bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of renal cell carcinoma and hematologic malignancy.
Authors: Varella Leticia , Chintapatla Rangaswamy , Wiernik Peter H. , Rusciano Valerie , Dutcher Janice P.
Published: February 2017

449

Background: An increased incidence of both RCC and HM occurring in the same patients has been reported. Also, a relationship between adenocarcinoma and HM has been previously suggested. Moreover, detailed family history in our patients with RCC suggested an increased incidence of HM in their family members. The purpose of this study is to characterize the HM in relatives of patients with RCC. Methods: Data from 700 patients with RCC seen by us from 2004 to the present were retrospectively evaluated through chart review. The patient, family history and pathology characteristics were collected to determine the frequency of HM in first and second-degree relatives of patients with RCC. Pedigrees were then constructed and subtypes of HM were characterized. Results: A family history of HM was observed in 74 relatives involving 59 families. Of these, 50/74 cases of HM were in first-degree relatives and 19/74 were in second-degree relatives. The most common HMs were lymphoma and leukemia: 24 non-Hodgkin’s lymphoma, 8 Hodgkin’s lymphoma, 8 lymphoma not further specified (NOS), 11 chronic lymphocytic leukemia, 1 chronic myeloid leukemia, 1 acute myeloid leukemia, 5 acute leukemia NOS and 4 leukemia NOS. Other HM observed were multiple myeloma in 2 patients, Waldenström’s macroglobulinemia, myelodysplastic syndrome, and myelofibrosis. Additionally, 2 relatives had blood cancers that were NOS. Of the 59 patients with RCC, 40 had clear cell histology, 4 papillary, 3 chromophobe, 1 sarcomatoid, 1 transitional and in 10, RCC histology was not recorded. Conclusions: HM is observed in patients with RCC with increased frequency compared with the SEER database. We now observed an increased frequency of HM in relatives of patients with RCC. The majority of HMs observed were B-cell malignancies, as we previously reported for HMs that occur in patients with breast cancer or RCC. The etiology of this association remains unclear, but suggests a common etiopathogenesis for RCC and B-cell tumors. Genetic mutations, hereditary immunological defects, and environmental factors may be involved. A larger study with statistical evaluation for confirmation is required. We plan to collect serum and tissue samples from patients and relatives for future molecular studies.
High-dose bolus interleukin-2: Correlating response rate with number of doses received.
Authors: Patel Jolly , Fishman Mayer N. , Goetz Dawn
Published: February 2017

452

Background: Administration of high-dose interleukin-2 (IL-2) in metastatic renal cell carcinoma (MRCC) has higher response and survival rates when compared to low dose or subcutaneous administration. In patients who achieve a response, it may be at the expense of more toxicity risk, from more doses. The association of the major response rate with the number of high dose boluses or cumulative dose received is of interest. The primary objective of this study is to evaluate a direct correlation with response and cumulative dose or the total number of doses received. Methods: A retrospective chart review was conducted of all patients at H. Lee Moffitt Cancer Center diagnosed with metastatic renal cell carcinoma who received high dose bolus IL-2 from September 30th, 1999 to September 30th, 2010. The cumulative dose and the number of doses of IL-2 received was recorded and associated with categorical complete response [CR], partial response [PR], stable disease [SD] or progressive disease [PD] response, by treating physician assessment. Sites of metastasis were also documented. The incidence of adverse effects such as renal failure, transaminitis, cardiac arrhythmias, thrombocytopenia as well as rates of infection and ICU transfers were tabulated. Results: 31 out of 55 patients analyzed were assessed at least with stable disease in response to IL-2. Six achieved a CR, 11 achieved a PR, 14 had stable disease and 24 patients had PD as best responses. Among those with CR or PR to IL-2, they received approximately 30 doses of IL-2 (p=0.027 vs. those not in that category). Converesely, those who received a higher cumulative dose were also more likely to respond (p=0.0077). With respect to adverse events, 58% of patients experienced acute renal insufficiency, 63% transaminitis, 40% arrhythmias, and 45% thrombocytopenia. 55% required dopamine use at any point and 11% required use of additional pressors; 15% required an ICU transfer at some point, and approximately 4% developed a documented infection. Conclusions: Cumulative dose or number of high dose bolus doses received is associated with a statistically significant difference in response rate, within the limitations of this retrospective analysis.
Efficacy of sorafenib in advanced renal cell carcinoma (RCC) independent of prior treatment, histology, or prognostic group.
Authors: Tafreshi Alireza , Thientosapol Eddy , Liew Mun Sem , Guo Yuan , Quaggiotto Melissa , Boyer Michael J. , Davis Ian D.
Published: February 2017

465^

Background: Multiple targeted therapies have become available for RCC over the past decade. Sorafenib is an orally active multikinase inhibitor which has been shown to improve progression free survival in low-risk and intermediate-risk status advanced clear-cell RCC after previous systemic therapy. Methods: Between May 2006 and December 2010, patients with advanced RCC with either clear cell or non-clear cell histopathology who had progressed on prior systemic chemotherapy or were treatment naïve, ECOG performance status 0-2, commenced treatment with sorafenib (400-mg twice daily continuously) through an expanded access clinical trial in two tertiary centres in Sydney and Melbourne. We report the pooled outcomes of these two studies. Results: Total 47 patients with metastatic RCC were treated with sorafenib. The median overall survival of advanced RCC was 11.9 months. After median follow up of 51.3 months, the median PFS was 6.5 months. 38 patients died by the time of analysis. Overall 1 patient showed complete response (CR), 6 patients (13%) had partial response (PR), and 29 patients (62%) had stable disease (SD) as the best response. 8 (17%) had non-clear cell histopathology and 5 (10%) had sarcomatoid features. In non-clear cell cohort, 5 patients (62.5%) showed SD. 23 (49%) patients were treatment naïve; 1/23 showed CR, 5/23 had PR and 13/23 had SD (clinical benefit: 83%). Overall 14 (30%) and 22 (47%) patients had high risk status according to MSKCC and Heng prognostic scores, respectively. Median PFS for poor prognostic patients was 5.1 and 4.2 months based on MSKCC and Heng scores, respectively. In MSKCC poor prognostic group, 1 patient had CR, 2/14 showed PR and 8/14 had SD (clinical benefit: 79%). In Heng poor prognostic group, one patient had CR, 2/22 showed PR and 13/22 had SD (clinical benefit: 73%). Sorafenib-related serious adverse events were seen in 10 patients. The most common adverse events were hand-foot syndrome (53%), rash (47%), fatigue (42%), nausea (40%), and diarrhoea (32%). Conclusions: This study confirms the efficacy and tolerability of sorafenib in a different spectrum of advanced RCC patients including non-clear cell histology, poor prognostic status and as first-line treatment. Clinical trial information: ACTRN12606000140550.
Identification of biomarkers for overall survival of patients with metastatic renal cell carcinoma treated with MGN1601.
Authors: Grünwald Viktor , Weikert Steffen , Schmidt-Wolf Ingo G.H. , Hauser Stefan , Weith Ekaterina , Schroff Matthias , Schmidt Manuel , Tschaika Marina , Wittig Burghardt
Published: February 2017

468

Background: The cell-based therapeutic cancer vaccine MGN1601 consists of two active pharmaceutical ingredients in fixed combination. Fourfold gene-modified, allogeneic tumor cells expressing IL-7, GM-CSF, CD80, and CD154 through MIDGE gene expression vectors are combined with the DNA-based immunomodulator dSLIMas a TLR-9 agonist. In the phase I-II clinical trial (ASET trial) heavily pre-treated patients with metastatic renal cell carcinoma (mRCC) were enrolled. Methods: TheASET study has been conducted as a multicenter, open, single-arm phase I-II study. The treatment phase (TP) consisted of 8 intradermal vaccinations, administered within 12 weeks. We analysed known mRCC prognostic factors for their predictive value, i.e. safety laboratory and immunological parameters, quality of life, local reactions and other patients’ characteristics. Results: 19 patients from the ASET study, who received at least one vaccination (ITT population), were included in the biomarker evaluation. The median overall survival (mOS) in the ITT population is currently 25 weeks. mOS of patients who discontinued TP prematurely was only 10 weeks. However, mOS of those patients who completed at least TP is not yet mature for statistical calculation (NR), but is currently estimated as 69 weeks, resulting in a highly significant difference (10 weeks vs. NR, p < 0.001). Patients with an absolute lymphocyte counts (ALC) at baseline of ≥1,000/μL had increased overall survival (mOS NR vs. 16 weeks, p = 0.013), if compared to those with an ALC <1,000/μL. Neutrophil lymphocyte ratios (NLR) at baseline of >3, bone and liver metastasis, high MSKCC score were identified as risk factors associated with lower overall survival. ALC ≥1,000/μL after three MGN1601 vaccinations (week 5) was even more significantly associated with increased overall survival (mOS NR vs. 17 weeks, p = 0.007). The NLR and quality of life improvement at week 5 as well as local reactions at injection sites seem to correlate with OS. Conclusions: MGN1601 shows promising efficacy in late stage mRCC patients. The identified parameters should be further investigated as potential biomarkers for efficacy. Clinical trial information: NCT01265368.
Defining heminephrectomy for cancer.
Authors: Klink Joseph C. , Khalifeh Ali , Samarasekera Dinesh , Panumatrassamee Kamol , Kaouk Jihad
Published: February 2017

473

Background: The word heminephrectomy originally referred to the removal of half of a kidney with a duplicated collecting system. In the era of partial nephrectomies, heminephrectomy is sometimes used to describe the removal for tumor of >30% of the parenchyma of a non-duplicated kidney. We herein propose a new definition of heminephrectomy: excision of the upper or lower pole of the kidney, removing at least 30% of the parenchymal mass, cutting to hilar fat, and transecting the collecting system. Methods: Our institutional database of robotic and laparoscopic partial nephrectomies was queried for patients who underwent a partial nephrectomy for tumor between 2002 and 2011. Patients who had a heminephrectomy for obstruction in a duplicated collecting system were excluded. The patients who had a heminephrectomy by our strict definition were compared to the remainder of patients who had a partial nephrectomy. Logistic regression was used to compare outcomes between the two groups. Results: 61 patients met our strict definition of heminephrectomy out of 643 patients who underwent a partial nephrectomy for tumor. Heminephrectomy and non-heminephrectomy patients were similar in age, gender, BMI, ASA score, proportion of left- versus right-sided tumors, solitary kidney status, preoperative creatinine and GFR. (all p>0.1). The tumors in the heminephrectomy group were larger (5.1 vs. 2.8 cm, p<0.001) and had a higher R.E.N.A.L nephrometry score (8.5 vs. 6.5, p<0.001). Operative outcomes reflected the high complexity of performing a heminephrectomy. Estimated blood loss was greater (373 vs. 267 ml, p=0.04), operative time was longer (214 vs. 185 minutes, p<0.001), warm ischemia time was longer (25 vs. 20 minutes, p=0.002), and the rate of intra-operative complications was greater (11% vs. 4%, p=0.02) in the heminephrectomy group. On multivariable analysis adjusted for age, preoperative GFR, R.E.N.A.L. score, and warm ischemia time, heminephrectomy was a significant predictor of lower post-operative GFR (p<0.001). Conclusions: Our strict definition of heminephrectomy performed for tumor in a non-duplicated system will allow precise clinical and research communication about heminephrectomy patients and may aid in the prediction of outcomes after partial nephrectomy.
Elevated pS6K levels in the sarcomatoid component of tumors derived from patients with metastatic renal cell carcinoma (mRCC).
Authors: Pal Sumanta Kumar , Tong Tommy , He Miaoling , Wu Huiqing , Liu Xueli , Carmichael Courtney , Lau Clayton , Nelson Rebecca A. , Figlin Robert A. , Jones Jeremy
Published: February 2017

475

Background: Consistent with other retrospective analyses, data from our institutional experience indicates that patients (pts) with sarcomatoid mRCC have a poorer outcome as compared to pts that lack sarcomatoid features (Pal SK, et al. Urol Oncol 2012). The preponderance of correlative studies to date focused on epithelial-to-mesenchymal transition (EMT) as a driver of sarcomatoid disease; however, the role of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signaling is poorly understood. Methods: Of 270 pts with mRCC in our institutional database, 21 pts were noted to have sarcomatoid features. Thirteen of these pts had available tissue from nephrectomy or diagnostic biopsy. An additional 13 pts with mRCC and available tissue were identified from the database who had a similar MSKCC risk stratification but lacked sarcomatoid features. Immunohistochemical staining were performed for moieties related to VEGF-mediated signaling (pS6K) and EMT (Twist, E-cadherin and N-cadherin). Results: Among matched pts with and without sarcomatoid features (n=13 for each group), 9 pts (69.2%) in each group had poor risk disease by MSKCC criteria, while the remainder had intermediate risk disease. Given our risk-matching approach, median survival was similar in both groups (6 mos in pts with no sarcomatoid features vs. 9 mos in pts with sarcomatoid features, p = NS). In evaluable specimens from pts with no sarcomatoid features, the proportion of cell staining positively for pS6K was 24.4%. A higher proportion of pS6K staining was found in pts with sarcomatoid mRCC, both in sarcomatoid components (60.0%) and non-sarcomatoid components (52.5%). Staining for N-cadherin, E-cadherin, and Twist were highly variable, and no observable differences between groups were identified. Conclusions: Although chemotherapeutic strategies are a common 1st-line approach to sarcomatoid mRCC, the finding of higher pS6K staining in this population suggest the potential for currently approved targeted therapies in this disease. Prospective assessment of VEGF- and mTOR-directed therapies for sarcomatoid mRCC, as in ECOG 1808 (NCT01164228), should be encouraged.
Updated interim analysis (IA) of COU-AA-302, a randomized phase III study of abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy.
Authors: Rathkopf Dana E. , Smith Matthew Raymond , De Bono Johann Sebastian , Logothetis Christopher , Shore Neal D. , De Souza Paul L. , Fizazi Karim , Mulders Peter , Mainwaring Paul N. , Hainsworth John D. , Beer Tomasz M. , North Scott A. , Fradet Yves , Griffin Thomas W. , Park Youn Choi , Kheoh Thian San , Small Eric Jay , Scher Howard I. , Molina Arturo , Ryan Charles J.
Published: February 2017

5

Background: AA, a specific inhibitor of CYP17, blocks androgen biosynthesis and improves overall survival (OS) in mCRPC post-docetaxel (Lancet Oncol 2012;13:983-92). This pre-specified updated IA (55% total OS events) extends previous IA for COU-AA-302 evaluating clinical benefit of AA vs prednisone (P) in mildly symptomatic or asymptomatic pts with progressive mCRPC without prior chemotherapy. Methods: 1088 pts were stratified by Eastern Cooperative Oncology Group performance status (ECOG-PS, 0 vs 1) and randomized 1:1 to AA 1000 mg + P 5 mg po BID vs Placebo + P. Co-primary endpoints: radiographic progression-free survival (rPFS) and OS. Median time with 95% CI was estimated using the Kaplan-Meier method. The O’Brien-Fleming Lan-DeMets α-spending function was used for OS. Results: At 55% IA, OS, rPFS and secondary endpoints all favored the AA arm (Table). Median follow-up = 27.1 mos. A post hoc sensitivity multivariate analysis for OS using known prognostic factors supported primary results (HR 0.74, P = 0.0017). Grade 3/4 AEs (AA, P) (%): hypertension 4.2 vs 3.1; hypokalemia 2.6 vs 1.9; ALT↑ 5.5 vs 0.7; AST↑ 3.1 vs 0.9. Conclusions: In updated IA of COU-AA-302, improvement in rPFS (risk reduction 47%) remained statistically significant. Risk of death decreased by 21% but did not reach pre-specified efficacy boundary. Median OS for AA (35.3 mos) is the longest reported for this mCRPC population. Secondary endpoints were clinically and statistically significant; safety profile despite longer exposure remains favorable. Targeting extragonadal androgen synthesis reduces morbidity associated with disease progression in mCRPC pts without prior chemotherapy. Clinical trial information: NCT00887198. [Table: see text]
Evaluation of the UCSF cancer of the prostate risk assessment for prediction of biochemical recurrence (CAPRA) to predict which patients need dose escalation in intermediate-risk disease.
Authors: Taussky Daniel , Krishnan Vimal , Bahary Jean-Paul , Nguyen-Huynh Thu-Van
Published: February 2017

54

Background: The University of California, San Francisco (UCSF) Cancer of the Prostate Risk Assessment (CAPRA) is a validated preoperative index which predicts recurrence free survival and the risk of adverse pathological features after prostatectomy. We analyzed the value of the CAPRA score to predict which patients might benefit from dose escalation in a randomized dose-escalation trial for intermediate risk patients. Methods: We analyzed 119 patients with intermediate risk prostate cancer (Gleason ≤ 6 and PSA 10-20 or Gleason 7 and PSA <10). Patients were randomized between external beam radiotherapy (EBRT) doses of either 70.2 Gy or 79.2 Gy (1.8 Gy per day). All patients had a follow up of at least 2 years. Biochemical failure (BF) was defined with the Phoenix definition. Difference between CAPRA groups was calculated using Kaplan-Meier method. Results: Twenty percent (24/119) had BF. Median time to BF was 60.5 months (1-102) and median follow up for patients without failure was 66 months (25-102). A CAPRA score of 0-2 (risk of recurrence 5y post prostatectomy <10%) was present in 16%, a score of 3-5 (5y risk 18-26%) in 72% and CAPRA 6 (5y risk 37%) in 12%. Stratified according to the 3 CAPRA groups 0%, 20% and 50% ofpatients had a recurrence. The difference between the 3 groups was significant (p=0.019). When stratified according to treatment arm, differences remained significant (p=0.025). None of the patients with a CAPRA 0-2 had biochemical recurrence, even with 70.2 Gy only. When analyzing only patients with a CAPRA score of 3-5, patients in the treatment arm with 79.2 Gy, had less BF with 15% compared to 26% in the arm with 70.2 Gy (p=0.187). The 2 survival curves start to split at 5y of follow-up. Conclusions: The CAPRA score seems to be a promising, clinically easily applicable tool to predict for patients who might benefit from dose escalation. Patients with a CAPRA score of 0-2 do not seem to benefit from dose escalation, but there is a trend for a benefit in patients with a CAPRA 3-5. Clinical trial information: NCT00033631.
Association of radical prostate cancer therapy with a survival benefit in the older man.
Authors: Cathcart Paul , Johal Amundeep , van der Meulen Jan , Emberton Mark
Published: February 2017

66

Background: Data from several recent randomised controlled trials have suggested that older men have little to gain from radical prostate cancer therapy. In contrast, observational studies have suggested that older men might be at increased risk of prostate cancer related death than their younger counterparts. Using a national cancer registry, we sought to explore this issue further. Methods: English national mortality records for an 11 year period between 1997 and 2008 were linked to national hospital admission records together with national cancer registration records to generate a working dataset. Complete data were available on 75,735 men. Competing risks regression analysis was employed to identify the effect of age on Prostate Cancer Specific mortality. Results: Older men were more likely to have high-grade prostate cancer (<70 yrs: 20% v’s >79 yrs: 36%) and be staged with locally advanced (<70 yrs: 20% v’s >79 yrs: 35%) or metastatic disease (<70 yrs: 18% v’s >79 yrs: 25%). Older men were less likely to receive radical therapy (<70 yrs: 46% v’s >79 yrs: 4%) although they were more likely to die of their disease. 8-year overall mortality for low, intermediate and high risk disease in men <70 was 8%, 11% and 31% compared to 34%, 36% and 54% for men >79. Comparable figures for 8-year prostate cancer specific mortality were 1%, 5% and 22% for men <70 and 8%, 10% and 32% for men >79.The Number Needed to Treat (NNT) to save one prostate cancer related death for men with low risk disease aged less than 70 was 100 compared to 20 and only 6 for men aged <70 with intermediate and high risk disease respectively. For men aged between 75 and 79, radical prostate cancer therapy was only associated with a survival benefit in men with high risk disease (OR: 0.49, 95% CI 0.36-0.66, p<0.001) for which the NNT was 5. Conclusions: Older men present with more advanced and more aggressive prostate cancer and as such are more likely to die from their disease. Radical therapy was associated with a survival benefit up to the age of 80 providing therapy was targeted to those with higher risk disease.
Association of germ-line genetic variation in the NK3 homeobox 1 gene with overall survival in advanced-stage castrate-resistant prostate cancer (CRPC).
Authors: Kohli Manish , McDonnell Shannon , Bevan Graham , Riska Shaun M. , Costello Brian Addis , Longenbach Sherri , Dronca Roxana Stefania , Moynihan Timothy Jerome , Pitot Henry Clement , Quevedo Fernando , Cerhan James Robert
Published: February 2017

75

Background: We investigated the association of germline variation in ten candidate genes important in prostate cancer biology (NKX3-1, JAK2, SLCO2B1, STAT3, CYP19A1, HSD17B4, TRMT11, PRMT3, HSD17B12, NCOA4) with overall survival (OS) in a cohort of metastatic CRPC stage patients. Methods: Patients (N=497) were enrolled at the time of androgen deprivation therapy failure for D2 stage prostate cancer. Candidate genes were selected from the literature and pilot studies. Genes were tagged using SNPs from HapMap with minor allele frequency (MAF) of >5% and r2≥0.8. DNA was extracted from peripheral blood and genotyped using Illumina Veracode platform. The primary endpoint was OS, defined as time from development of CRPC to death. Principle components analysis was used for gene-levels tests. To account for multiple testing we calculated the false discovery rate (FDR). For SNP level results we estimated per allele (ordinal model) hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and adjusted for age and Gleason score (GS). Results: We successfully genotyped 60 SNPs (from 10 genes) in 497 Caucasian subjects. The median age of the CRPC cohort was 71 years (range 43,93). The GS distribution was 51% subjects with GS≥8; 32% with GS7 and 17% with GS<7. After a median follow up of 2.1 years (IQ range: 1.2-3.6), 297 subjects had died. In unadjusted gene level analyses, NKX3-1 (p=0.04; FDR=0.03) was associated with OS. After adjusting for age and GS the result remained significant (p=0.03). Two of the 5 genotyped SNPs in this gene were associated with OS after adjustment for age and GS: rs10503733 (dominant model p=0.03, HR=0.77; 95 CI=0.60-0.98; A>C; MAF = 0.22) and rs7005368 (dominant model p=0.05, HR=1.38, 95CI=1.0-1.92; G>A; MAF=0.07). Both SNPs are in Hardy Weinberg Equilibrium and in complete LD (D'=1), although r2 is low (r2=0.025) due to different allele frequencies. Conclusions: Variation in the homeobox NKX-1 gene, a prostate specific tumor suppressor gene involved in prostate development and carcinogenesis is significantly associated with OS in CRPC after accounting for age and GS. Further validation is needed to develop these as prognostic biomarkers.
Relationship of oral glycine with radiation-induced HIF1-alpha and tumor growth delay in a prostate cancer xenograft.
Authors: Kessler Elizabeth Riley , Su Lih-Jen , Yang Xiaoping , Altunbas Cem , Flaig Thomas W. , Li Chuan-Yuan , Kavanagh Brian D.
Published: February 2017

81

Background: Preclinical studies have shown that nitric oxide (NO) is produced by upregulation of inducible nitric oxide synthase (iNOS) in activated macrophages recruited to the site of cytotoxic injury from radiation or chemotherapy. NO stabilizes hypoxia-inducible factor 1-alpha (HIF1α), leading to increased vascular endothelial growth factor, thus promoting tumor angiogenesis as a recovery mechanism from the initial cytotoxic insult. Because glycine (G) suppresses macrophage activation, we hypothesized that dietary supplementation with G would inhibit HIF1α expression and enhance tumor growth delay by preventing recovery angiogenesis. Methods: PC3 cells were transfected with a HIF1α-inducible luciferase reporter and grown as nude mice xenografts. As tumors grew to 100mm3, mice were continued in 1 of 4 conditions: 1) control (C) diet ; 2) a 5%G diet; 3) C diet with ad libitum drinking water treated with L-NAME (500mg/L), an iNOS inhibitor; or 4) C diet with a single injection of carrageenan (2mg/500uL), a selective macrophagicidal agent. After 3 days tumors were irradiated with 0 Gy (sham) or 6 Gy using a 160kV source. Tumor growth and quantitative bioluminescence data were then collected (n = 4 mice/group). Results: HIF1α expression as assessed by bioluminescence increased more than two fold 4-6 days after 6 Gy (p<0.05) in the C diet group but did not significantly increase in either the L-NAME, 5%G , or carrageenan groups. Tumor growth curves for the 6 Gy L-NAME and 5%G diet groups showed a corresponding statistically significant growth delay compared to 6 Gy C diet. No clear difference in bioluminescence or growth was noted in any 0 Gy cohort. Conclusions: The results support the hypothesis that radiation injury indirectly upregulates HIF1α via an iNOS dependent pathway. Inhibition of this pathway can enhance in vivo radiation-induced tumor growth delay and can be achieved via dietary supplementation with G. Thus, dietary G supplementation might have a clinical role for patients treated with radiotherapy for prostate cancer as a non-toxic means of achieving radiosensitization.
Intermediate versus short-course hormone therapy and mortality in men with high-risk prostate cancer treated with radiation therapy.
Authors: Nanda Akash , Chen Ming-Hui , Moran Brian Joseph , Braccioforte Michelle H. , D'Amico Anthony Victor
Published: February 2017

83

Background: Radiation therapy (RT) plus 28-36 months of hormonal therapy (HT) is standard-of-care for men with high-risk prostate cancer (HRPC) based on randomized trials comparing these HT durations to 4-6 months. However, it is unknown whether shorter durations of HT may also decrease mortality. We evaluate the impact of intermediate-course HT on the risk of all-cause mortality (ACM) in men with HRPC treated with RT. Methods: The study cohort comprised 554 men with HRPC (PSA > 20; Gleason score 8 or higher; or clinical stage T2c or higher) consecutively treated at the Chicago Prostate Cancer Center between 1997 and 2007. All men received brachytherapy with or without external beam RT and HT of intermediate (> 6 to 24; median 12 months) or short (up to 6; median 4 months) duration. A Cox regression multivariable analysis was performed assessing whether intermediate compared to short-course HT was associated with a decreased risk of ACM, adjusting for age, year and type of RT, treatment propensity score, and known PC prognostic factors. Results: After a median follow up of 4.3 years a total of 64 (11.6%) men died. Intermediate compared to short-course HT was associated with a significantly decreased risk of ACM (adjusted hazard ratio 0.44, 95% confidence interval 0.20 - 0.94, P = 0.03). Other significant covariates are shown in the table. The 5-year estimates of ACM for intermediate versus short-course HT were 7.0% and 15.7%, respectively. Conclusions: In men with HRPC treated with RT, a median HT duration of 12 months was associated with a significantly decreased risk of ACM when compared to a median HT duration of 4 months. This raises the hypothesis that HT durations shorter than 28-36 months may be sufficient to decrease mortality in men with HRPC. The ongoing RADAR trial by the Trans Tasman Radiation Oncology Group comparing 18 to 6 months of HT may provide level I evidence to validate this hypothesis. [Table: see text]
Is there a withdrawal syndrome with abiraterone acetate (AA)?
Authors: Albiges Laurence , Auclin Edouard , Rousseau Benoit , Boughalem Elouen , Levy Antonin , Loriot Yohann , Di Palma Mario , Massard Christophe , Fizazi Karim
Published: February 2017

89

Background: The withdrawal syndrome phenomenon in prostate cancer is defined as a subset of patients (pts) who experience decreasing prostate-specific antigen (PSA) values with or without clinical improvement from the withdrawal of androgen receptor (AR) inhibitors or steroids used as endocrine therapies in castration-resistant prostate cancer (CRPC). In view of its steroidal backbone and structural similarity to progesterone, abiraterone acetate (AA) might act as an AR agonist in certain subsets of CRPC. So far, this phenomenon has not been reported with AA. The aim of this study was to assess the incidence and clinical meaning of such a PSA decrease in pts after AA discontinuation Methods: A retrospective review of 218 consecutive pts treated with AA for metastatic CRPC received after docetaxel between 01/2009 and 08/2012 was conducted in two French centers. PSA values were evaluated before, during and at the end of AA treatment. We retrospectively collected PSA values performed after AA discontinuation (at 4 weeks) and until further treatment or death. Pts were typically kept on prednisone at AA discontinuation. Results: Amongst 218 consecutive patients, 66 pts (30%) were assessed for PSA follow-up after AA discontinuation; reasons for no assessment were mostly: immediate chemotherapy (13%), death (21%); ongoing AA (23%), non evaluated (14%). Amongst the 66 pts, AA therapy was associated with a PSA decrease in 65% pts. Median AA treatment duration was 5.1 months[1.5-39.9]. Twenty-one out of 66 pts (32%) had a PSA decrease when measured at AA disruption and 4 weeks afterwards. The median PSA decrease was 19% [3-68%]. A PSA decrease of greater than 50% was observed in 4 pts (19%). The median duration before progression was 5.5 weeks [1.7-54]. Two of the 4 pts with a PSA decrease>50% exhibited clinical benefit. PSA decrease duration in the 4 pts was7.1 wks [1.1-11.5]. Conclusions: A serum PSA decrease occurred in 32% of pts after AA discontinuation. PSA decrease greater than 50% was observed in 6% of pts with a potential clinical benefit. This event was usually of minor magnitude and short-term. Physiopathological explanations for this observation remain unclear and may be related to the direct activity of AA on the AR.
Cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC): Final quality-of-life (QOL) results with safety data from the United Kingdom (UK) Early Access Programme (EAP) (NCT01254279).
Authors: Bahl Amit , Masson Susan , Malik Zafar I. , Birtle Alison J. , Sundar Santhanam , Jones Robert J. , James Nicholas David , Mason Malcolm David , Bottomley David , Lydon Anna , Chowdhury Simon , Wylie James , De Bono Johann Sebastian
Published: February 2017

91

Background: Several drugs can now improve survival in mCRPC after docetaxel, including cabazitaxel, a next generation taxane. TROPIC (NCT00417079) showed an overall survival benefit of 2.4 months for cabazitaxel compared with mitoxantrone for mCRPC. The UK EAP provided patients access to cabazitaxel; detailed QOL and safety data were recorded. Interim analysis suggested improvements in QOL, particularly pain scores and a good safety profile. We report final QOL and updated safety data. Methods: 108 patients recruited at 12 centres received cabazitaxel 25mg/m2intravenously every 3 weeks with oral prednisolone 10mg daily. EQ-5D questionnaires and health state visual analogue scale (VAS) were completed at baseline, at alternate cycles and at 30 days post treatment. Safety assessments followed each cycle. Results: According to EQ-5D and VAS scores, QOL was stable with an overall trend towards improvement in patients who continued treatment. Paired ‘within patient’ analyses also support this trend. Improved pain was noted more frequently than deterioration at all time points and pain scores were at least stable in 96% of patients at cycle 10. A median of 6 cycles were given. 34 patients (31%) received 10 or more cycles. Grade 3/4 adverse events were uncommon, the most frequent being fatigue (9.3%), diarrhoea (2.8%) and neutropenic sepsis (1.9%). 85% received prophylactic granulocyte colony stimulating factor. Conclusions: Almost 1/3 of patients completed 10 or more cycles in the UK EAP. QOL was stable with trends to improved EQ-5D and VAS scores. Improved or stable pain was observed in the majority of patients continuing therapy. The UK EAP provides the first data on QOL benefit with cabazitaxel in mCRPC post docetaxel and demonstrates manageable toxicity. Final safety data will be available for presentation. Clinical trial information: NCT01254279. [Table: see text]
Trans-Pacific variation in outcomes for men treated with primary androgen deprivation therapy for localized prostate cancer.
Authors: Cooperberg Matthew R. , Hinotsu Shiro , Namiki Mikio , Carroll Peter , Akaza Hideyuki
Published: February 2017

92

Background: Primary androgen deprivation therapy (PADT) is endorsed as an option for monotherapy for localized prostate cancer by guidelines in Asia but not in the United States (US) or Europe. PADT use is common, however, in both the US and Japan. Prior studies on either side of the Pacific have reported disparate outcomes for PADT; we aimed to explore these differences in a direct comparison study. Methods: Data were drawn from the US community-based CaPSURE registry and from J-CaP, comprising men in Japan treated with PADT. 1934 men treated with PADT were included from CaPSURE, and 16,300 treated in J-CaP. Risk adjustment was based on the validated Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score. Cox proportional hazards regression was used to assess prostate cancer-specific mortality (CSM), adjusting for age, J-CAPRA, year of diagnosis, and treatment type (combined androgen blockade [CAB] vs. castration (medical or surgical) monotherapy). Results: Men treated with PADT in J-CaP were older than those in CaPSURE (mean age 75.0 vs. 72.7, p<0.001), and had higher risk disease (mean J-CAPRA score 3.0 vs. 2.1, p<0.001). They were more likely to be treated with CAB: 67.1% vs. 44.5% (p<0.001). In the Cox model, the hazard ratio (HR) for PCSM was 0.31 for J-CaP compared to CaPSURE, 95% CI 0.25–0.40. In J-CaP, CAB improved survival compared to castration alone (HR 0.81, 95% CI 0.66–1.0), but this effect was not observed in CaPSURE (HR 0.96, 95% CI 0.69–1.34). For all-cause mortality, the HR for J-CaP was 0.27 (95% CI 0.24–0.30). Conclusions: Adjusting for multiple factors including disease risk and type of androgen ablation, men treated with PADT in Japan compared to the US have more than 3-fold lower CSM and 4-fold better overall survival. CAB improved outcomes compared to castration alone in J-CaP but not in CaPSURE. These findings support existing guidelines both encouraging PADT in Asia and discouraging its use in the West. The reasons for these substantial differences likely include both genetic and dietary/environmental factors, as well as potential confounding variables such as comorbidities. Such factors may explain varying biology of prostate cancer on both sides of the Pacific.
REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy.
Authors: Perol Maurice , Ciuleanu Tudor-Eliade , Arrieta Oscar , Prabhash Kumar , Syrigos Konstantinos N. , Göksel Tuncay , Park Keunchil , Kowalyszyn Ruben Dario , Pikiel Joanna , Czyzewicz Grzegorz , Orlov Sergey , Lewanski Conrad R. , Alexandris Ekaterine , Zimmerman Annamaria , Chouaki Nadia , John William J. , Yurasov Sergey , Garon Edward B.
Published: February 2017

LBA8006^

Background: RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The REVEL study evaluated the efficacy and safety of RAM+DOC vs. PL+DOC (DOC) in patients (pts) with stage IV nonsquamous (NSQ) and squamous (SQ) NSCLC after platinum-based therapy. Methods: Pts with NSQ and SQ stage IV NSCLC were randomized 1:1 (stratified by sex, region, ECOG PS, and prior maintenance therapy) to receive DOC 75 mg/m2 in combination with either RAM 10 mg/kg or PL on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS), and objective response rate (ORR). Results: Between Dec 2010 and Feb 2013, 1,253 pts (26.2% SQ) were randomized (RAM+DOC: 628; DOC: 625). Pt characteristics were balanced between arms. ORR was 22.9% for RAM+DOC and 13.6% for DOC (P<0.001). The hazard ratio (HR) for PFS was 0.762 (P<0.0001); median PFS was 4.5 months (m) for RAM+DOC vs. 3.0m for DOC. REVEL met its primary endpoint; the OS HR was 0.857 (95% CI 0.751, 0.98; P=0.0235); median OS was 10.5m for RAM+DOC vs. 9.1m for DOC. OS was longer for RAM+DOC in most pt subgroups, including SQ and NSQ histology. Grade ≥3 adverse events (AEs) occurring in >5% of pts on RAM+DOC were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all pts: 2.1% vs. 1.6%; SQ pts: 3.8% vs. 2.4%). Conclusions: REVEL demonstrated a statistically significant improvement in ORR, PFS, and OS for RAM+DOC vs DOC in NSCLC pts with stage IV NSCLC as second-line treatment after platinum-based therapy. Benefits were similar in NSQ and SQ pts, and no unexpected AEs were identified. Clinical trial information: NCT01168973.
Prognosis of metastatic internal mammary sentinel nodes (IMSN) in breast cancer.
Authors: Avisar Eli , Libson Shai , Perez Eduardo
Published: February 2017

103

Background: The presence of positive internal mammary nodes has historically been associated with a significant worse prognosis. Recent studies have also demonstrated a worse prognosis associated with drainage to the internal mammary nodes. Intense search for those nodes, biopsy, appropriate staging and modern treatment for positive IMSN might improve outcome. We sought to study the prognosis of pathologically positive IMSN at our institution. Methods: A retrospective analysis of a prospectively collected database including all breast cancer patients identified with an IMSN that was biopsied between 2005 and 2012 was performed. Demographics, histologic markers, patterns of recurrence as well as survival data were collected. Univariate and multivariate analysis were performed. Results: Thirteen of 82 patients with a biopsied IMSN were metastatic (16%). In 8 of those (62%), the biopsy resulted in a change in staging. In all cases of positive IMSN additional radiation to the internal mammary chain was added. Eighteen percent (18%) of positive nodes did not show drainage to the internal mammary basin during Lymphoscintigraphy. There was no statistical difference in regional and distant recurrences between the patients with positive IMSN and those with negative IMSN. Furthermore there was no difference in disease specific survival. Conclusions: Intense search for IMSN presence and biopsy of those nodes is associated with changes in staging and treatment for metastatic IMSN. In our study, pathologically positive IMSN were associated with a non- inferior prognosis than negative IMSN.
Crowdsourcing the collateral damage from breast cancer treatment.
Authors: Love Susan M. , Obidegwu Amaka , Fischetti Christine A
Published: February 2017

110

Background: Survivorship research focuses on quality of life after cancer treatment, but is usually initiated by providers and lacks the voice of the patient. In an effort to explore the patient perspective, we convened a collaboration of advocacy groups to “crowdsource” women’s questions regarding collateral damage from breast cancer treatment. These concerns will be incorporated into the Health of Women [HOW] Study, an ongoing, online cohort study open to anyone aged 18 or older. Methods: Emails to current HOW participants were sent out July 2013 to solicit questions. In October 2013, a new webpage was designed to collect responses; we then partnered with other advocacy organizations and began collecting responses, which were then categorized to guide questionnaire development. Results: Sixteen advocacy organizations came together to support this project. Emails to current HOW participants resulted in 1,191 responses. The website landing page resulted in 5,099 responses. Overall, 16.8% of respondents complained of fatigue, 16.3% of memory problems, 15.7% of anxiety and/or depression, and 14.0% of numbness/neuropathy. Other less frequently reported problems included problems with nail growth, vision, hearing, urinary tract infections, and allergy-like symptoms. Conclusions: We received an overwhelming number of responses about collateral damage. Many of the issues are known side effects, while others are less commonly reported. We will next compare responses to previously validated questionnaires, develop a comprehensive collateral damage questionnaire for inclusion in the HOW Study, and generate a report for publication to be distributed to participants and the medical community.
Understanding potential communication gaps between oncologists and patients with advanced breast cancer: A survey of oncologists.
Authors: Brufsky Adam , Citron Marc L. , Percassi Deana
Published: February 2017

124

Background: About 232,670 cases of breast cancer will be diagnosed in the US in 2014, of which 86,088 (37%) will be metastatic advanced breast cancer (ABC). The 2013 Global Count Us, Know Us, Join Us survey found that 53% of US women with ABC wanted more time to discuss their needs during clinic visits, and 60% believe their cancer treatment options are limited. To better understand unmet patient needs and potential communication gaps with physicians, surveys were developed for women with ABC, their caregivers, and oncologists. The oncologists’ survey results are presented. Methods: The Make Your Dialogue Count survey for oncologists has 32 items. Responses are single or multiple response numeric text or rated on a 4-point Likert scale. Harris Poll conducted this online survey from June through July 2014 among randomly selected, licensed US medical oncologists who treat ≥ 5 women with ABC per month. Responses for geographic region and number of years in practice by sex were weighted to match actual proportions in the population. Results: By July 15, 2014, 228 oncologists responded. At initial diagnosis, showing care and compassion was very important to 79% of oncologists; helping patients cope with diagnosis (62%) and manage cancer symptoms (56%) and discussing expected treatment response (57%) and side effects (51%) were also very important. Most oncologists (88%) revealed that treating women with ABC has a negative emotional toll. Although 81% of oncologists believe it to be unprofessional to let their emotion affect treatment recommendations, 26% reported that their emotions kept them from providing some information. Notably, 31% of oncologists reported that in certain situations, they have not discussed with patients that ABC is incurable. Conclusions: Caring for terminally ill patients has an emotional impact on oncologists. For some, their emotions have influenced what treatments they recommend and what information they impart. Our findings show that oncologists are compassionate and share disease- and treatment-related information and highlight the need to develop communication strategies that facilitate exchange between oncologists and their patients with ABC.
Integrative oncology from the patient advocate perspective.
Authors: Fonfa Ann
Published: February 2017

133

Background: As a 20+ year breast cancer survivor I sought to find and offer information on natural cancer strategies. At first I needed them for my own cancer protocol, then to help others Integrative Oncology refers to the simple, natural and non-toxic approaches that can reduce toxicity, possibly enhance the efficacy of conventional treatment, and create feelings of well-being and control in people dealing with cancer. Many studies, some from long ago, have pointed to the strong patient interest in Integrative Oncology (formerly known as CAM). Yet the professional oncology community’s knowledge has failed to keep up. Trained to seek level 1 studies, they have failed to note the preponderance of all the other evidence available supporting natural approaches. Due to cost, most natural products/substances are not reviewed at level 1 and probably will never be. Methods: We’ve created a simple program we call 3 Steps 4 Health, which offers anyone in cancer treatment a guide to improved health. We will present the research that backs up these simple ideas that can be incorporated into anyone’s protocol. We also have a handout to reduce toxicities that is evidence-based to help with those adverse effects that plague modern cancer patients. So many suffer from neuropathy – there are quite a few methods to protect or treat this with complementary therapies that can be integrated into conventional treatment. Results: ASCO has pointed to the value of Yoga, of ginger, and other natural approaches but oncology professionals have been slow to adopt or recommend. Conclusions: We will provide evidence-based information on integrative oncology and the 3 Steps 4 Health program.