bluuebunny/crossref_metadata_2025 huggingface dataset:
A single center review of the experience with mitomycin C (MMC) and the risk of thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS)
Authors: Arce-Lara C. E. , Cataland S. , Brady C. , Kraut E. , Otterson G. , Villalona-Calero M. , Bekaii-Saab T.
Published: March 2020

15167

Background: MMC related TTP/HUS has been reported between 4 and 15%, with a higher incidence in patients receiving cumulative doses of 60 mg or higher. It tends to occur within 4 months of drug administration independently of patients’ cancer status. The ability of MMC to upregulate enzymes relevant for new cytototoxic agents (topoisomerase I for CPT-11 and thymidine phosphorylase for capecitabine) make phamacobiologically based therapeutic combinations including MMC attractive. Methods: All patients (n=100) that participated in four institutional clinical studies from 2000 through 2004 were included. The studies were OSU 9947 (phase I trial of CPT-11 and MMC in solid tumors, n=31) OSU 0151 (phase II trial of CPT-11 and MMC in advanced esophageal and stomach cancer, n=41) OSU 0155 (phase II trial of CPT-11 and MMC in patients with refractory breast cancer, n=26) OSU 0330 (phase I study of capecitabine and MMC in patients with advanced GI tumors n=2). In each study, the maximum cumulative dose of MMC was 36 mg/m2. All patients were followed for clinical signs or symptoms of TTP/HUS including the presence of anemia, thrombocytopenia and renal insufficiency and had a thorough review of the peripheral smear. Results: The median cumulative dose was 12 mg/m2 (range 3–36 mg/m2). No patients met the clinical diagnosis of TTP/HUS except for one patient had anemia, thrombocytopenia and renal insufficiency but did not manifest any other findings consistent with TTP/HUS such as changes in mental status, azotemia or any other clinical symptom. The laboratory abnormalities resolved without intervention within seven days with subsequent continuation on the clinical trial. Conclusions: In this study we have demonstrated that by capping the cumulative dose of MMC to 36 mg/m2, the incidence of TTP/HUS is minimal. Furthermore, our preliminary analysis of an additional 100 patients treated with MMC at OSU shows no reported cases of TTP/HUS (additional data will be presented at the meeting). Since MMC is effective in a wide variety of solid tumors including breast, lung and GI malignancies and is inexpensive and easy to administer, further exploration of MMC in the treatment of solid malignancies is indicated including rational combination studies.

No significant financial relationships to disclose.
Interim results of a weekly, metronomic dosing of paclitaxel, oxaliplatin, leucovorin, 5-FU (POLF) in the treatment of metastatic pancreatic cancer (PC)
Authors: Chue B.
Published: March 2020

15175

Background: Metastatic PC has a dismal prognosis and few effective therapies, resulting in early death and poor quality of life. Weekly “metronomic dosing” of chemotherapy allows for increase dose density, dose intensity, and anti-angiogenic effects, yet affords good tolerability, allowing for a better quality of life and perhaps better efficacy. We report the encouraging interim results of the first nine patients treated twelve weeks with this POLF regimen. Methods: Nine patients ages 35 to 75 with metastatic biopsy proven PC were treated with weekly POLF (P: 60 mg/m2, O: 50mg/ m2, L: 20 mg/m2, F: 425 mg/m2) for twelve weeks. One patient (A.B.) also received intermittent Cetuximab. Glutathione, calcium, and magnesium were used to prevent Oxaliplatin- related neuropathy. Patients were seen weekly. Sequential CA 19–9 levels and CT scans were obtained. Results: After 12 weeks of treatments, 7/9 patients had greater than 50% reduction of CA 19–9 levels (see table ), improvement of cancer-related symptoms and shrinkage of tumor. Patient D.P. had a bilirubin of 27 and patient L.C. had bilirubin of 9.6, both of which normalized with treatment without need for stent placement. Patient A.B. was severely debilitated (ECOG 4) following progression of disease after 2 prior lines of chemotherapy but is alive and well after two years since diagnosis, with ECOG 0. The regimen was well tolerated with only one grade 3 neurotoxicity (L.C.) and one grade 3 diarrhea (B.P.). Median survival has not been reached. Conclusions: Weekly combination of Paclitaxel, Oxaliplatin, Leucovorin, and 5-FU has significant activity against advanced PC with manageable side effects. A Phase II study is opened to enrollment, and we welcome participation.

[Table: see text]

No significant financial relationships to disclose.
Factors affecting survival in pancreatic carcinoma: Analysis from a oncology unit of a general hospital in Peru
Authors: Pimentel P. , Beltran B. E. , Riva L. , Reategui R. , Portugal K. , Del Castillo R.
Published: March 2020

15184

Background: Pancreatic carcinoma (PC) is one of the most devasting neoplasm , usually diagnosed in advanced stage with a poor outcome . We present the experience in a Medical Oncology Unit in a National General Hospital, analysing the risk factors for survival in PC. Methods: This is a retrospective study with data collected on 224 patients with PC in all stages between 1999 and 2004. Only 82 patients were included because the rest had clinical and radiological diagnosis without histological studies. Survival was calculated using the Kaplan-Meier method. Clinical, surgical and histopathological records were examined by univariate and multivariate analysis to identify the independent prognostic predictors of survival. Results: All of patients had a confirmed hystopathologic diagnosis of PC. Median age was 69 years ( 33–87), 38/82 (46%) were women; 65/82 (79%) had tumor localized in pancreas head and 22/82 (26%) were stage I /II . 60/80 ( 73%) had advanced stages III/IV. Only 19/82 ( 23%) had Whipple surgery with curative intent. On diagnosis Performance status(PS). 2- 4 was present in 56% (46) .For different reasons only 16/82 received treatment based in gemcitabine. Median overall survival for all patients was 5.4 months, with 1 year survival of 32% .On univariate analysis, P.S. ( p=0.077), Whipple surgery with curative intent (p=0.026), Gemcitabine treatment (p=0.002) and CEA ( p=0.002) significantly influence survival. On multivariate analysis, only P.S (p< 0.05), Gemcitabine based treatment ( p=0.005) and CEA ( p= 0.045) independently influence survival. Conclusions: In this retrospective analysis we identified performance status, CEA and Gemcitabine based treatments as independent prognostic factors that influence survival in PC, adressing the role of standar gemcitabine regimens in the treatment of advanced PC and the need of continue research for improve the outcome of this challenging disease.

No significant financial relationships to disclose.
Trimodality treatment (TMT) for locally advanced esophageal cancer in Pakistan; Analysis of prognostic factors influencing survival
Authors: Syed A. A. , Jamshed A. , Muhammad B. , Azhar R. , Yusuf M. A. , Khan Y. I. , Ahmed Q. , Shehzad K. , Rehman K. , Faruqui Z.
Published: March 2020

15185

Background: The prognosis of patients with locally advanced esophageal cancer is poor. TMT for locally advanced esophageal cancer is being utilized with increasing frequency. In this study, we investigate the prognostic factors influencing survival in patients with locally advanced esophageal cancer following TMT. Methods: The study included 22 patients with esophageal carcinoma treated between January 2003 and December 2005 at Shaukat Khanum Memorial Hospital and Research Centre. Median age was 49 years (range 26 - 68). There were 15 (68%) males and 7 (32%) females. All patients had EGD with biopsy and CT chest. Twelve (54.5%) had squamous cell carcinoma and 10 (45.5%) patients had adenocarcinoma. Five patients (23%) had tumour in the middle third and 17 (77%) had lower/gastroesophageal lesions. Preoperative radiation consisted of 50.4 Gy / 28 fractions with concomitant chemotherapy day 1 and 29 (Cisplatin 75 mg/m2 day 1 and infusional 5FU 1000 mg/m2 day 1–5). Esophagectomy was done at 6 - 12 weeks following chemoradiation. The pathologic down-staging was evaluated by the 5-score tumor regression grade (TRG) of Mandard. Results: Post TMT pathologic TNM stage was; Stage 0 in 8 pts (36%), stage II in 5 pts (23%) and stage III in 9 pts (41%). 13 (59%) pts had R0 and 9 (41%) pts had R1 resection. The 4-year disease free survival was 29% with a median survival of 19 months. The number of patients with TRG score 1, 2, 3, 4 and 5 were 7 (32%), 4 (18%), 5 (23%), 2 (9%) and 4 (18%) respectively. Tumor regression grade 1–2 (p=.0016) and negative circumferential margins >2 mm (p=.0019) had a positive influence on DFS. Age (< 50 vs ≥ 50 years), sex, hemoglobin at presentation (≤ 12 vs > 12 gm/dl), tumor site (middle vs lower/GE junction), pathological nodal status (node positive vs node negative) and histological subtype (squamous cell vs adenocarcinoma) did not influence survival (p= 0.92, p= 0.82, p= 0.69, p= 0.79, p= 0.41 and p= 0.32 respectively). Conclusions: TMT results in prolonged disease free survival in patients with complete response or microscopic residual foci (TRG 1–2). Positive or circumferential margins <2mm is associated with poor prognosis.

No significant financial relationships to disclose.
Major changes in breast cancer incidence in the United States over the period 2002 to 2004
Authors: Ravdin P. , Cronin K. A. , Howlader N. , Berg C. D. , Feuer E. J. , Berry D. A.
Published: March 2020

1533

Background: We have recently reported that a steep decrease in the incidence of breast cancer occurred in the United States in 2003 relative to 2002 (BCRT 100: S5, 2006). This decrease was most evident in patients older than 50, and largely occurred because of a decrease in the incidence of estrogen receptor positive breast cancer. This decrease occurred after the report in 2002 of the results of first of the Women s Health Initiative trials of postmenopausal hormone therapy (HT). This publication showed that use of a combined estrogen/progestin combination was associated with increased risk of breast cancer and heart disease and led to an immediate and substantial decrease in the use of HT in the US. Dramatic shifts in breast cancer incidence are unusual, and provide unique opportunities to test models that have been developed to explain trends in breast cancer incidence and mortality. We have been engaged in modeling trends in breast cancer incidence and mortality, in collaborative effects such as the Cancer Intervention and Surveillance Modeling Network (CISNET), to understand these and other processes (NEJM 353:1784–1792,2005). These models have practical implications for understanding the impact of changes in risk factors, use of prevention strategies, screening, and treatment of breast cancer. Methods: SEER public use incidence data from 1990 to the end of 2003 will be updated with information from the release in the spring of 2007 of incidence data for 2004. We will analyze the full data set through 2004 and report on the trends in incidence of breast cancer in the population as a whole and by subsets (such as age, estrogen receptor status, stage etc). We will also use the most recent and detailed data about HT use and screening mammography during this period as part of modeling. Results: We are awaiting SEER data from 2004 which will be released by April of 2007. Conclusions: Our first SEER based multi-year analysis of breast cancer incidence following the change in HT use in the US will be presented. Modeling of these trends in incidence will be discussed in the context of understanding the role of various contributors to the change in breast cancer incidence and what insights on the evolution of preclinical disease might be possible.

No significant financial relationships to disclose.
Algorithm of monitoring of patients with family history of cancer as a method of cancer prevention
Authors: Petrova V. D. , Sinkina T. V. , Zarubina N. A. , Terekhova S. A. , Dimitriadi J. N. , Selezneva I. A. , Lazarev A. F.
Published: March 2020

1542

Background: Existent genetic tests are not able to provide effective forecasting of all cancer sites and all those methods are generally expensive. At the same time approximately 50% of population has cancer susceptibility and 10% - hereditary cancer syndromes. The purpose of this study was to develop the algorithm of monitoring to provide effective forecasting and prevention of cancer in patients with hereditary cancer susceptibility. Methods: The algorithm of monitoring of patients with family history of cancer includes 2 stage: I - diagnostic, II - treatment and rehabilitation. In the I stage patients with 3 and more relatives by blood who had cancers of any site are revealed by oncologist. Their genealogical trees are analyzed by geneticist. All those patients are registered in the registry of “cancer”-families’ members, interviewed and got all the necessary diagnostic procedures with the following multivariative analysis (of more than 200 geno- and phenotypic characteristics). Patients with determined high risk of malignancies undergo deep clinical and instrumental examination, site-by-site searching for cancer, molecular genetic tests. In the II stage individual recommendations for the patients are developed, pretumour lesions are treated, preventative surgery is performed (resection of a target organ) and the measures for strengthening of anti-tumour resistance are taken. All the patients of the registry get the periodic health examination for term of life: preventive examination once per 6 months, multivariative analysis once per 3 years. Results: The registry of “cancer”-families’ members included 421 families - 1833 patients (232 men and 1601 women at the age of 28–74). In 2003–2006 there were revealed obligatory pre-cancer lesions in 637 patients, cancers in situ - in 45 patients, and cancers of different sites - in 69 patients (in I stage - 78.3%, II stage - 18.9%, III stage - 2.8%, IV stage - 0). Conclusions: This algorithm of monitoring of the patients from the registry of “cancer”-families’ members made it possible to provide high effectiveness of cancer prevention and early detection.

No significant financial relationships to disclose.
Self-exam is the most common method of breast cancer identification
Authors: Rosenberg A. , Burke L. , Vos P. , Liles D.
Published: March 2020

1543

Background: Breast cancer survival is improved by early diagnosis. The role of self-exam as an adjunct to screening mammography has been questioned as some studies suggest that self-examinations lead to unnecessary diagnostic procedures without improving survival. Methods: Patients who had been diagnosed with breast cancer and who were attending a university-based cancer clinic were interviewed, using a structured questionnaire, to determine the way in which their breast cancers were first identified. Inference was conducted using exact methods (Clopper-Pearson intervals for proportions and Fisher’s test for odds ratios). Results: Breast cancers were first identified by mammogram in 16% of women, by provider in 9%, by the spouse in 2%. Seventy-five percent (95% CI=61% to 85%) of patients first identified their tumors by self exam. Self-identifiers occurred in all demographic groups. These women included those with all types of insurance: private insurance (68%), Medicare (60%), Medicaid (100%), or no insurance (85%); all levels of education: 77% with college education and 75% with high school; all income levels: for example, among 79% with annual incomes of <$10K and 73% with incomes >$50K; and among both black (91%) and white (66%) women. Of the women who reported both regular mammograms and regular self-examination (N=35), 77% (95% CI=60 to 90%) were self-identifiers. However, cancers found by mammography were more likely to be Stage I than were those identified by self-examination (odds ratio=3.9, 95% CI .9 to 17.5, p=.047). Conclusions: Most breast cancers (75%) were found by self-examination, even among women who had regular mammography. We did not find any demographic factor that predicted mammography as the primary method of tumor identification. These findings suggest that self-examination remains an important method of breast cancer identification.

No significant financial relationships to disclose.
Phase II multicenter, two-stage study of E7389 in patients with hormone refractory prostate cancer with advanced and/or metastatic disease stratified by prior chemotherapy
Authors: Molife R. , Cartwright T. H. , Loesch D. M. , Garbo L. E. , Sonpavde G. , Calvo E. , Das A. , Wanders J. , Petrylak D. P. , de Bono J.
Published: March 2020

15513

Background: E7389 is a synthetic macrocyclic ketone derivative of the marine sponge product halichondrin B. A unique tubulin depolymerizer, E7389 induces nonproductive tubulin aggregates and inhibits tubulin polymerization. E7389 has demonstrated activity in refractory breast cancer and non small cell lung cancer with response rates of 14.7% and 9.7%, respectively. E7389 inhibits the growth of prostate cancer cell lines, including those (DU145) with over-expression of beta-tubulin III, which may confer resistance to taxanes. Methods: Phase II Simon two-stage study explores the activity and safety of E7389 as monotherapy without concomitant steroids in patients with histologically proven adenocarcinoma of the prostate that has progressed despite maintained castration. Patients are stratified into two groups that are analyzed separately, including those who failed either no prior chemotherapy (except mitoxanthrone or estramustine) or no more than one prior regimen with a tubulin binding agent, such as docetaxel. E7389 1.4 mg/m2 is administered as a 2 to 5 minute bolus IV infusion on Days 1 and 8 of 21-day cycles. PSA measurements are obtained at the end of each cycle. The primary objective is to assess PSA response using Bubley criteria. Results: Thus far, 57 patients (37 taxane pretreated and 20 taxane naïve) have been treated. The median age is 71 (range 48–91) with 43% of patients over 75. A total of 160 treatment cycles have been given (median: 2; range: 2–7). Twelve study drug related serious adverse events have been reported in 9 patients: PE (2), melena (2), fever, neutropenia, febrile neutropenia, UTI, anemia, DVT, chest pain, and renal failure (1). Based on preliminary data, the taxane-treated group has 2 PSA responses in the first 21 patients, and the taxane-naïve group has 4 PSA responses in the first 14 patients, allowing both groups to progress to Stage 2 with further accrual. Conclusions: In patients with hormone refractory prostate cancer, there is some evidence of single agent activity for E7389 in taxane naïve and taxane pretreated patients with acceptable toxicity. Preliminary results of activity allow further recruitment to proceed.

[Table: see text]
Durable complete responses and near complete responses to sunitinib in metastatic renal cell carcinoma
Authors: Heng D. Y. , Rini B. I. , Garcia J. , Wood L. , Bukowski R. M.
Published: March 2020

15514

Introduction: Sunitinib is a tyrosine kinase inhibitor with activity against VEGFR and PDGFR recently approved by the FDA for the treatment of advanced renal cell carcinoma (RCC). There is no existing literature that details complete responses (CRs) in patients taking sunitinib for metastatic RCC. Methods: Seventy-four patients with metastatic RCC receiving sunitinib at the Cleveland Clinic Taussig Cancer Center on clinical trials were reviewed to determine the number of patients with RECIST-defined CRs. Additionally, patients who achieved near-CRs defined as a greater than 90% reduction in composite tumor volume or residual disease of less than or equal to 1 cm were reviewed. Results: Two patients (2.7%) achieved a RECIST-defined CR lasting >15 months. The patients who obtained CRs had non-bulky pulmonary metastases, favorable or intermediate MSKCC risk profiles, were treated with sunitinib in the first-line setting and had a significant reduction in composite tumor measurements within the first two cycles. An additional 2 patients achieved near-CRs, including one patient that previously progressed on bevacizumab. These 2 near-CR patients remain progression-free for more than 19 months. Finally, 1 patient achieved sufficient downstaging and reduction of tumor volume such that the remaining lesion could be excised, resulting in a surgical CR. This patient is currently off sunitinib and remains progression-free 4 months after surgery. Conclusion: Sunitinib is capable of producing durable CRs in cytokine-naïve metastatic RCC patients with non-bulky pulmonary metastases. Additionally, near-CRs can be seen despite non-pulmonary metastatic sites and prior VEGF-targeted therapy.

No significant financial relationships to disclose.
Is the natural history of prostate cancer different according to serum neuroendocrine profile?
Authors: Banu E. , Scotte F. , Banu A. , Medioni J. , Brizard M. , Levy E. , Oudard S.
Published: March 2020

15536

Background: Elevated neuron-specific enolase (NSE) and chromogranine (CgA) values correlate with poor prognosis in prostate cancer (PC) patients (pts). They are correlated with the histological phenotype and a short hormone-sensitivity interval. The impact on the outcome was less explored. Methods: Eligible PC pts were required to have serial CgA and NSE specimens after the initial diagnosis in the venous blood, using commercial kits. Markers were defined as abnormal (+) or normal (-) with a threshold of 20,6 and 100 ng/mL for NSE and CgA, respectively. The endpoint was to evaluate the clinical impact of serum NSE and CgA on the natural history (NH) of the PC using the multivariate Cox regression analysis, stratified by Gleason score and adjusted by age at diagnosis. NH was calculated between the initial diagnosis and death or last follow-up for censored pts. Results: Blood samples were obtained from 213 PC pts, 53% with a metastatic hormone-refractory disease at the moment of the analysis. Seven, 36% and 10% of pts had either an abnormal NSE, CgA or both. Normal serum NSE and CgA were found in 47% of all pts and only in 35% of metastatic hormone-refractory PC pts. Median age was 64 years (range 41–82), 41% of pts had a Gleason score 8–10. Median NSE and CgA levels were 13.3 and 92 ng/mL, respectively. The median of the NH was not reached yet. The adjusted risk of death was multiplied by 3.1 for pts with abnormal NSE or/and CgA (HR=3.5, unadjusted for age). A borderline relationship was observed at the multivariate analysis between NH and the neuroendocrine profile ( Table ). Conclusions: NSE was the most powerful predictor of the NH in PC pts, regardless the moment of the rise during the NH. A systematic NSE and CgA assessment could be proposed for all pts.

[Table: see text]

No significant financial relationships to disclose.
Phase II study of single-agent vinflunine in platinum-refractory transitional cell carcinoma of the urothelium (TCCU)
Authors: Vaughn D. J. , Srinivas S. , Stadler W. M. , Pili R. , Petrylak D. , De Marco S. , Smith D. C. , Nason S. , De Wit E. , George C.
Published: March 2020

15543

Background: Vinflunine (VFL) is a new microtubule inhibitor of the vinca alkaloid class with clinical activity in TCCU (S. Culine, BJC 2006). This trial was conducted to define VFL activity in platinum-refractory TCCU patients (pts). Methods: Multicenter, single-arm study. Primary endpoint: Objective response rate (Independent Review; WHO criteria). Planned sample size: 150 pts. Main pt eligibility: at least one measurable lesion; documented progression within 12 months of last dose of platinum-containing regimen; calculated creatinine clearance (Cr Cl) = 20 mL/min. VFL 320 mg/m2 IV infusion over 20 minutes was administered every 3 weeks. In pts with poor performance status, prior pelvic irradiation, or renal impairment (Cr Cl 20–60 mL/min), initial dose (ID) was 280 mg/m2, escalated to 320 mg/m2 if well tolerated. Results: Enrollment of 150 pts complete. Baseline pt characteristics (first 118 pts treated): Gender: male 78%, female 22%. Median age: 66 years (range 40–83). Renal impairment: 32%. Prior chemotherapy: cisplatin: 69%; carboplatin: 47%, gemcitabine: 94%. Total of 402 VFL cycles administered (range: 1–12). 320 mg/m2 ID: 35 pts; 280 mg/m2 ID: 83 pts. Main toxicity was hematologic (Grade (G) 3/4): neutropenia: 19%/37%; thrombocytopenia: 3%/0%; anemia: 13%/0%; febrile neutropenia: 320 mg/m2 ID: 5 pts; 280 mg/m2 ID: 3 pts. Main non-hematologic toxicities: constipation: 320 mg/m2 ID: 63% (G3/4: 14%/3%); 280 mg/m2 ID: 59% (G3/4: 12%/1%); fatigue: 320 mg/m2 ID: 43% (G3/4: 6%/0%); 280 mg/m2 ID: 35% (G3/4: 7%/0%). Severe diarrhea or vomiting was infrequent. No G3/4 peripheral neuropathy was noted. Responses have been observed by the investigators, but independent review is on-going. Conclusions: VFL has a manageable toxicity profile in pts with platinum-refractory TCCU. Independently reviewed response rate and other efficacy endpoints of the entire cohort will be presented.

No significant financial relationships to disclose.
The role of neoadjuvant chemotherapy in muscle invasive bladder cancer and correlation of clinical outcome with translational studies
Authors: Hussain S. A. , Ward D. , Palmer D. H. , Barton D. , Veeranna V. , Porfiri E. , Martin A. , Wallace M. , James N. D.
Published: March 2020

15551

Background The aim of this study was to investigate the outcome in patients with muscle-invasive bladder cancer (MIBC) receiving neo-adjuvant chemotherapy (neo-CT) prior to organ-preservation (chemo-radiation) or cystectomy. Additional translational studies were performed. Methods Patients with stage T2-T4, N0, M0 TCC bladder with calculated GFR =40ml/min were eligible. Neo-CT comprised gemcitabine (1,000 mg/m2 d1, d8, q21) plus cisplatin (35 mg/m2 d1, d8, q21) for 4 cycles . Following chemotherapy (CT) patients underwent surgery or radiotherapy (RT) with or without chemotherapy (CRT) treatment based on response to neo-CT and clinician and patient preference. Serial blood samples were collected for proteomic analysis. Results 20 patients have been recruited : 18 males 2 females; median age 70 years (range 47–86); stage T2; 9, T3A; 7, T3B; 4, all G3. 1 patient progressed before CT. 61 cycles of CT have been administered. Treatment has been well tolerated with only 1 neutropenic sepsis episode. 3 of 20 patients developed early progression and did not receive radical treatment. For the remaining 17 patients, choice of definitive treatment (surgery vs. RT/CRT) was based on response to neo-CT. 6 patients with residual disease at post-neo CT cystoscopy underwent surgery. 11/19 (58%) patients had a complete response (CR) to neo-CT, 9 of whom were treated by RT/CRT and 2 patients with pCR declined radical treatment (both alive at 10 and 19 months follow-up (FU)). At median FU of 12 months, 3/6 patients treated surgically and 2/9 patients treated by RT/CRT have died. 1-year survival by intention to treat analysis was 70%. We have used SELDI using the IMAC protein chip array to generate proteomic profiles of the patient sera collected to date. Although the number of samples is limited, the data suggest that there are changes in the pre- chemotherapy serum proteome of 3 patients that developed early progression (relative to 8 patients with CR to neo-CT ). Conclusions Neo-CT is active and well tolerated in MIBC. Proteomic profiling may further improve patient selection. Early data show serum proteome analysis can detect markers of early progression, and may therefore help select patients for different modalities more appropriately. Recruitment is ongoing.

No significant financial relationships to disclose.
Effect of complementary alternative medical (CAM) therapy on tumor response, control and recurrence in prostate cancer patients (PCpts) treated with radiation therapy (RT)
Authors: Cain L. R. , Flynn J. , Kelly D. , Eden B. , Sumner M. , Anderson K. , Birdsall S. , Martin J. , Dounaevskaia L. , Alschuler L.
Published: March 2020

15585

Background. CAM therapy in pts receiving RT has been questioned due to possible interference with oxidative mechanisms aimed at killing tumor cells. We addressed this controversy by analyzing tumor response, control and recurrence in PCpts treated with RT + CAM. Methods. The population consisted of 125 RT-treated PCpts with localized tumors: CAM cohort (n=69; median age=62.5 yrs; range=46–81); nonCAM cohort (n=56; median age=61.0 yrs; range=48–80). For the CAM cohort, 41%, 42%, 9% and 7% had T1c, T2a, T2b and T2c tumors respectively with 1 T3b tumor; for the nonCAM cohort, 39%, 38%, 14% and 7% had T1c, T2a, T2b and T2c tumors respectively with 1 T3a tumor. RT consisted of external beam therapy (4500–5000 cGy) in conjunction with high dose rate brachytherapy (600- 650 cGy/fraction x 2–3 fractions) administered over 6–8 weeks; this occurred for 65/69 CAM and 52/56 nonCAM pts. The remaining pts received either HDR monotherapy, tomotherapy, or IMRT + tomotherapy. In addition, 5/69 CAM and 2/56 nonCAM pts received hormonal therapy. CAM regimens included at least one antioxidant (range=1–7) including Green Tea Extract; Melatonin; and high-potency multivitamins. All pts were monitored ≥ 24 months post radiation therapy. Results. In the CAM cohort, median pretreatment PSA was 5.95ng; nadir PSA was 0.08ng; and last PSA was 0.18ng with median followup of 28.96 (range=24–46) months; 3 biochemical failures were seen at 6, 10 and 12 months. In the nonCAM cohort, median pretreatment PSA was 6.4ng; nadir PSA was 0.06ng; and last PSA was 0.166ng with median followup of 28.26 (range=24–43) months; 2 biochemical failures at 13 and 28 months with 1 death at 37 months were seen. Conclusion. Concomitant CAM treatment does not effect RT-mediated tumor response, control or recurrence rates in PCpts with localized disease. Neither the magnitude of the response or its durability for at least 2 years are negatively affected by CAM-based antioxidant supplements designed to improve patient tolerance and quality of life. Investigations in well-defined populations receiving consistent CAM regimens offer the opportunity to elucidate positive benefits for patient management.

No significant financial relationships to disclose.
Enhanced orotate phosphoribosyltransferase activity in renal cell carcinoma and its prognostic significance
Authors: Mizutani Y. , Toiyama D. , Shiraishi T. , Nakamura T. , Mikami K. , Takaha N. , Okihara K. , Ukimura O. , Kawauchi A. , Miki T.
Published: March 2020

15590

Background: 5-Fluorouracil ( 5-FU ) is an anticancer agent clinically used against various cancers including renal cell carcinoma ( RCC ). 5-FU is a prodrug and orotate phosphoribosyltransferase ( OPRT ) is the principal enzyme which directly converts 5-FU to an active anticancer metabolite, 5-fluoro-2’-deoxyuridine 5’-monophosphate. Furthermore, OPRT is the key enzyme in the de novo DNA and RNA synthetic process, which converts orotic acid to orotidine 5’-phosphate. Little is known about the significance of OPRT in a variety of cancers including RCC. We investigated OPRT activity in 83 RCC and evaluated the association between OPRT activity and the stage/grade of RCC. The relationship between OPRT activity in RCC cells and their sensitivity to 5-FU was also examined. Methods: OPRT activity in non-fixed fresh frozen RCC and normal kidney were determined enzymatically by the 5-FU phosphorylation assay. The sensitivity of RCC cells to 5-FU was assessed by the microculture tetrazolium dye assay. Results: OPRT activity was approximately 8.5-fold higher in RCC compared to normal kidney. OPRT activity in T3/4 RCC was 3-fold higher than that in T1/2 RCC. OPRT activity in M1 RCC was 2.5-fold higher than that in M0 RCC. In addition, OPRT activity in Stage III/IV RCC was 3-fold higher than that in Stage I/II RCC. The level of OPRT activity in Grade 3 RCC was 3-fold higher than that in Grade 1/2 cancer. Patients with RCC with low OPRT activity had a longer postoperative disease-specific survival than those with high activity in the 5-year follow-up. OPRT activity in RCC cells positively correlated with their sensitivity to 5-FU. Conclusions: The present study has demonstrated that OPRT activity in RCC was higher than that in normal kidney, and that OPRT activity positively correlated with the stage/grade of RCC. Moreover, higher OPRT activity in RCC predicted worse prognosis and higher sensitivity to 5-FU. These results suggest that OPRT activity may be used as both a prognostic parameter and a predictive indicator for 5-FU efficacy in RCC.

No significant financial relationships to disclose.
A phase II study of the c-Met RTK inhibitor XL880 in patients (pts) with papillary renal-cell carcinoma (PRC)
Authors: Ross R. W. , Stein M. , Sarantopoulos J. , Eisenberg P. , Logan T. , Srinivas S. , Rosenberg J. , Vaishampayan U.
Published: March 2020

15601

Background: XL880 is a novel inhibitor of receptor tyrosine kinases targeting MET and VEGFR2/KDR. (IC 50 for MET 0.4nM and KDR 0.8 nM). PRC is a rare (10–15%) subtype of kidney cancer which is notoriously resistant to systemic treatment. The familial form of PRC is associated with germline activating mutations of MET, while amplification and overexpression of MET is seen in the sporadic form. In an ongoing phase I dose escalation study of XL880 in forty patients with advanced solid tumors, five partial responses (PRs) were noted in 3 of 4 treated patients with PRC, and in two pts with thyroid cancer. The MTD in this study was 3.6 mg/kg of XL880 administered orally daily for 5 consecutive days every 2 weeks. Methods: In this phase 2 study, XL880 is administered orally as a single agent at a dose of 240 mg on days 1–5 of each 14 day cycle. Previously untreated pts with a histologic diagnosis of metastatic PRC are eligible and are stratified based on the presence or absence of MET germline mutations. Planned enrollment is 15 evaluable pts in each stratum. Inclusion criteria also include ECOG performance status < 3 and absence of brain metastases. Tumor response is assessed every 8 weeks by RECIST criteria. Archival primary tumor and lymph node metastasis were collected for pharmacodynamic assessments. Results: To date, 6 pts have been enrolled and received XL880. Five pts have tested negative for MET germline mutations; results for one pt are pending. Of 3 pts with at least one post baseline tumor assessment, 1 pt has demonstrated a PR and two pts have demonstrated stable disease > 3 months, one of whom has improvement in bone scan and bone pain. Hypertension has been reported in 2 pts who responded to anti- hypertensive treatment. Two SAEs have been reported as unrelated; pulmonary embolism and intratumoral hemorrhage. MET expression was detected in untreated primary and metastatic tumor. Reduction in Ki67, and an increase in TUNEL labeling were observed in the post treatment sample. Conclusions: XL880 is the 1st orally available small molecule inhibitor of MET to enter the clinic and appears to be generally well tolerated. Anti-tumor activity has been observed and XL880 may represent an active treatment option for pts with PRC. Enrollment continues and updated results will be presented.

No significant financial relationships to disclose.
Serum prostate-specific antigen screening for prostate cancer: Analysis of the costs and benefits
Authors: Mermershtain W. , Bone D. , Shteiman T. , Ariad S.
Published: March 2020

15602

Background: PSA (prostate specific antigen) blood test used as a diagnosing aid for prostate cancer. Physicians disagree on the test performance policy and its necessity, and as a result the referring practices vary from physician to another. We examine whether the use of PSA test in General Health Services, was performed rationally, and cost effectively. Methods: Phase 1: Collection of data on all the prostate cancer patients registered at the Soroka University Medical Center until 2004 and people insured by the Clalit Health Services, that underwent PSA tests in 2002–2004. Phase 2: Cross examination of the patients’ data with data on patients undergoing the test. Phase 3: Determining the number of excessive tests (over 4 tests per person a year). Phase 4: A random study of 90 medical files of patients that underwent a PSA test. The number of references made not according to the instructions (in the files) was multiplied by the number of conducted tests (except those in phase 3), thus reaching the number of irrational tests. Phase 5: Multiplying the number of tests in phases 3–4 by the public rates of the Health Ministry for PSA tests (62 NIS). In addition, a questionnaire was distributed among primary care physicians to learn about their attitudes regarding defensive medicine. Results: In years 2002–2004, 19,418 patients underwent 25,674 PSA tests. 88.6% of the tests turned out as irrational - accumulating to a cost of 1,410,438 NIS. In the course of the recent years there is a trend of increase in the number of tests provided not according to the custom instructions, and this state of affairs suggests lack of awareness to such a high rate of irrational tests, or alternatively, awareness and failure to assign appropriate importance to the problem. Likewise, it was found that there are doctors referring patients to PSA tests as a result of defensive medicine. Conclusions: High percentage of the referrals to PSA test was provided not according to the customary instructions, and some of these referrals stems from defensive medicine. We suggest, guiding rules must be set for referring patients to PSA tests. It is necessary to update primary care doctors on the use and miss use of the tests.

No significant financial relationships to disclose.
Oncologic significance of pathologic T2 positive surgical margin in robotic-assisted laparoscopic prostatectomy
Authors: Levinson A. , Berkman D. S. , Goluboff E. T. , Samadi D. B.
Published: March 2020

15607

Background: A positive margin (PM) after radical prostatectomy (RP) in organ confined (pT2) prostate cancer (CaP) is considered a surgical error. In addition, capsular incision may occur at a higher frequency with robotic and laparoscopic techniques than with traditional open RP. However, the mechanism and significance of capsular violation may be different between open RP and Robotic Assisted Laparoscopic Prostatectomy (RALP). We sought to determine biochemical disease free survival (BDFS) for patients (pts) who underwent RALP at our institution who had a pT2 PM and compared them to those who did not. Methods: We reviewed our prospective IRB approved database for RALPs performed by a single surgeon. To permit adequate follow-up only cases prior to March 2006 were included. Biochemical failure (BF) strictly defined as any PSA >0.1ng/ml. No pt received adjuvant therapy without a BF. Results: Since Jan 2003, 435 consecutive pts underwent RALP for clinically localized CaP. 211 of these cases were before March 2006, of which 194/211 (92%) had sufficient data for analysis. Mean follow-up was 9.8 mos (range 0.7–41.6). Mean age, preoperative PSA, and path Gleason Score were 60 yrs, 6.6 ng/ml, and 6.9, respectively. Pathologic stages: pT2 77%; pT3a 13%; pT3b 7%, pT4 3%. Overall, 7.2% (14/194) experienced BF at a median of 2.5mos (0.7–15.3). BDFS rates by pathologic stage were pT2 95.3% (142/149), pT3a 91.7% (22/24), pT3b 76.9% (10/13), and pT4 71% (5/7). pT2 pts with a PM had the same rate of BF, (4.4% 1/23), as pT2 pts with negative margins (NM) (4.8% 6/126, p=0.932) and pT3 NM (0% 0/19, p=0.36), but was statistically less than pT3 PM (27.8% 5/18, p=0.035). In multiple linear regression analysis, preoperative PSA >10ng/ml was the most predictive variable of BF even after adjusting for Gleason sum, pathologic stage, and surgical margin status. Conclusions: There may be a different mechanism between a PM in organ confined open RP pts and RALP pts. In our series of RALPs, only one of 23 pT2 PM pts suffered a biochemical recurrence. BDFS for these pts was 95.7%, and did not vary significantly from pT2 NM nor pT3 NM pts. A larger series with longer follow-up will determine whether the oncologic significance of a PM in pT2 RALP pts is different than that of open RP pts.

No significant financial relationships to disclose.
Prostate weight as an independent predictor for both extracapsular extension and positive surgical margins during robotic- assisted laparoscopic radical prostatectomy
Authors: Msezane L. , Zorn K. C. , Gofrit O. N. , Steinberg G. D. , Zagaja G. P. , Lin S. , Shalhav A. L.
Published: March 2020

15608

Background: Pre-operative prediction of pathological stage represents the cornerstone of prostate cancer management. Patient counseling is routinely based on pre-operative PSA, Gleason score and clinical stage. In this study, we evaluated whether prostate weight (PW) is an independent predictor of extracapsular extension (ECE) and positive surgical margin (PSM). Methods: Between February 2003 and November 2006, 709 men underwent robotic-assisted laparoscopic radical prostatectomy (RLRP). Pre-operative parameters (patient age, pre-operative PSA, biopsy Gleason score, clinical stage) as well as pathological data (prostate weight, pathological stage) were prospectively gathered after IRB approval. Evaluation of the influence of these variables on ECE and PSM outcomes were assessed using both univariate and multivariate logistic regression analysis. Results: Mean overall patient age, pre-operative PSA and PW were 59.6 years, 6.5ng/ml and 52.9g (range 5.5–198.7g), respectively. Of the 393, 209 and 107 men with PW <50g, 50-<70g and >70g, ECE was observed in 20.1%, 15.3% and 9.3%, respectively (p=0.015). In the same patient cohorts, PSM was observed in 25.4%, 14.4% and 7.5%, respectively (p<0.001). In a multivariate logistic regression analysis, PW, in addition to pre-operative PSA, biopsy Gleason score and clinical stage, was an independent risk factor for ECE (p<0.001). Similarly, in multi-variate analysis, PW was observed to be a risk factor for PSM (p<0.001). Conclusions: PW is an independent predictor of both ECE and PSM, with an inverse relationship having been demonstrated between both variables. PW should be considered when counseling patients with prostate cancer treatment.

No significant financial relationships to disclose.
Phase I/II study of sequential-intermittent docetaxel (D) and imatinib (Im) in hormone refractory prostate cancer (HRPC) (NYU 04–47)
Authors: Lan F. , Ballard H. , Chen A. , Chachoua A. , Taneja S. , Ferrari A.
Published: March 2020

15613

Background: Platelet-derived growth factor (PDGF) is frequently expressed in advanced prostate cancer (PC) lesions where it supports PC cell growth and neo-angiogenesis. Im. is a PDGF inhibitor that blocks cell cycle progression in G1-S through inhibition of erk1–2 kinase. D. blocks cell cycle progression in G2-M. Anti-tumor responses can increase when the block to cell cycle progression in G2M precede the blocks in G1-S. This study was designed to determine tolerablity and activity of sequential D followed by Im in HRPC patients (pts). Methods: Eligibility: 2 prior hormone manipulations, any prior chemotherapy, PSA= 5 ng/ml, ECOG PS 0–2. Treatment schema: D IV day 1 followed in 24–36 hours by Im PO daily x 14 days, every 21 days until toxicity or progression. Cohorts (C) planned were: #1, D. 60 mg/m2, Im. 400 mg; #2, D 70mg/m2, Im 400 mg; #3, D 70mg/m2, Im 600 mg. Results: 12 pts enrolled: 6 in C#1, 3 each in C#2,3. Median age,73 (range: 61 to 85). Median number cycles (Cy) 3 (range: 2 to 10). Toxicity grade (TG)1–2 observed in 9 (75%) pts (6, 2, 1 in C#1, 2,3 respectively): anemia 9, neutropenia 1, lymphopenia 6, thrombocytopenia 3, hyperglycemia 8, hyponatremia 2, abnormal bicarbonate 7, hypoalbuminemia 3, fatigue 5, neuropathy 3, nausea/vomiting 3, constipation 2, pain 2, fever 2, increased creatinine 2. TG3: afebrile neutropenia, 4 pts. Cy1. TG 4: febrile neutropenia,1 pt C#1,Cy1; GI bleed/intestinal perforation, 1 pt C#3, Cy7. PSA decline =50%: 1 pt C#2; 2 pts C#3. Conclusions: sequential and intermittent dosing of D and Im was well tolerated with high doses of both drugs. The most common toxicity was neutropenia which was prevented with growth factors. The MTD was not reached. PSA responses occurred at the higher doses. An ongoing phase II study of sequential D. 70mg/m2 and Im. 600 mg x 14 days will define activity.

No significant financial relationships to disclose.
Phase II trial investigating the effects of zoledronate and dexamethasone in hormone resistant prostate cancer
Authors: Din O. , Horsman J. , James N. , Wood K. , Kirkbride P.
Published: March 2020

15629

Background: Response rates to second line therapy in hormone resistant prostate cancer have been shown to be relatively low. Current options of management include dexamethasone, zoledronate or more recently, cytotoxic chemotherapy. Many trials have studied their effects as monotherapy. The aim of this study is to assess the efficacy and safety of the combination of zoledronate and dexamethasone in these patients. Methods: 20 patients were identified in 2004–2005. All had histologically confirmed prostatic adenocarcinoma and biochemically confirmed hormone resistance. All patients had bone metastases as confirmed on radionuclide imaging. Treatment consisted of 6 cycles of zoledronate at a dose of 4 mg, given at 4 weekly intervals, in combination with dexamethasone 2–4 mg once a day. Calcium/vitamin D supplementation was given throughout the zoledronate treatment. Data was collected prospectively on serum PSA, quality of life and pain score. Results: Of the 20 patients in the study, 11 completed the full 24 weeks of treatment. Reasons for not completing the study included disease progression, treatment toxicity, fracture and death. The overall response rate, as defined by an initial fall of serum PSA of more than 50%, was 35% (7 out of 20 patients). In those who responded, the sustained fall in PSA, during the trial period, lasted on average 3.0 months. Conclusion: This study has demonstrated clinically significant effects on tumour response for the combination of zoledronate and dexamethasone in hormone resistant prostate carcinoma. With the emergence of newer chemotherapeutic agents, this combination could be used as an effective, but less toxic alternative.

No significant financial relationships to disclose.
Deleted In Cancer 1 (DICE1): Search for a function in prostate carcinoma (PCa)
Authors: Filleur S. , Wieland I. , Nelius T. , Kennedy R. , De Riese W. , Wieacker P.
Published: March 2020

15634

Background: Recently, DICE1 gene (MIM 604331 ) was identified to colocalize with the microsatellite marker D13S284 in 13q14.3, a region frequently affected by allelic deletion in PCa. We previously showed that DICE1 mRNA expression is down-regulated in PCa cell lines compared to normal prostate tissue, due to DICE1 promoter hypermethylation; suggesting that DICE1 is a tumor suppressor gene. Methods: Human PCa cell lines PC3 and DU145 were lipo-transfected with mammalian expression plasmids encoding for the full length DICE1 gene or for its N- (APAI construct) and C-terminal (DEAD construct) fragments. The constructs expression was determined by semi-quantitative PCR and quantified by Real-time PCR. Clonogenic formation and apoptotic assays were performed. Results: The PCR analysis showed that the expression of DICE1, APAI and DEAD domains in transfected PC3 and DU145 cell lines was increased 30.6, 75.2 and 27.9 fold in PC3 cells and 4.3, 5 and 2.5 fold in DU145 cells, respectively, compared to non-transfected cells. The function analysis showed that the ectopic expression of DICE1 suppressed clonogenic growth of PC3 and DU145 cell lines. Surprisingly, we showed that like DICE1, DEAD and APAI inhibit the PC3 and DU145 clonogenic growth suggesting that both regions are involved in prostate tumor growth inhibition. The apoptosis assay could not show any DNA fragmentation activity for DICE1. Conclusions: We demonstrated that DICE1 is a tumor suppressor in PCa. DICE1 mRNA expression is down-regulated in PCa cell lines compared to normal prostate tissue and its ectopic expression in PCa cell lines inhibits their capacity to form clonogenic colonies in vitro. The functional analysis could not reveal any role of DICE1 in PCa apoptosis, suggesting that other molecular mechanisms are involved.

No significant financial relationships to disclose.