiation of ST was not associated with OS from ST. Conclusions: In our experience, the prognosis of pts with metastatic ACC receiving systemic therapy is poor with most pts receiving ≤ 2 lines of therapy. Patients receiving first or second line EDPM seemed to have worse outcomes than noted in previously published trials, possibly due to our patients being sicker at baseline. Metastasis to the lung or bone at initiation of ST did not impact OS.
Adverse effects of androgen deprivation therapy on cognitive impairment for men with prostate cancer: A meta-analysis.
Authors: Sun Maxine , Cole Alexander P , Hanna Nawar , Trinh Quoc-Dien
Published: September 2018

e16506

Background: Use of androgen deprivation therapy (ADT) may confer a higher risk of cognitive impairment. Published results are variable and lack consensus. Our objective was to perform meta-analysis of the risk of overall cognitive impairment in men receiving ADT for prostate cancer. Methods: Relevant studies were identified through the search of English language articles indexed in PubMed Medline, PsycINFO, Cochrane Library and Web of Knowledge/Science until December 21st2016. Articles were included if they were published in English, reported on original research with adult male subjects undergoing treatment for prostate cancer, incorporated longitudinal comparisons, and included a control group. Controlled intervention studies were required to assess an established cognitive-related endpoint that was measured by a validated instrument, and measure cognitive impairment based on the International Cognition and Cancer Task Force (ICCTF) criteria. The effect of ADT on cognitive impairment was pooled using a random-effects model for controlled intervention and case-control studies separately. Results: Of 221 abstracts, 25 were selected for full-text review, and 8 studies, with 2 controlled studies and 6 case-control studies were identified. Overall cognitive impairment was not significantly different when the results of the 2 prospective studies were pooled (OR: 1.57, 95% CI: 0.50–4.92, P= 0.44), with significant heterogeneity between estimates ( I2: 83%). In retrospective data, the odds of developing any cognitive impairment were significantly higher in men treated with ADT (HR: 1.37, 95% CI: 1.06–1.77, P= 0.02), with considerable heterogeneity ( I2: 84%). Conclusions: The relationship between overall cognitive impairment and use of ADT defined according to the ICCTF criteria in a pooled-analysis of two prospective studies was inconclusive. Although retrospective studies suggest a higher risk of overall cognitive impairment after ADT, we caution readers not to over-interpret this finding given the limitations of retrospective data. Better well-designed prospective studies are needed to assess the effect of ADT on cognitive impairment with long-term follow-up.
Biomarkers for early prognostication of outcome in patients with bone-metastatic castration-resistant prostate cancer treated with enzalutamide.
Authors: Schlack Katrin , Boegemann Martin , Krabbe Laura-Maria , Kannen Karoline , Semjonow Axel , Klaile Yvonne
Published: September 2018

e16507

Background: Enzalutamide (Enza) prolongs survival in men with mCRPC in pre- and post chemotherapy setting. Commonly used prostate-specific antigen (PSA) may lead to non-straightforward prognosis. This is especially true for bone mCRPC (bmCRPC) in which initial bone-flare may add to difficult decision making. During other therapies, bouncing of alkaline phosphatase (ALP-Bounce) was shown as a promising surrogate for survival outcome. The purpose of this study was to evaluate the prognostic ability of ALP-Bounce compared to standard PSA and lactate dehydrogenase (LDH) after initiation of Enza. Methods: Patients with bmCRPC were included and analyzed. PSA, LDH and ALP were monitored at 2, 4, 8 and 12 weeks under very early Enza treatment. ALP-Bounce vs. no Bounce was analyzed using Kaplan-Meier estimates and uni- and multivariate (UV/MV) cox-regression models. ALP-Bounce was defined as an increase of ALP after initiation of Enza with a subsequent, significant decline below baseline during the first 8 weeks of therapy. Results: Eighty-nine men were evaluable for analysis. The median overall survival (OS) of men with ALP-Bounce was 19 months (95% confidence interval: 7.9-30.1) compared to 12 months (7.7-16.3) for no Bounce. Analysis of progression-free survival (PFS) showed similar results with 8 (0-16.3) vs. 3 months (1.9-4.1). In UV no ALP-Bounce (Hazard Ratio (HR): 1.9 (1.1-3.3); p = 0.02), no PSA-decline ≥50% (HR: 2.3 (1.5-3.7); p < 0.01) and no LDH-Normalization (HR: 2.5 (1.6-4.1); p < 0.01) were significantly associated with worse PFS. In MV only no ALP-Bounce showed a trend towards worse PFS (HR: 2.1 (0.9-4.5); p = 0.09). In UV no LDH-normalization was a significant prognosticator of poor OS (HR: 2.6 (1.6-4.2); p < 0.01) while ALP-Bounce and PSA decline ≥50% were non-prognostic. In MV no LDH-normalization remained an independent prognosticator of poor OS (HR: 2.0 (1.1.-3.5); p = 0.02). Conclusions: ALP-Bounce and LDH-Normalization may add to identification of bmCRPC-patients with favorable prognosis during early therapy with Enza. The early occurence of ALP-Bounce might be beneficial. These results have to be validated in a prospective trial.
Expression of androgen receptor, somatostatin receptor subtypes, aurora kinase A, and interleukin-6 in prostate cancer before androgen ablation.
Authors: Gernone Angela , Trabucco Senia , Cascardi Eliano , Resta Leonardo , Silvestris Franco , Napoli Anna
Published: September 2018

e16508

Background: Neuroendocrine differentiation (NED) in prostate cancer (PC) can be detected by immunohistochemistry as single cells in conventional adenocarcinoma. NEPC is a poor-recognized late presentation of hormone refractory subtype of PC AR-negative. NEPC correlates with poor prognosis, tumor progression during androgen-deprivation therapy and frequent visceral metastases. Aurora kinase A (AURKA) and Interleukin-6 (IL-6) cooperate to induce NED. The aim of this study was to correlate the expression of somatostatin receptor (SSTR) 1- 2- 3- 4- 5 subtypes, AURKA and IL-6 in primary PC with NED pattern before androgen ablation and OS. Methods: PC tissues were reviewed from 60 pts who had undergone biopsy or radical prostatectomy for previously untreated advanced or metastatic PC from 2010 to 2016. 10 samples expressed histologically chromogranin A (CgA), a marker of NED expression. Median age was 67 years (47-80), Gleason score ≥ 7, median PSA was 60 ng/ml (1.3-1000), ECOG 0/1 and bone-visceral sites measurable in 90% of cases. For comparison purposes, 8 pathology specimens from pts with primary PC negative for CgA expression were used. Results: SSTR1-2-4-5 were detected only in the nucleus of PC cells in 10/10 samples. AR was expressed in all 10 samples CgA positive. SSTR3 and AURKA were not expressed in all 10 samples. IL-6 was detected in 9/10 samples. All 10 pts developed early onset of CRPC, more aggressive clinical course with rapid occurrence of visceral metastases and OS was < 12 mos. Conclusions: In metastatic prostate cancer, pretreatment NED pattern can be a predictor for progression and survival after hormonal and during standard chemotherapy. Most likely NEPC become AR negative during disease progression and in response to androgen deprivation therapy. We supposed, according to other data, that the novel potent AR-targeted drugs should be not used in this subset of patients. SSTRs and somatostatin analogs are not potential targets for prostate cancer.