bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary results of phase II study of irinotecan and capecitabine combination as first line chemotherapy for advanced and metastatic gastric cancer
Authors: Farhat F. , Bachour M. , El Seoudi M. , Kattan J. , Ghosn M. , Nasr F. , Moukadem W. , Younes F. , Mroueh R. , Chahine G.
Published: March 2020

14030

Background: Chemotherapy has a proven palliative role in advanced gastric cancer. The most widely investigated single-agent chemotherapy is 5-fluorouracil with partial response rates up to 20%. Single-agent irinotecan achieved response rates of 18%-23%. We investigated the combination Irinotecan plus Capecitabine for previously untreated locally advanced or metastatic gastric cancer. Methods: We conducted a phase II study with the combination of Irinotecan 80 mg/m2 on day 1, 8, and 15, and capecitabine 625 mg/m2 twice daily on days 1 to 14 repeated every 4 weeks. Patients were evaluated every second cycle. Previous chemotherapy for metastatic disease was not allowed. Patients must have measurable disease, ECOG PS < 2, life expectancy > 2 months, adequate hematological, liver and renal functions. Response was evaluated according to RECIST and toxicities according to NCI common toxicity criteria 3.0. Results: Between February 2002 and December 2005 31 patients were enrolled (20 male and 11 female). The median age was 57 years [range 37–74 years]. 142 cycles were administered with a median of 4.6 cycles per patient [range 1–10 cycles]. 29 patients were evaluable for response, and two are on ongoing treatment. Partial response rate was 38.5% . 9 patients (29%) had stable disease. Overall tumor control rate was 67.5%. Median time to progression and overall survival were 5.8 months [range- 1–16] and 10.58 months [range- 1–21] respectively. There was no grade III-IV reported toxicity including no hand and foot syndrome. Conclusions: Irinotecan and capecitabine in combination show an interesting tumor control rate (67.5%) with extremely well tolerated toxicity in patients with extensive gastric cancer.

No significant financial relationships to disclose.
Multicenter phase II study of pemetrexed and oxaliplatin as first-line therapy in advanced gastric cancer
Authors: Celio L. , Sachetta S. , Mosconi S. , La Torre I. , Barone C. , Berardi R. , Amoroso V. , Pinotti G. , Di Costanzo F. , Bajetta E.
Published: March 2020

14045

Background: We have previously reported that single-agent pemetrexed is active in metastatic gastric cancer. On the basis of the potential synergism of pemetrexed and oxaliplatin, we explored the combination in patients with locally advanced/metastatic gastric carcinoma. Methods: The primary objective was activity of the combination. Eligible patients had to ≥1 measurable lesion according to RECIST. Pemetrexed 500 mg/m2 was given intravenously over 10 minutes, and oxaliplatin 120 mg/m2 was given over 2 hours; both drugs were given on day 1 of a 21-day cycle. Patients were to receive ≥6 (maximum of 8) cycles unless disease progression occurred. Vitamin supplementation was given as well as dexamethasone. A total of 43 patients were planned in a two-stage design with 13 patients in the first stage. An interim analysis was planned at the end of the first stage, so the trial could be stopped if ≤3 responses were observed. Results: Between May 2004 and January 2005, 13 patients (6 females) entered the study. Median age was 52 years (range, 27–75). One patient (7.8%) had locally advanced disease, and 5 patients (38.5%) retained primary gastric cancer. Main disease sites included lymph nodes (100%) and liver (23.1%). A total of 60 cycles were administered (median 6; range, 2–6). All 13 patients were evaluable for efficacy with 3 complete and 2 partial responses (ORR 38.5%; 95% CI, 13.9%-68.4%). Stable disease occurred in 3 patients (23.1%). G3 toxicities were neutropenia (30.8%), vomiting, hepatic toxicities and leucopenia (7.7%) each; no G4 toxicity were found. Conclusions: This interim analysis suggests that the activity and tolerability of the combination in advanced gastric cancer is very promising. Study accrual was ended in October 2005, and final results will be presented at the meeting.

No significant financial relationships to disclose.
Phase II study of cisplatin, epirubicin, oral UFT, and leucovorin as first-line chemotherapy for metastatic gastric cancer
Authors: Idelevich E. , Karminsky N. , Dinerman M. , Katsenelson R. , Ben Zvi N. , Ben Baruch N. , Man S. , Shani A.
Published: March 2020

14049

Background: A phase II study was conducted to assess the efficacy and tolerability of combination therapy with cisplatin, epirubicin, oral UFT and leucovorin in patients (Pts) with metastatic gastric cancer. Methods: Pts with previously untreated metastatic or unresectable measurable gastric adenocarcinoma received cisplatin 60 mg/m2 and epirubicin 50 mg/m2 on day (d)1, UFT 300 mg/m2 was administered in conjunction with oral leucovorin 30 mg/day in divided daily doses d 1–22, followed by a 7-day rest period. Results: Thirty-nine pts were enrolled in this study. Two achieved a complete response and 13 a partial response, giving an overall response rate of 38.5%. Disease stabilization was achieved in further 16 pts (41%). Median time to progression and median survival were 6.4 and 10.7 months respectively. Grade 3/4 neutropenia, anemia, throbocytopenia, occurred in 10%, 5%, and 2% of pts respectively, and febrile neutropenia occurred in 7 pts (one episode each). Grade 3 diarrhea occurred in 5% of the pts. There were no treatment related deaths. Conclusions: Cisplatin, epirubicin, and oral UFT plus leucovorin, a convenient outpatient regimen, has significant activity and tolerable toxicities in pts with metastatic gastric carcinoma.

No significant financial relationships to disclose.
Adjuvant chemoradiotherapy for gastric adenocarcinoma: Kaiser institutional experience with INT 0116
Authors: Kerwin T. L. , Miller M. J. , Tome M. A.
Published: March 2020

14114

Background: The standard of care for resectable gastric or gastroesophageal adenocarcinoma is total or partial gastrectomy followed by adjuvant chemoradiotherapy as defined by the Intergroup 0116 study. We have reviewed our institutional experience with this regimen in hopes of defining patient subsets which are most likely to benefit, as well as those who are least likely to benefit, such that alternative therapies may be recommended. Methods: A retrospective review was conducted for 38 consecutive patients treated for gastric or gastroesophageal adenocarcinoma with total or partial gastrectomy followed by chemoradiotherapy. Chemotherapy was with 5-FU 425 mg/m2/day and Leukovorin 20 mg/m2. Radiotherapy was with 45 Gy in 25 fx delivered through AP-PA fields or a 3-field technique, at the discretion of the treating physician. Results: The median patient age is 55 years old. The median follow-up is 29 months. There were 14 D0 resections, 21 D1 resections, and 3 D2 resections. The number of patients with N0, N1, N2, and N3 disease are respectively 4, 20, 11, 3. One patient did not complete treatment due to disease progression. There were positive margins in 8 patients. Four patients developed fatal treatment-related complications. Median overall survival for patients with positive margins is 19 months and for negative margins is 34 months. Median overall survival for N0/N1 patients is 36 months and for N2/N3 patients is 22 months. Eighteen patients recurred at a median of 14 months - 5 locally, 9 regionally in the abdomen, and 4 distantly. Death occurred in 16/18 recurrences. Conclusions: The overall survival of patients in this study is consistent with previously-reported data. The adequacy of surgical resection is relevant as it affects nodal staging. Positive margin status and advanced nodal involvement are predictors for poor outcomes, indicating that alternative therapies may be more appropriate for these patients given the potential toxicity of the current recommended treatments.

No significant financial relationships to disclose.
Automatic segmentation of pancreatic images using ISODATA alorithm
Authors: Biswal B. , Shah N. , Shah N. , Trivedi M. , Nayak S. , Dave H.
Published: March 2020

14149

Background: Pancreatic cancer is the second most common gastrointestinal malignancy in the United States, where it ranks 4th among all deaths caused by cancers. Early detection of pancreatic cancer remains a challange. Methods: MR images with different T1 and T2 weighting from the anatomical regions with the same imaging parameters were obtained. ISODATA segmentation algorithm, a multivariate method was used to reliable detect the various clusters in the data sets. Results: In all the four subjects, the pancreatic region was found to be from a different (and unique) cluster. This cluster covered the pancreatic region in all the four subjects. Conclusions: The ISODATA algorithm presented could detect the pancreatic region without manual tracing.

No significant financial relationships to disclose.
Gemcitabine-based transcatheter arterial chemoembolization for unresectable cholangiocarcinoma in thirty-eight patients: Single institutional experience
Authors: Gamblin T. C. , Geller D. A. , Marsh J. W. , Carr B.
Published: March 2020

14152

Background: Survival for patients with unresectable cholangiocarcinoma is reported to be 5–8 months. Systemic chemotherapy has been disappointing and not shown to significantly improve survival. Transcatheter arterial chemoembolization (TACE) has been shown to prolong survival in hepatocellular carcinoma patients but experience with cholangiocarcinoma is limited. We report our experience with the well-tolerated drug gemcitabine. Methods: Thirty-eight patients with unresectable cholangiocarcinoma were treated with one or more cycles of gemcitabine-based TACE between 2001 and 2005 at our institution. Follow-up imaging was performed on all patients after each TACE procedure. Regimens of TACE included: gemcitabine only (16), gemcitabine followed by cisplatin (2), gemcitabine followed by oxaliplatin (5), gemcitabine and cisplatin (12), and gemcitabine and cisplatin followed by oxaliplatin (3). Actual survival is reported, as 35 of 38 have died from disease (92%). Results: Patients were 57.5 years of age (range 36–87) and a median of 3 treatments (range 1–10) were administered. Median survival from time of first treatment was 10.3 months. Patients receiving gemcitabine followed by cisplatin or oxaliplatin had improved survival (mean 16.5 and 10.5 months respectively) when compared to gemcitabine alone (mean 6 months). Patients receiving gemcitabine and cisplatin as a combination had improved survival (mean 13.4 months) compared to single agent gemcitabine. Patients who progressed on gemcitabine and cisplatin and then received oxaliplatin also showed improved survival (mean 14.3 months) compared to gemcitabine only. Neutropenia, thrombocytopenia and hyperbilirubinemia were the most common toxicities observed. Three patients in the entire series exhibited grade 3 thrombocytopenia while seven patients had grade 3 and one had grade 4 bilirubin levels. Conclusions: This series provides evidence in favor of TACE rather than historically reported alternatives such as systemic chemotherapy or chemotherapy/RT. Our results suggest that gemcitabine based TACE is well tolerated and perhaps best delivered as a combination therapy for patients with unresectable cholangiocarcinoma.

No significant financial relationships to disclose.
Magnetic resonance imaging of the bone marrow (MRBM) as an outcome measure for patients with metastatic prostate cancer
Authors: Gignac G. A. , Morris M. J. , Schwartz L. H. , Lis E. , Scher H. I.
Published: March 2020

14521

Background: Previously we have shown that the distribution of osseous metastases in prostate cancer (PC) matched the distribution of the normal adult marrow. Over 90% of advanced PC patients have disease in bone. Imaging the marrow has the potential to allow detection of metastases before osseous response has occurred and provides a three dimensional volumetric measure that can be quantified and monitored serially for changes over time. We are examining the use of MRBM as an indicator of treatment effect in patients with metastatic PC. Methods: Patients with PC and 2 or more MRBM surveys were identified and extracted from a database of all patients at MSK who have had radiologic studies. Cases were further identified on the basis of having metastatic disease, followup MRBM within 4–7 months, concurrent PSA and bone scans. MRI reports were stratified as either “progression” or “stable/improved” assuming a clinician would change therapy if progression was documented. PSA was similarly recorded, using a definition of ≥ 25% increase from baseline to indicate progression. Bone scans were stratified on the basis of new lesions verses no new lesions. Results: Twenty-five patients were eligible for review with a median baseline PSA of 7.34 ng/ml (0.05–473 ng/ml). Average percent change of PSA at followup was 651% (0–11033%). Treatment included: hormones (11), chemotherapy (5), calcitriol (4) and observation (5). The change in MRBM was concordant in 73% of patients with progression by PSA. These results are demonstrated below in the Table. Conclusions: MRBM is a novel means to assess metastatic disease to bone. This preliminary analysis suggests that MRBM can be early indicator of treatment failure. We plan to explore it prospectively as an outcome measure for PC using a lesional analysis. Grant Support: PEPSICO, PCF, NCI 102544, CA102544 and 5T32CA09207. [Table: see text]

[Table: see text]
Long-term survival following nephrectomy for renal cell carcinoma: The 15 year University of California-Los Angeles experience
Authors: Lam J. S. , Goel R. H. , Pantuck A. J. , Figlin R. A. , Belldegrun A. S.
Published: March 2020

14532

Background: Significant advances in the diagnosis, staging, and treatment of patients with renal cell carcinoma (RCC) during the last 2 decades have resulted in improved survival of a select group of patients and an overall change in the natural history of the disease. We describe the pathologic characteristics and long-term survival in patients treated for localized and metastatic RCC at a single tertiary care institution. Methods: Between 1990 and 2005, 1431 patients diagnosed with a renal mass underwent surgical resection and were evaluated for differences in clinicopathologic characteristics and survival based on the University of California-Los Angeles Integrated Staging System (UISS). Data were analyzed using standard statistical methods. Results: Following surgical resection, RCC was found in 1269 patients at pathologic evaluation. Of these patients, 473 had evidence of metastatic dissemination at time of surgery. The primary tumor in patients with metastatic disease was more likely to be clear cell (78.8% vs. 72.9%, p = 0.02), collecting duct (1.3% vs. 0.1%, p = 0.01), or undifferentiated (4.8% vs. 1.6%, p = 0.002) RCC, and less likely to be papillary (12.0% vs. 18.7%, p = 0.002) or chromophobe (3.1% vs. 6.7%, p = 0.006) RCC compared to patients with non-metastatic disease, respectively. The 2-year, 5-year, and 10-year survival was significantly higher in non-metastatic patients compared to patients with metastatic disease present at time of surgery (87.0% vs. 42.4%, 70.0 vs. 21.8%, 50.0% vs. 16.5%, p < 0.001, respectively). Conclusions: Over the last 15 years, patients with non-metastatic disease at the time of surgery have improved survival rates and are more likely to have papillary or chromophobe primary tumors than patients with metastatic disease. UISS stratification of patients with RCC provides a unique tool for risk assignment and outcome analysis to help determine follow-up regimens and eligibility for clinical trials. [Table: see text]

No significant financial relationships to disclose.
Biomarkers and obesity in surgically treated patients with prostate cancer
Authors: Shazer R. , Bharne A. , Nepomuceno E. , Mirocha J. , Ramirez C. , Luthringer D. , Holden S. , Agus D. B. , Gross M.
Published: March 2020

14536

Background: Obesity is associated with poor outcomes in prostate cancer (PC). We explored if biomarkers for proliferation and estrogen signaling relate to obesity and surgical outcomes in PC patients (pts) treated by radical prostatectomy (RP). Methods: Pts with RP at a single institution between 1993 and 2002 were reviewed (1156 pts). The analysis subset included pts with full preoperative staging and anthropometric variables (541 pts). Clinical variables examined included: age, PSA, pre-operative hemoglobin (Hgb), ethnicity, and body mass index (BMI). Surgical outcomes included: estimated blood loss (EBL), Gleason score ≥ 7 (GS >7), extra-capsular extension (ECE), positive margins (MR+), and pathologic stage (pT2 vs. pT3/T4). Biomarkers examined in a convenience subset (n = 61) included proliferation index (Ki67% in cancer cells) and ERα positivity (nuclei staining ≥5% in cancer or peri-tumoral stromal cells). Obesity was defined as BMI ≥ 30 kg/m2. A step-wise logistic regression analysis was used to determine odds ratio (OR) in relation to obesity. Results: Mean ± standard deviation for pre-operative data included: age 62.7 ± 7.5 yrs; PSA 8.4 ± 6.8 ng/dl; Hgb 13.6 ± 1.8 g/dl; and BMI 26.5 ± 3.8 kg/m2. Pt reported ethnicities included: white (432 pts), Black/African-American (69 pts), Asian/Pacific Islander (20 pts), Hispanic (16 pts). BMI correlated highly with race (Kruskal-Wallis p = 0.002) and weakly with EBL (Spearman 0.11, p = 0.009) and Hgb (Spearman 0.15, p = 0.002). No correlation was observed between obesity and Gleason score. Regression models showed obesity was independently associated with ECE (OR 2.5, 95% CI 1.2–5.3) and pT3/T4 (OR 1.9, 95% CI 1.0–3.3). Biomarker analysis showed Ki67% correlated with GS >7, (Spearman 0.25, p = 0.048), but not BMI. No ERα positivity was noted in cancer cells. Stromal ERα positivity was noted in 21/30=70% of non-obese and 15/31=48% of obese pts (Fisher’s exact test p = 0.12). Conclusion: We confirm the association between obesity, ethnicity, and poor surgical outcomes. Biomarker analysis shows that obesity has no effect on proliferation index or tumor grade. However, we observe a trend towards down-regulation of stromal ERα expression in obese patients.

No significant financial relationships to disclose.
Pre-biopsy PSA and biopsy gleason sum; evaluating the independence of two independent variables
Authors: McCann T. , Pierorazio P. M. , Mitchell R. , Desai M. , Olsson C. A. , Benson M. C. , McKiernan J.
Published: March 2020

14555

Background: Traditionally PSA, Gleason sum and Clinical Stage are considered independent predictors of outcome for prostate cancer. The purpose of this study is to investigate a codependence between prostate specific antigen (PSA) and Gleason sum and whether this relationship has evolved during the PSA era. Methods: The Columbia Urologic Oncology Database was reviewed and 2,522 patients were identified who underwent radical prostatectomy from 1988 to 2005; a retrospective cohort of 1,786 patients with complete data was included. Patients were stratified by Gleason sum into groups with Gleason sum <7, =7 and >7. PSA was correlated to Gleason sum to examine a possible relationship between the two variables. Two-sample t-tests with 95% confidence intervals were utilized to determine differences between groups and were confirmed by ANOVA techniques. A Cox regression model using an interaction term between PSA and Gleason sum was fit to determine if an interaction exists between the two variables. Patients were further stratified into two cohorts by median year of surgery (1998) and the PSA-Gleason sum relationship was evaluated over time. Results: Median patient age was 61.9 years. 1,081 patients were identified with Gleason sum <7. 540 patients had a Gleason sum =7. 165 patients had a Gleason sum >7. The mean PSA values were 6.05, 6.89 and 8.41 for <7, =7 and >7 groups respectively. Differences between the means were statistically significant and validated by the ANOVA technique (p < 0.001). A Cox regression model validated PSA, Gleason sum and clinical stage as independent predictors of outcome. The addition of an interaction term into the Cox regression model between PSA and Gleason sum demonstrated a significant interaction effect between PSA and Gleason sum (p < 0.001). The relationship remained between PSA and Gleason sum within the pre and post 1998 groups (p < 0.001). Conclusions: PSA and Gleason sum are highly interrelated variables, although they each carry additional information that significantly contributes to the prediction of biochemical failure (PSA ≥0.2 ng/ml). For an individual patient, the higher the initial PSA the higher the risk of having a high Gleason sum on biopsy. This relationship has remained constant over the PSA era.

No significant financial relationships to disclose.
Cisplatin versus carboplatin-based chemotherapy in inoperable or recurrent urothelial carcinoma: A retrospective analysis
Authors: Bamias A. , Kastritis E. , Bozas G. , Koutsoukou V. , Antoniou N. , Katsifotis H. , Konstantinidis K. , Skolarikos A. , Deliveliotis C. , Dimopoulos M. A.
Published: March 2020

14558

Background: Cisplatin-based chemotherapy represents the standard for patients with inoperable or recurrent urothelial carcinoma. Carboplatin-based chemotherapy is reserved for not-fit-for-cisplatin patients. Recent data suggest that carboplatin-based chemotherapy may be effective in fit-for-cisplatin patients. We examined the differences in the outcome according to the compound used as first-line treatment. Methods: We selected patients who received first-line combination chemotherapy based on cisplatin or carboplatin. The major end point was survival. Survival curves were estimated with the Kaplan-Meier method, while cox regression analysis was used for multivariate models. Results: 445 patients, treated with cisplatin (330) or carboplatin (115)-based chemotherapy were included in this analysis. After a median follow-up of 52 months, there was no significant difference in survival between the two treatment groups (Table). Subgroup analyses according to PS, distant metastases, Hb, weight loss, showed that the use of cisplatin was independently associated with improved survival only in the PS 2,3 subgroup (see Table). When patients were stratified according to the Bajorin prognostic criteria (PS 0,1 vs. 2,3 and/or distant metastases yes vs. no; J Clin Oncol 1999, 17: 3173), again cisplatin-based chemotherapy was associated with a trend towards improved outcome only in the worst prognostic group (Table). Conclusions: Carboplatin-based chemotherapy may be equally effective to cisplatin-based treatment in patients with inoperable or recurrent urothelial cancer and no or one adverse factors. Cisplatin-based treatment may be beneficial in patients with poor prognosis. Nevertheless, the clinical relevance of this superiority is limited due to the poor outcome and the poor tolerance of cisplatin-based combination chemotherapy in this group of patients. (see Table) Median survival (95% CI) after first-line chemotherapy for advanced urothelial carcinoma. [Table: see text]

No significant financial relationships to disclose.
A phase II report of longitudinal bone marker time trends in racially diverse prostate cancer patients receiving zoledronic acid with androgen deprivation
Authors: Phooshkooru V. R. , Spencer H. J. , Kohli M.
Published: March 2020

14568

Background: Evidence for preventing androgen deprivation (AD) induced osteoporosis with bisphosphonate therapy in prostate cancer patients has emerged largely from trials conducted in caucasian patients. Osteoporosis related skeletal event incidence in African Americans (AA) receiving AD is significantly lower than caucasians and the effect of bisphosphonates therapy uncertain. We conducted a prospective study to evaluate the efficacy of zoledronic acid in preventing osteoporosis in racially diverse population receiving AD. Methods: Asymptomatic, prostate cancer patients (16 caucasians and 6 AA) with normal renal function undergoing AD, started within the last 9 months were randomized to receive (Arm A) CaCO3/vitamin D (500 mg/200U TID) or (Arm B) CaCO3/vitamin D and zoledronic acid (4 mg IV every 3 months for a year). Bone turnover markers including urine N-telopeptide, serum osteocalcin, serum bone specific alkaline phosphatase(BsAP) were serially measured every 3 months and bone mineral density (BMD) measured by DXA at hip, femur, spine and ward’s triangle at 0, 6 and 15 month intervals. Primary endpoint was to obtain BMD changes and bone turnover rates for each treatment arm. Nonparametric methods for analyzing longitudinal data were used to compare DXA-derived BMD measures and bone turnover rate markers in patients receiving zoledronic acid to the control group. Results: Data is presented for 16/22 patients who have completed 15- month follow up. Time trend analysis of bone formation (BsAP, osteocalcin) and resorption (N-telopeptide) markers and DXA measurements of BMD (spine and hip) are shown in the table. Conclusions: This study suggests that zoledronic acid preserves BMD at spine in racially diverse patients and, likewise provides preliminary estimates of BMD changes that occur over 15 months in patients receiving zoledronic acid and placebo. Larger AA cohorts are needed for prospective validation of the observed effect with zoledronic acid. [Table: see text]

[Table: see text]
A plasmid DNA vaccine encoding prostatic acid phosphatase (PAP) elicits antigen-specific T cells in patients with stage D0 prostate cancer
Authors: McNeel D. G. , Dunphy E. J. , Johnson L. E. , Frye T. P. , Staab M. J. , Horvath D. L. , Straus J. , Alberti D. , Liu G. , Wilding G.
Published: March 2020

14570

Background: Prostatic acid phosphatase (PAP) is a tumor antigen in prostate cancer. Clinical trials conducted in patients with metastatic prostate cancer targeting PAP by means of antigen presenting-cell vaccines have suggested clinical benefit in terms of disease progression and overall survival. Ultimately, tumor vaccines may be most effective in the setting of minimal residual disease. We have been investigating plasmid DNA vaccines encoding PAP in rodent models. We found these to be safe and effective in eliciting PAP-specific CD8 T cells and saw evidence of anti-tumor efficacy. We report here the initial immunological results from a dose-escalation portion of a phase I trial testing a DNA vaccine encoding PAP in patients with minimal residual stage D0 prostate cancer. Methods: Patients with clinical stage D0 prostate cancer with rising PSA were vaccinated over a 12-week period, 6 times at 14-day intervals, with a plasmid DNA vaccine encoding PAP (pTVG-HP). Vaccinations were administered intradermally with 100 mcg, 500 mcg, or 1500 mcg doses, and with 200 mcg of GM-CSF co-administered as a vaccine adjuvant. Immunological responses were evaluated by antigen-specific T cell proliferation and IFNγ secretion, and by ELISA for PAP-specific IgG. Results: At present 9 patients have been enrolled in a dose-escalation portion of the trial, and 6 have completed all immunizations. No serious adverse events have been observed, and no patients have discontinued treatment. To date, immunological analysis has been performed for the first, lowest dose cohort. PAP-specific CD4 and CD8 T cell responses, measured by antigen-specific T cell proliferation, were elicited following immunization in 2 of 3 patients. PAP-specific IgG antibodies were not detectable in these patients following vaccination. Conclusions: Intradermal immunization of patients with stage D0 prostate cancer with pTVG-HP has been without evidence of adverse events in doses up to 500 mcg. CD4 and CD8 T cell responses have been observed, consistent with a predominantly cellular immune response, at even the lowest dose of vaccine. Immunological analysis will be performed for patients completing the other dose levels, and all patients will be followed for changes in serum PSA levels.

No significant financial relationships to disclose.
Prognostic factors for patients with metastatic urothelial carcinoma treated with cisplatin and 5-fluorouracil-based regimens
Authors: Tsai Y. , Lin C. , Hsu C. , Huang K. , Huang C. , Cheng A. , Vogelzang N. J. , Pu Y.
Published: March 2020

14583

Background: Combination of cisplatin and 5-fluorouracil (5-FU) has activity in metastatic urothelial carcinoma (UC). To identify patient subgroups most likely to benefit and compare survival to that in previously described patient series, long-term survival, as a function of known and suspected prognostic variables, was determined. Methods: The survival status of 79 patients with metastatic urothelial cancer treated on two phase II trials of cisplatin and 5-FU-based regimens was updated. P-HDFL regimen (n = 35) was cisplatin 35 mg/m2 IV 24hr D1, 8; 5-FU 2,600 mg/m2 and leucovorin 300 mg/m2 IV 24hr D1, 8, 15; repeated every 28 days (Cancer 2006, in press). TP-HDFL regimen (n = 44) was paclitaxel 70 mg/m2 IV 1hr D1, 8; cisplatin 35 mg/m2 IV 24hr D1, 8; 5-FU 2,000 mg/m2 and leucovorin 300 mg/m2 IV 24hr D1, 8; repeated every 21 days (Proc ASCO 22:407b, 2003 [abstr 1637]). Univariate and multivariate Cox proportional hazards models were constructed. Results: Karnofsky performance status (KPS) <80%, presence of visceral metastasis, and alkaline phosphatase ≥220 U/l are three significant poor prognostic factors for survival. The percentage of patients who harbored zero-risk, one- or two-risk, and three-risk categories was 27%, 61%, and 13%, respectively. Among patients with no risk factors, the median survival time was not reached yet after a median follow-up of 43.0 months. Patients with one or two risk factors had a median survival duration of 12.3 months (95% CI 8.6–16.0). Patients with all three risk factors had a median survival of 4.6 months (95% CI 1.4–7.9). There was a significant difference in survival between the three groups (P < .0001). Conclusions: Previously described prognostic factors, including KPS <80%, visceral metastasis, and alkaline phosphatase ≥220 U/l, for survival in metastatic UC were confirmed in patients treated with cisplatin and 5-FU-based regimen.

No significant financial relationships to disclose.
Clinical course of patients with metastatic papillary renal cell carcinoma
Authors: Steiner T. , Roigas J. , Kirchner H. , Doehn C. , Heynemann H. , Siebels M. , Loening S. , Jocham D. , Fornara P. , Rohde D. , Stieff C. G.
Published: March 2020

14591

Background: For a long time it has been discussed, whether patients (pts.) with metastatic papillary renal cell carcinoma (mRCC pap) demonstrate different behaviour compared to those with clear cell mRCC. Methods: Clinical data of 61 pts. with mRCC pap were retrospectively assessed at 8 treatment centres. Results: Median follow-up was 20 (1–114) months, median age at time of diagnosis was 62 (24–85) years. Men were affected predominantly (50/61 pts.; 82%). 21 pts. (34%) showed metastases at time of diagnosis. The remaining 40 pts. had metachroneous metastatic disease. Mean time to metastases development was 30.4 (3–143; median 16.5) months. Metastatic sites were: lung (37; 61%), bone (24; 38%), liver (20; 33%), lymph nodes (24; 38%). Local recurrences occurred in 17 pts. (28%). Others sites of metastatic disease were brain in 6 pts. (10%), peritoneal carcinosis in 5 pts. (8%) and others. A surgical approach was performed primarily in 11 pts. (18%): lung 2; local recurrence and lymphomas 7; liver 1; brain 1. 26/61 pts. with metastatic disease received an immuno- (interferon-a ± interleukin-2) or immunochemotherapy (in combination with vinblastine or 5-fluorouracile) as first line treatment. In total, 42/61 pts. (69%) received an interferon- or interleukin-based immunotherapy. No treatment at all was performed in 12 pts. (20%) because of poor performance status. 5/42 pts. (11.4%) achieved an objective response to immuno(chemo)therapy. In the Kaplan-Meier-analysis, median overall survival after diagnosis of metastatic disease was estimated to be 13 ± 1.5 (95% CI 9.9–16) months for the entire study group and 12 ± 2.5 (95% CI 7.1–16.3) from the beginning of systemic treatment. Conclusions: Clinical data of a large population of pts. with mRCC pap have been assessed in this retrospective analysis for the first time. Compared to pts. with clear cell mRCC, these patients are characterized by: I) more frequent local recurrences; II) lower remission rates to immuno(chemo)therapeutic approaches; III) poorer prognosis with regard to overall survival. These findings should be taken into account when planning future studies.

No significant financial relationships to disclose.
The biologic therapy of prostate cancer using plasminogen activator inhibitor-1 (PAI-1)
Authors: Chen S. , Henry D. O. , Wong M. K.
Published: March 2020

14596

Background: Treating prostate cancer through the expression of intrinsic biologic modifiers is a relatively unexplored aspect of prostate cancer therapy. Plasminogen Activator Inhibitor-1 (PAI-1) is expressed at low levels in prostate cancer cells. PAI-1 is both an anti-angiogenesis agent, and also potently inhibits tumor proteases responsible for tumor invasion and metastases such as uPA and tPA. Thus we hypothesized that stimulation of tumor endogenous PAI-1 would result in a particularly powerful and profound prostate cancer regression. We present proof-of-concept from our experimental models that demonstrate significant tumor regression in experimental prostate tumors and supports this hypothesis. Methods and Results: Human prostate adenocarcinoma (PC3 cell line) xenograft tumors engineered to conditionally express either PAI-1 or Green Fluorescent Protein (GFP, control) were used to test our hypothesis. Stable cell lines were created that conditionally express either GFP or PAI-1 under the regulation of a doxycycline-responsive promoter (Tet-On). Thus gene expression is switched on in the presence of doxycycline. PC3 tumors were inoculated and allowed to reach at least 200 mm3 in size whereby the tumor-bearing mice were given doxycycline-doped drinking water. Genes were significantly turned on within 48 hours as monitored by the appearance of a GFP signal in control mice. The induction of PAI-1 results in significant inhibition of tumor growth as compared to GFP control. Importantly, in vitro induction of PAI-1 expression in PC-3 has no direct effects on cell growth as compared to any PC-3 control. Histological analysis of these tumors revealed a rich nexus of fine angiogenic vessels at the interface between control tumors and surrounding stroma. PAI-1 secreting tumors were significantly smaller and were pale, bland, and lacked peritumoral vessels. Protease activity measured by in-situ zymography directly on these tumors revealed that this was significantly reduced in PAI-1 expressing tumors as compared to GFP controls. Conclusion: PAI-1 expression results in tumor inhibition through direct anti-angiogenic effects and inhibition of tumor protease activity.

No significant financial relationships to disclose.
Use of zoledronic acid (ZA) and interleukin-2 (IL-2) to activate and expand Vγ9Vδ2 T cells for therapeutic use in patients with metastatic renal cell carcinoma (mRCC)
Authors: Malkovsky M. , McNeel D. G. , Wallace M. , Schell K. , Wilding G. , Eikhoff J. , Staab M. J. , Horvath D. , Straus J. , Liu G.
Published: March 2020

14607

Background: Approximately 3–6% of human peripheral blood lymphocytes express the γδ T cell receptor (TCR). The majority of these cells express the Vδ2 TCR variable segment associated with the Vγ9 segment. Vγ9Vδ2 T cells can recognize phosphorylated nonpeptidic microbial metabolites and alkylamines. This recognition of phosphorylated molecules requires neither antigen uptake/processing, nor MHC class I/II expression, allowing for a rapid response to immune challenge. Aminobisphosphonates are a class of agents capable of activating human Vγ9Vδ2 T cells. Here we conduct a study using ZA with low-dose IL-2 in order to augment Vγ9Vδ2 T cells for therapeutic use in mRCC. Methods: Patients with immunotherapy naïve mRCC were treated with ZA (4 mg IV d1) with IL-2 (ranging from 1–7 MU/m2 SQ days 1–5, repeated weekly × 3, in 4 week cycles). Blood was collected at various timepoints between day 1 and 15 of the first cycle of therapy to assess the relative frequency, proliferative capacity, and cytolytic activity of each subjects’ Vg9Vd2 T cells. Clinical responses were assessed using RECIST criteria. Results: To date, 7 patients have received treatment on protocol. No objective clinical responses were observed by RECIST criteria but prolonged stable disease (with one minor response) was observed in 2 patients (on study for 280 and 224 days respectively) on this trial. A relative increase in Vγ9Vδ2 T cell frequency could be detected by day 8 of therapy including one patient with an increase in Vγ9/Vδ2 positive T cells from 9.6 to 19.4%. Results of the change in Vγ9Vδ2 T cell frequency, proliferative capacity, and cytolytic activity against RCC cell lines will be presented in detail. Conclusions: Modest amplification of Vγ9Vδ2 T cell frequency was seen; however, not to the degree appreciated in preclinical models. At present, we are planning a dose-titration of ZA with fixed dosed IL-2 in order to optimize this therapeutic strategy. The exploitation of Vγ9Vδ2 T cells as a therapy for mRCC is novel, and the current study suggests this approach deserves further evaluation.

No significant financial relationships to disclose.
Urinary dysfunction appears to be the primary determinant of castration versus observation for prostate cancer patients with PSA failure
Authors: Zagory J. A. , Chang C. , Knight S. , Lyons E. A. , Bennett C. L.
Published: March 2020

14621

Background: After undergoing definitive treatment for a primary localized disease, prostate cancer patients may experience a rise in their prostate specific antigen (PSA) levels. Treating PSA failure with hormonal treatment has many health related quality of life (HRQOL) implications, including urinary, bowel, sexual, and male hormonal problems. Predictors of choice between hormonal treatment versus watchful waiting have not been investigated. Methods: Patients were approached after consecutive rises in PSA levels (n = 31). Patients completed HRQOL and decision satisfaction questionnaires, and a literacy assessment. Results: Patients were between 56 and 85 years old; 55% were African American. 71% of African Americans and 50% of whites had low functional literacy. 58% of patients chose hormonal therapy to treat their PSA rise; 81% of patients reported urinary problems. All patients reported decision satisfaction (see Table). Factors associated with castration versus watchful waiting were primarily related to poor urologic function, and were not specifically prostate cancer related (dysuria, nocturia, urination frequency). Conclusions: Primary treatment of urinary dysfunction, rather than castration, should be evaluated as initial therapy for prostate cancer patients with PSA failure. [Table: see text]

No significant financial relationships to disclose.
Zoledronic acid (ZA) to prevent bone loss during combined androgen blockade with finasteride (CAB+F) for clinically localized or recurrent non-osseous prostate cancer (PC)
Authors: Tucker S. , Binder RN S. , Chua RN C. , Houts PhD A. C. , Fortner PhD B. V. , Schwartzberg L. S.
Published: March 2020

14628

Background: Androgen suppression (AS) is increasingly used as primary therapy for early PC and recurrent PSA-only PC. AS decreases bone mineral density (BMD), increases markers of osteoclastic and osteoblastic activity, and increases fracture risk. CAB+F is a maximal form of AS which has not been described in prospective trials. We present the first analysis of a prospective study of ZA to prevent bone loss in men receiving CAB+F. Methods: We performed a prospective non-randomized study of ZA in men receiving CAB+F for non-osseous PC. CAB+F consisted of 48 weeks of an LH-RH agonist and antiandrogen (bicalutamide or flutamide) plus finasteride 5 mg QD. Men received ZA 4 mg intravenous at entry and every 3 months. Calcium 1000 mg and calcitriol 0.5 mcg were given QD. Baseline and serial measures of osteocalcin (OC) and deoxypyridinoline (DPD) were assayed. Baseline BMD of the lumbar spine (LS) was measured by DEXA. Quality of life (QOL) was measured with a validated symptom-based scale for pen-based computers. Results: From 7/2004 through 12/2005, 26 men with PC met eligibility criteria and enrolled. ECOG status at entry was 0 for all. Mean age was 64 (range 46–81), mean PSA was 10.6 ng/mL (range 3.23–33.0) and median Gleason sum (GS) was 7 (range 5–9). Mean testosterone was 455 ng/dL. High risk PC (PSA > 20, or GS > 7, or T3 stage) was seen in 7/26 men. In preliminary analysis of men completing 48 weeks of CAB+F (n = 13), mean (±SD) LS BMD (gm/cm2) increased significantly from 1.245 (±0.170) to 1.425 (±0.198) (p = 0.002). Baseline mean OC (ng/ml) decreased from 7.69 (±0.20) to 2.50 (±1.48) and baseline mean DPD (nmol/mmol Cr) decreased from 6.75 (±5.72) to 4.20 (±2.03). All men achieved PSA < 0.1 by 24 weeks. Serial QOL data is significant for decreased sexual interest and mild fatigue compared with baseline. No grade 3 or 4 toxicities were seen. Expanded QOL and toxicity data will be described. Conclusion: ZA given at baseline and every 3 months in conjunction with maximal AS, CAB+F, significantly improves BMD of the lumbar spine and suppresses biochemical markers of both bone resorption and formation.

No significant financial relationships to disclose.
Evaluation of angiogenis activation during interleukin-2 infusion in patients with renal cell cancer (RCC)
Authors: Simonelli C. , Talamini R. , Bearz A. , Berretta M. , Monini P. , Sgadari C. , Sartor I. , Ensoli B. , Vaccher E. , Tirelli U.
Published: March 2020

14640

It is well known that during IL-2 administration a complex activation of the cytokine network is on going, but few data are available about the effect of this activation on angiogenesis. In our Institution all patients with metastatic RCC undergo to the following schedule of IL-2 infusion: IL-2 10 MIU continuous infusion (ci) 5/7 days, one week off followed by IL-2 10 MIU ci 5/7 days, 4 week off (1 cycle); for a total number of 2 cycles. We evaluated the activation of angiogenesis measuring the plasma level of VEGF MMP2 and MMP9 before, during and after the 5 days IL-2 ci. In 13 patients analysed, before IL-2 ci, we have the following median level of plasma VEGF (773+ 378 pg/ml), MMP2 (55.9 + 19.9 ng/ml) and MMP9 (1146+498 ng/ml). The baseline median values of VEGF MMP-9 showed a trend to correlate with the number of metastasis before therapy. During 3 days of IL-2 ci we did not observed any significant increase of VEGF MMP2 and MMP9 as well as after 24 hours from the end of the 5 days ci. On the contrary, at the same time-points, during and after IL-2 ci, we observed the activation of pro-inflammatory cytokines network, measured by the statistically significant increased levels of neopterin IFN-γ and TNF-α and sIcam.This preliminary observation demonstrated that IL-2 ci, even if it highly activates the release of pro-inflammatory factors, does not affect the release of angiogenic surrogate markers such as VEGF MMP2 and MMP9. On the basis of our experience we can suggest that the most suitable time to test angiogenesis inhibitors during IL-2 therapy appear to be the intervals between IL-2 administration and not during IL-2 infusion when the most severe side effects occur and it is not observed a significant increase of angiogenic factor release.

No significant financial relationships to disclose.
A phase II study of S-1 in patients with hormone-refractory prostate cancer: The S-1 Cooperative Study Group (Prostate Cancer) study
Authors: Akaza H. , Ikemoto I. , Namiki M. , Usami M. , Kobayashi M. , Fujimoto H. , Tsukamoto T. , Naito S.
Published: March 2020

14650

Background: S-1 is an oral fluoropyrimidine antitumor drug that combines three pharmacological agents: tegafur, a prodrug of 5-fluorouracil;gimeracil, an inhibitor of dihydropyrimidine dehydrogenase; and potassium oxonate, which reduces gastrointestinal toxicity. We evaluated the efficacy and safety of S-1 in patients with hormone-refractory prostate cancer. Methods: To be eligible patients (pts) had to have given informed consent, an age of <80 years, elevations of serum prostate specific antigen (PSA) on three consecutive occasions despite effective hormonal therapy and antiandrogen withdrawal for at least 4 weeks, adequate organ function, a PS of 0–2, and a life expectancy of ≥3 months. S-1 was given orally at 40 mg/m2 b.i.d. for 28 consecutive days followed by a 14-day rest period. This 42-day cycle was repeated until confirmation of disease progression. Results: 32 pts were enrolled at 15 institutions. Their median age was 73 years (55 to 79). The median number of courses administered was 2.5 (1 to 11). On the basis of the change in the PSA level, 3 pts had a complete response (CR, <4 ng/ml), and 4 had a partial response (PR, ≥50% decrease), yielding a response rate of 21%. There was no change (NC) in 15 pts, and progressive disease (PD) in 10 pts. The median time to PSA progression was 71 days (95% CI: 44 to 161) overall, 234 days (152 to 435+) in the CR+PR group, and 157 days in the CR+PR+NC group. Grade 3 major toxicity comprised anorexia (3 pts) and anemia (2 pts). No toxicity-related deaths occurred. Conclusions: S-1 is active and well tolerated as a single agent in patients with hormone-refractory prostate cancer. Effectiveness and safety will be confirmed in subsequent large-scale phase II studies.

No significant financial relationships to disclose.
HDR brachytherapy combined with hypofractionated EBRT for intermediate-high risk prostate cancer
Authors: Akimoto T. , Hiroyuki K. , Shirai K. , Harada K. , Ebara T. , Ito K. , Yamamoto T. , Nakano T.
Published: March 2020

14655

Background: To report on biochemical outcome and late complication in pts with localized prostate cancer (LPC) treated with HDR-brachytherapy (HDR-BT) combined with hypofractionated EBRT. Methods: From 06/2000 to 12/2004, 108 pts with intermediate (37 pts.) or high-risk (63 pts.) LPC were treated with hypofractionated EBRT (3 Gy × 17 fr., thrice a week) followed by HDR-BT (5 Gy × 5; 9 pts, 7 Gy × 3; 15 pts, 9 Gy × 2; 76 pts). HDR-BT was administered a week after the completion of the hypofractionated EBRT. The planning target volume was defined as the prostate gland with a 5-mm margin all around, and the planning was conducted based on CT images. Biologically effective doses (BED) to the prostate was between 83–84 Gy. All patient received androgen ablation. Acute and late toxicities were scored according to the EORTC/RTOG morbidity grading scales. Median follow-up duration was 27 months from HDR-BT and 39 months from initiation of androgen ablation. Results: All pts completed treatment. The 5-year actuarial PSA relapse-free survival rates for intermediate and high-risk pts were 100% and 93% respectively. Acute genitourinary (GU) toxicity was 64% in grade 0–1, 31% in grade 2 and 6% in grade 3. Urethral stricture developed in 3%, with a median time from the completion of HDR brachytherapy to the occurrence of 22 months (19–26 months). Ten pts had grade 2 rectal bleeding, with a median time from the completion of HDR brachytherapy to the occurrence of 11 months (7–14 months). No pts developed grade 3 or more severe rectal complication. The incidence of acute and late toxicity did not differ according to the fractionation schema of HDR-BT. Conclusion: Our data demonstrate the successful feasibility of HDR-BT combined with hypofractionated EBRT as a safe method for escalating the total dose to the prostate without significant increasing risk of acute and late GU and rectal toxicities.

No significant financial relationships to disclose.