bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study of combination S-1 and weekly docetaxel (TXT) for advanced or recurrent gastric cancer
Authors: Ozaki T. , Satoh T. , Shimizu T. , Miyazaki M. , Kurata T. , Fukuoka M. , Tamura K.
Published: March 2020

14108

Background: S1, a novel oral fluoropyrimidine derivative, and docetaxel (TXT) have both been identified as active against the treatment of gastric cancer. The two drugs have incompletely overlapping principal toxicities, no cross resistance and have reported synergistic anti-tumor effect in vivo. Response rate of S1 and TXT for advanced gastric cancer were 46.5% and 17.1%, respectively. One report showed that full dose of S1: 80 mg/m2 daily for 2 weeks and TXT: 40 mg/m2 intravenously on day1, every 3 weeks was recommend dose (RD), however, dose of TXT has been limited low by neutropenia and allergic reactions. Weekly administration schedule of TXT has been reported as safe and effective treatment for advanced gastric cancer. The primary objective of this study was to determine the maximum tolerated dose (MTD) of combination with S-1 and weekly administration schedule of TXT, the toxicity profile and RD for phase II. Methods: Eligibility criteria includes histologically diagnosed metastatic or recurrent, or unresectable locally advanced gastric cancer, 2 prior regimens were permitted, ECOG PS 0–1, age>20, adequate organ function and written informed consent. Fixed full dose of S1: 80 mg/m2 daily was administrated orally for 3 weeks. TXT was infused intravenously over 60 minutes (Level 1: 15mg/m2; Level 2: 20mg/m2; Level 3: 25mg/m2) on day1, 8 and 15. This schedule was repeated every 5 weeks. Pharmacokinetic study was performed of S1 on day 7, 8 and of TXT on day1, 8 in order to evaluate the drug interactions. Results: Total 14 patients were registered in this study. Three patients were enrolled at the dose level 1, 6 patients at level 2 and 5 patients at level 3, respectively. No DLTs (dose-limiting toxicities) occurred at both level 1. One out of 6 patients developed DLT of Grade 3 diarrhea at Level 2. DLTs were observed in 3 out of 5 patients at level 3. There are febrile neutropenia, Grade3 stomatitis and continuous Grade 4 neutropenia. Pharmacokinetic study suggested no drug interactions between S1 and TXT. Conclusions: MTD was level 3. RD for multi-center phase II trial was Level 2 (S1 80 mg/m2 for 3 weeks and TXT: 20 mg/m2 day1, 8 and 15, every 5 weeks). This combination was active and well tolerated for advanced gastric cancer.

No significant financial relationships to disclose.
Combination irinotecan, capecitabine and celecoxib in patients with advanced biliary cancers
Authors: Lee F. , Roach M. , Parasher G. , Hunt C. , Heywood G.
Published: March 2020

14126

Background: Patients with metastatic biliary cancers continue to face a very grim prognosis with no effective chemotherapy. Median survival is around 6–9 months. Irinotecan and capecitabine have modest activity against cholangiocarcinoma. Cyclooxygenase-2 (COX-2) enzyme expression is reported in many human cholangiocarcinoma cell line studies and is linked to tumor cell resistance to chemotherapy-induced apoptosis. We hypothesized that adding a COX-2 inhibitor would improve the therapeutic benefits in patients with biliary tumors. Methods: From 9/2003 to 2/2005, a total of 12 patients were treated with a combination regimen, delivered at a cycle interval of 21 days, that consisted of 120 mg/m2 irinotecan given intravenously over 60 minutes on day 1, 1500 mg/m2/day capecitabine taken orally in divided doses on days 1–14 and 400 mg/day celecoxib taken orally in divided doses on days 1–21. Results: A total of 117 treatments were administered to the 12 patients (9 females and 3 males; median age, 56 years; 10 cholangiocarcinoma and 2 gallbladder cancer). Based on the tumor marker CA19–9, 7 of the patients had a partial response (7/12, 58%). Of the seven patients for which sequential CT evaluation was available, the partial response rate was 43% (3/7) and two additional patients had stable disease. The median progression-free survival was 13 months and the median overall survival was 17 months. We encountered grade II neutropenia and anemia (2/12 each, 17%) and grade I diarrhea and hand-foot syndrome (33% and 7%, respectively). Conclusions: These data suggest that the combination of irinotecan, capecitabine and celecoxib is an effective palliative regimen for patients with metastatic biliary cancers. Further development of this regimen is severely hindered by the potential cardiovascular risk associated with long-term use of COX-2 inhibitor.

No significant financial relationships to disclose.
Results of a prospective study with FOLFOX and Ca/Mg infusions for treatment of advanced and metastatic gastric carcinoma
Authors: Des Guetz G. , Assouad S. , Spano J. , Chouahnia K. , Gil-Delgado M. , Wind P. , Morere J. , Breau J.
Published: March 2020

14131

Background: Gastric cancer is often diagnosed in locally advanced or metastatic stages and prognostic is particularly bad. Results of a Phase II study of oxaliplatin, fluorouracil, and folinic acid was previously published (Louvet et al, J Clin Oncol. 20:4543–8, 2002). Grade 3 peripheral neuropathy occurred in 21% of patients (oxaliplatin-specific scale). Seven patients withdrew because of treatment-related toxicity. For these patients, tolerance of chemotherapy must be considered. Ca/Mg infusions seem to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy (Gamelin et al, Clin Cancer Res 15: 4055–61, 2004). Methods: In this study, in our medical Oncology department, we treated a first group of patients with FOLFOX 4 and a second group with FOLFOX S (FOLFOX S: LV5FU2 Simplified (Folonic acid 200 mg/m2, 2h, 5FU 400 mg/m2,bolus, 5FU infusion 1200 mg/m2, 44h) + oxaliplatin: 85 mg/m2, 2h, d1-d15) combined with infusions of Ca gluconate and Mg sulfate (1 g) before and after oxaliplatin and then we evaluated efficacy and toxicity. Results: Of the seventeen patients with advanced and/or metastatic stomach carcinoma enrolled between August 2000 and December 2004: Median age was 59 range (26;73) years, 12 were male, 5 female with a WHO performance status (PS) <3. There were 7 patients with objective response. Of the 13 evaluable patients for neurotoxicity, 6 were treated with FOLFOX 4 and 7 with FOLFOX S combined with Ca/Mg infusions. Neurotoxicity gr II was noted for 3/6 patients of the FOLFOX 4 group but for 1/7 patients also treated with Ca/Mg infusions. No grade 3/4 leukopenia, or thrombocytopenia were observed. Conclusions: This oxaliplatin-containing regimen is effective in the treatment of advanced gastric cancer. This regimen combining FOLFOX and Ca/Mg infusions seems to have a more favourable toxicity profile.

No significant financial relationships to disclose.
Phase II clinical trial of curcumin in patients with advanced pancreatic cancer
Authors: Dhillon N. , Wolff R. A. , Abbruzzese J. L. , Hong D. S. , Camacho L. H. , Li L. , Braiteh F. S. , Kurzrock R.
Published: March 2020

14151

Background: Pancreatic cancer is virtually always lethal, and the only FDA-approved therapies- gemcitabine and erlotinib- produce objective responses in less than 10% of patients. Curcumin (diferuloyl methane) is a plant- derived compound that inhibits the nuclear factor-kappa B (NF-kappa B) transcription factor (central to pancreatic cancer growth) and has substantial antitumor activity in preclinical models. We evaluated the toxicity and anti-tumor activity of curcumin, and its impact on survival and biologic correlates. Methods: Patients received 8 grams of curcumin (Sabinsa Corp.) by mouth daily for two months. Maintenance therapy was continued at the same dose and schedule until disease progression. Results: Seventeen patients were enrolled as of the date of analysis. Six were inevaluable: noncompliance (n = 1), never dosed (n = 1), noted to have gastric obstruction after one dose (n = 1), and too early (n = 3). Eleven patients were evaluable for response and 15 were evaluable for toxicity. To date, four patients have stable disease (2+, 2+, 3+ and 7 months) and one patient had a brief partial remission (73% reduction in tumor size by RECIST) that lasted one month. No toxicities have been observed. Serum was available for evaluation of pre-and post-dose cytokine levels in thirteen patients. Interestingly, the patient with the partial remission had marked increases (4–35 fold) in serum IL-1 receptor antagonist, IL-6, IL-10 and IL-8 levels. One to three other patients also had post-treatment increases in one or more of the above cytokines, albeit to a lesser extent (2–6 fold). Conclusions: We conclude that curcumin is well tolerated and our preliminary results suggest biologic activity in pancreatic cancer. Supported in part by the National Cancer Institute grant R21 CA 104337–01, The Topfer Fund for Pancreatic Cancer and Pancreatic SPORE grant 1 P20 CA10193–03.

No significant financial relationships to disclose.
Pharmacokinetics (PK), safety and tolerability of atrasentan (ABT-627, ATN) in combination with docetaxel (DOC) in men with hormone refractory prostate cancer (HRPC)
Authors: Petrylak D. P. , Mohile S. G. , Shelton G. , Carr R. A. , Steinberg J. , Sleep D. , Melia J. , Rieser M. J. , Nanus D. , Milowsky M. I.
Published: March 2020

14512

Background: ATN (Xinlay) is an oral selective endothelin A receptor antagonist in Phase III clinical development for the treatment of HRPC. ATN is extensively metabolized by oxidation and glucuronidation. In vitro, CYP3A is the predominant isozyme involved in oxidative metabolism of ATN and DOC; ATN inhibits CYP3A with an IC50 of ∼3 μM (15-fold the mean plasma Cmax for 10 mg/d ATN). Methods: 11 men with HRPC received DOC 75 mg/m2 by 1-h IV infusion on day (D) 1 of each 21-D cycle (C), and ATN 10 mg po qd starting D8C1 and prednisone(Pred) 5 mg orally twice daily.Three oral doses of dexamethasone 8 mg were administered starting 12 hours before DOC. On coadministration days, ATN was taken at the start of the DOC infusion. PK were to be determined over 24 h following DOC alone (D1C1) and in combination with ATN (D1C2), and following ATN alone (D20C1) and in combination with DOC (D1C2). Plasma concentrations of ATN and DOC were determined using a validated LC/MS/MS method. Results: Preliminary PK results are summarized (N = 10, mean ± SD) in the table below. Some patients (pts) had D1C2 PK performed D1C4 (N = 4), D1C5 (N = 3) or not at all (N = 1). No unexpected adverse events (AE) were observed. One subject experienced neutropenic fever related to DOC. This resolved with treatment and ATN/DOC was resumed. Efficacy: 3/5 DOC naive and 2/6 DOC resistant pts had a >50% post treatment PSA decline. One DOC resistant pt demontrated post treatment calcicfication of liver metastases accompanied by a >45% PSA decline. Conclusions: No PK interaction was observed between ATN and DOC when coadministered at full standard single agent dosages implying 10 mg QD ATN did not alter CYP3A4 activity in gut or liver. Treatment with ATN/DOC was well tolerated and demonstrated activity in DOC resistant pts, further justifying a planned Southwest Oncology Group phase III study comparing ATN/DOC/Pred to DOC/Pred. [Table: see text]

[Table: see text]
Phase II trial of weekly docetaxel (D) and complete androgen blockade (CAB) prior to radical prostatectomy (RP) in high-risk localized prostate cancer (PC) patients (pts)
Authors: Mellado B. , Font A. , Aparicio L. A. , Gallardo E. , Mel J. R. , Alcaraz A. , Areal J. , Gómez Veiga F. J. , Hannaoui N. , Gascón P.
Published: March 2020

14515

Background: Pts with high-risk localized PC have an increased risk of positive margins and recurrence after RP or radiotherapy alone. Neoadjuvant hormonotherapy (HT) has not shown a survival benefit prior to surgery, while outcomes are improved when HT is combined with radiotherapy. D-based chemotherapy improves survival in metastatic PC. These data support the investigation of multi-modality approaches to improve the aggressive behavior of high-risk localized PC. The main objective of this study was to assess the pathologic complete response (pCR) rate of the study combination. Secondary objectives were clinical activity, toxicity profile, time to progression and survival. Methods: Pts with clinical stage T1–2 (+ Gleason ≥ 7 (4+3) and/or PSA≥20 ng/mL) and T3 PC received 3 cycles of D (35 mg/m2 i.v. days 1, 8 and 15, every 28 days) concomitant with a depot goserelin (10.8 mg sc) plus flutamide (750 mg po daily for 3 months). RP was performed 2–4 weeks after the end of neoadjuvant therapy. Results: Fifty six pts have been included into the trial. Available data from 32 pts receiving neoadjuvant therapy were analyzed for this presentation. Median age was 69 years (53–75). Median follow-up was 3.6 months. Clinical stage was T1 (20%), T2 (53%) and T3 (27%); Gleason was ≥ 7 (4+3) in 25 (78%) pts. Eight (28%) pts had a PSA ≥ 20 ng/ml. A total of 85 cycles were administered (median 3) with a 100% median relative dose intensity for D. Grade III/IV toxicities per patient were liver toxicity (15.6%) and diarrhea (9.4%). Among the 16 pts who underwent RP to date, one (6%) achieved pCR, 11 (69%) had negative surgical margins and 9 (56%) had organ-confined disease. Conclusions: Neoadjuvant weekly D plus 3-month CAB is well tolerated and induces pCR in high-risk localized PC pts. Updated results will be available for the meeting. These results are encouraging while the true impact of neoadjuvant chemo-HT in this group of pts has to be determined in randomized trials.

No significant financial relationships to disclose.
Degarelix: A gonadotropin-releasing hormone receptor (GnRH) blocker, tested in two one-year multicenter, randomized, dose-finding studies in prostate cancer patients
Authors: Gittelman M. , Pommerville P. , De La Rosette J. , Persson B. E. , Jensen J. K. , Olesen T. K.
Published: March 2020

14516

Background: The GnRH receptor blocker degarelix has immediate onset of action in suppressing gonadotropins (LH and FSH), testosterone (T) and prostate specific antigen (PSA) and does not cause T surge. Its long-term efficacy and safety in different maintenance dosing regimens were evaluated in prostate cancer (CaP) patients. Methods: Degarelix was investigated in two multicenter, one-year studies in North America and Europe/South Africa. Degarelix initiation doses of 200 and 240 mg administered subcutaneously, followed by three maintenance doses (80, 120 and 160 mg). Therapeutic effect was assessed by measuring T and PSA levels. 314 patients (age 47–93, median 73 years) with histologically confirmed CaP, PSA ≥2 ng/mL received degarelix subcutaneously every 28 days. Median baseline T was 4.1 ng/mL and PSA was 20 ng/mL. 19% of patients had metastatic, 24% had locally advanced and 30% had localized CaP. 27% were M0/MX and not T-staged. Tumour grade was well differentiated (Gleason 2–4) in 13%, moderately differentiated (5–6) in 38%, and poorly differentiated (7–10) in 49% of the patients. Results: T levels ≤0.5 ng/mL were achieved in 92% of patients at Day 3 and 95% of patients at Day 28 among those treated with 240 mg (40 mg/mL) degarelix. From Day 28 until Day 364, 100% of patients receiving maintenance doses of 160 mg had T levels consistently ≤0.5 ng/mL. No evidence of T surge was detected. PSA decreased by 90% at 8 weeks after starting therapy, 94% at 12 weeks and 96% at 24 weeks. Twelve patients (6%) withdrew from the study due to adverse events, largely related to androgen deprivation. There were no cases of systemic allergic reactions. Conclusion: Degarelix treatment for one year resulted in fast, profound and sustained suppression of T (≤0.5 ng/mL) and fast, profound and sustained reduction of PSA levels. Degarelix was well tolerated without evidence of T surge or systemic allergic reactions. [Table: see text]

[Table: see text]
Phase I study of interleukin 2 (IL2) maintenance after induction with weekly docetaxel and estramustine in patients with metastatic hormone refractory prostate cancer (HRPC)
Authors: Jiang P. , Higano C. S.
Published: March 2020

14526

Background: Patients with HRPC commonly respond to docetaxel, but many develop asthenia and other docetaxel related toxicities that impair quality of life and hence, many clinicians prescribe a “chemotherapy vacation”. IL2 exerts its anti-tumor effect through activation of T cells and NK cells and at high dose has been shown to have efficacy (and toxicity) in men with HRPC (Maffezzini, The Prostate 1996). Low dose IL2 and 13-cis-retinoic acid given as maintenance after cytoreduction of advanced solid tumors was associated with increased numbers of circulating NK cells as well as further tumor responses (Recchia, Proc ASCO 2001). A phase I trial of low dose IL2 maintenance after chemo induction was undertaken. Methods: Chemotherapy naive pts with metastatic HRPC were induced with weekly docetaxel 35 mg/m2 on day 2 and estramustine 280 mg/M2 TID on days 1 and 2 for 3 wks followed by 1 wk off for a total of 12 doses of chemotherapy. Responding pts received maintenance IL2 for 5 days/wk for 3 wks, followed by 1 wk off. During the 3rd wk, a boost dose was administered on days 2 and 3. Level 1 maintenance was 0.5 x106 IU/m2 SC bid, level 2 was 0.75 × 106 IU/m2 SC bid. Level 1 boost was 3 × 106 IU/m2, level 2 was 4.5 × 106 IU/m2 SC bid. Cohorts of 3 patients were treated at a given dose level according to standard dose escalation schemes for toxicity. IL2 was continued until objective progression was documented. Results: 15 pts, median age of 70 (range 46–78), median PSA 32.7 (range 2.28 to 1248) were enrolled. After chemotherapy, 12 pts had > 50% (7 had > 75%) decline in PSA, 3 pts had < 50% decline. 13 pts went on to receive IL2. The MTD for maintenance IL2 was 0.5 × 106 IU/m2 SC bid (4 pts at level 1 had no toxicity but 3 of 4 at level 2 had grade 2 toxicity requiring a drop to level 1). MTD for the boost was 3 × 106 IU/m2 (4 with no toxicity at level 1, 3 of 3 with grade 2 toxicity at level 2 requiring a drop to level 1). The most common toxicities were fatigue, nausea, chills, edema. One pt has received IL2 maintenance for 25 months. Conclusions: IL2 maintenance can be safely administered at the MTD. Immunological studies before/after chemotherapy and during IL2 are pending.

No significant financial relationships to disclose.
Ultrasensitive PSA nadir on testosterone inactivating pharmaceuticals accurately predicts early prostate cancer progression
Authors: Scholz M. C. , Lam R. , Guess B. , Strum S. , Johnson H. , Jenrrich R.
Published: March 2020

14531

Background: Prostate cancer has a variable natural history. Researchers and clinicians sorely need a marker identifying men destined for early progression to bone metastasis (EPBM). Prostate cancer is uniquely sensitive to testosterone inactivating pharmaceuticals (TIP) especially when TIP is initiated prior to the onset of bone metastasis. Moul 1 reported 10 year median response in men with a rising PSA after surgery. With such effective therapy, predicting EPBM requires a marker signaling TIP resistance. Elevated PSA nadir is a likely candidate. Methods: Retrospective chart review of 159 men with prostate cancer started on TIP before 1/1/00 with negative bone scan and PSA < 100. The predictive value of Gleason score, initial PSA, PSA doubling-time (DT), clinical stage, and ultra-sensitive PSA nadir were evaluated for their ability to predict EPBM within 72 months of starting TIP. TIP consisted of an antiandrogen and LHRH agonist. Results: Median follow was 9.25 years. Median values for patient age, initial PSA, PSA nadir, and PSA doubling time were 65.9, 9.6, 0.03 and 10 months respectively. Sixty men were staged as: T1c-T3b, 46 PSA relapse, and 53 stages T3c, D0 or D1. Thirty-five men developed EPBM. PSA nadir was the most accurate predictor of EPBM (see Table). Only 8% of men with PSA nadir ≤0.05 had EPBM compared to 78% with high nadirs. Cox regression analysis indicated that PSA nadir, Gleason score, and PSA doubling time < 12 months independently predicted EPBM. Median and maximum time to PSA nadir were 4 and 8 months respectively. Conclusions: Ultra-sensitive PSA nadir is a more accurate indicator of early progression to bone metastasis (90%) than Gleason score (75%) as well as being more sensitive and specific (72% vs. 37%) and (95% vs. 86%) respectively. This prognostic information provided by PSA nadir is obtainable within the first 8 months of starting TIP in virtually all patients (97%). 1. Moul JW et al. J Urol 2005, 171: 1141–7. [Table: see text]

No significant financial relationships to disclose.
Cytoreductive nephrectomy for metastatic renal cell carcinoma in the presence of nonconventional histology
Authors: Kassouf W. , Sanchez-Ortiz R. , Tamboli P. , Matin S. , Swanson D.
Published: March 2020

14535

Background: While randomized trials show a survival benefit for cytoreductive nephrectomy in the setting of metastatic conventional (clear cell) renal cell carcinoma (mRCC), the benefit of cytoreductive surgery for patients with mRCC of nonconventional histology (papillary, chromophobe, unclassified) is unknown. We evaluated our experience with cytoreductive nephrectomy for nonconventional mRCC at M. D. Anderson. Methods: From 1990–2004, 464 patients with mRCC underwent cytoreductive nephrectomy; of these, 89 patients had nonconventional mRCC and form the basis of this report. The remaining 375 patients with conventional mRCC formed a comparative group. Overall survival (OS) and disease-specific survival (DSS) data were evaluated by Kaplan and Meier analysis, with univariate and multivariate log rank tests. Results: Compared to patients with conventional histology, patients with nonconventional mRCC were younger (p < 0.045), more likely to have nodal metastases (p < 0.0001), and more likely to have sarcomatoid dedifferentiation (21.2 versus 13.2%, p = 0.056). In multivariate analysis, the median survival for nonconventional histology was significantly worse than for conventional mRCC (11.1 versus 19.5 months, p = 0.0081), even after adjusting for stage, grade, performance status, age, and presence of sarcomatoid dedifferentiation. Although positive nodal status was associated with a decreased survival in nonconventional histology (p < 0.0001) in our multivariate analysis, even node negative patients demonstrated a worse survival when compared to those with conventional histology (p = 0.03). Interestingly, patients with nonconventional mRCC who had complete resection of their retroperitoneal nodal metastases with cytoreduction showed a trend towards improved survival, as has been reported in patients with conventional mRCC and nodal disease. Conclusions: Patients with nonconventional mRCC have a higher incidence of nodal metastases and demonstrate a worse prognosis than those with conventional histology, who undergo cytoreductive surgery. Aggressive cytoreduction with removal of all nodal disease may improve outcomes. More effective systemic therapies are needed to improve upon the results seen with aggressive surgery.

No significant financial relationships to disclose.
Upper urinary tract cancer: Prognostic factors for bladder tumours development and systemic relapse
Authors: Merlin F. , Riolfi M. , Sava T. , Consoli F. , Griso C. , Manno P. , Porcaro A. B. , Ghimenton C. , Comunale L. , Cetto G.
Published: March 2020

14560

Background: Transitional cell carcinomas (TCC) of the renal pelvis and ureter are relatively uncommon. An important characteristic of TCC is multifocality throughout the all urinary tract simultaneously and/or subsequently. To clarify the association between UTTCC and bladder tumors, we retrospectively analysed 86 patients with UTTCC in order to evaluate prognostic factors for recurrence and to identify risk factors for development of bladder cancers. Methods: All 86 upper tract transitional cell carcinoma patients (pts) were treated surgically between January 1988 and July 2005. Median age was 69 years (range: 34–91). We observed a male predominance (71%) and 78% of patients were heavy smokers. Forty-five (52.3%) patients had a diagnosis of bladder transitional carcinoma. The median age of this group of patients was 70 range 40–87). In fifteen cases (17%), bladder tumour occurred first than upper tract neoplasia; in 14 patients bladder and upper tract tumours were synchronous. Results: Median survival was 97 months; 49 (57%) patients are alive and 43 are disease-free. Grading, stage T, lympho-vascular invasion and squamous differentiation were significant prognostic factors for systemic relapse (p < 0.05). Twenty-eight pts (32.5%) developed subsequent transitional bladder cancer after a median time of 12 months; multifocality of primitive tumours was significant predictive factor. Invasive UTTCC were less likely associated with bladder cancer. We observed that superficial bladder cancer developed more frequently in pts with well differentiated (G1–2) primitive cancer (90% of cases), without lympho-vascular invasion and with history of heavy smoke exposition. Conclusions: In our study, T, N and G confirmed to be the most important prognostic factors for systemic relapse. Lympho-vascular invasion highly predicts metastasis. Our analysis highlights that upper urinary tract cancers seem to have different history and different pattern of association with bladder tumours, according to specific prognostic factors. The development of recurrent superficial bladder cancer is more frequently associated with small well differentiated multifocal upper tract tumours.Therefore follow-up should be oriented according to these characteristics.

No significant financial relationships to disclose.
Non-seminomatous retroperitoneal histology in patients with a pure testicular seminoma and an elevated serum alpha feto-protein
Authors: Karanikolas N. T. , Secin F. P. , Stasi J. , Carver B. S. , Dotan Z. , Sheinfeld J.
Published: March 2020

14561

Background: There is controversy regarding the management of patients with pure testicular seminoma (PTS) and elevated alpha-fetoprotein (AFP) level (Nazeer, Oncol Rep 1998;5:1425). Our objective was to determine the retroperitoneal histology and clinical outcome of patients with pure testicular seminoma and elevated serum AFP level. Methods: Between 1989 and 2004, 15 patients with PTS and elevated AFP level underwent post chemotherapy retroperitoneal lymph node dissection (PC-RPLND) at MSKCC. All diagnoses of PTS were confirmed by a MSKCC uropathologist. Clinical and pathologic data were obtained from our prospective surgical database and subsequently analyzed. Results: The median pretreatment AFP level was 339 ng/ml (interquartile range [IQR]: 42, 1,006). Clinical stage at initial presentation was IIa in 1, IIb in 1, IIc in 9, and III in 4. According to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, 6 patients had good, 6 had intermediate, and 3 had poor risk for disease. The histology at PC-RPLND demonstrated teratoma in 6 patients (40%), fibrosis/necrosis in 6 patients (40%), and viable germ cell tumor in 3 patients (20%; 1 embryonal, 1 yolk sac, and 1 seminoma). Overall, 8 of 15 (53%) had persistent nonseminomatous retroperitoneal histology after chemotherapy. At a median follow-up of 4.2 years (IQR: 2.3, 7.1), 10 patients were alive without disease, 2 were alive with disease, and 3 died of disease. Cancer-specific survival rate was 83% at 5 years (95% confidence interval: 47, 96). Conclusion: Contrary to prior reports (Nazeer, Oncol Rep 1998;5:1425), patients with pure seminoma and an elevated AFP level should be managed as having nonseminomatous germ cell tumor (GCT), including post chemotherapy RPLND because more than half will harbor either teratoma or viable GCT.

No significant financial relationships to disclose.
Interleukin-2, interferon alpha and 5-fluorouracil immunochemotherapy with and without 13-cis-retinoic acid in patients with metastatic renal cell carcinoma: Results of a prospective randomized trial
Authors: Bierer S. , Bode M. E. , Brinkmann O. A. , Hertle L.
Published: March 2020

14571

Background: Combined immunochemotherapy with interleukin 2, interferon alpha and 5-fluorouracil in patients with metastatic renal cell carcinoma has shown objective response rates up to 30% and more. The therapeutic effect of adding 13-cis-retinoic acid still remains controversial. Methods: Between 05/2001 and 11/2003 we randomly assigned patients with metastatic renal cell carcinoma either to receive a combined immunochemotherapy of interleukin 2 (s.c.), interferon alpha (s.c.) and 5-fluorouracil (i.v.) = group A or the same regimen plus 3 × 20 mg 13-cis-retinoic acid daily (p.o.) = group B. 83 patients were eligible (41 in group A and 43 in group B). All patients had ECOG 0 or 1 and no prior systemic therapy. Objective response (OR = Complete response, CR + Partial response, PR + Stable disease, SD), time to progression (TTP) and median survival were determined. Results: Patient characteristics were well balanced between both groups. There was no significant difference in objective response between both groups (A/B: CR 2%/2%, PR 22%/5%, SD 46%/69%, p = 0.8). The responders in both groups showed no significant difference in TTP (A/B: 11.5/9.5 months, p = 0.4). Median survival was 23 months for all patients with no significant difference between the two groups (A/B: 26/22 months, p = 0.42). Slightly more therapeutic side effects (e.g. mucositis) were seen in group B. Conclusions: The addition of 13-cis-retinoic acid to a combined immunochemotherapy of interleukin 2, interferon alpha and 5-fluorouracil in patients with metastatic renal cell carcinoma does not seem to have a therapeutic benefit.

No significant financial relationships to disclose.
Sequential administration of cisplatin (c), gemcitabine (g) and docetaxel (d), as first-line treatment in patients with advanced transitional cell carcinoma (TCC) of the urothelial tract: A multicenter phase II study
Authors: Androulakis N. , Boukovinas I. , Bozionelou V. , Kalykaki A. , Potamianou A. , Pallis A. , Vamvakas L. , Gkioulbasanis I. , Souglakos I. , Sfakiotaki G.
Published: March 2020

14574

Background: The GC combination has become a standard of care for advanced TCC. D has demonstrated broad single agent activity in many solid tumors including bladder cancer. We evaluated the safety and the activity of their sequential administration in patients (pts) with locally advanced or metastatic TCC who have not received prior chemotherapy. Methods: Chemotherapy-naïve pts with histologically proven locally advanced or metastatic TCC were enrolled. G 1100 mg/m2 was administered over 30-minutes IV on days 1 and 15, C 80 mg/m2 on day 1 with the adequate hydration and D 80 mg/m2 over 1 h on day 15. Results: From 4/2004–12/2005, 26 pts (25 male, 1 female), median age 65.5 years (range, 48–75), (PS 0/1/2: 16/8/2) were enrolled onto the study. The majority (19pts, 73.1%) had metastatic disease. A median of 4 cycles (range 1–9) was given for a total of 113 cycles. There were 12 delayed cycles due to toxicity and 15 dose reductions. Three (16.7%) complete responses (CRs) and 6 (33.3%) partial responses (PRs) [2 of them were converted to CR with additional surgery] were observed in 18 evaluable pts [overall RR of 50%; 95% CI 26.9%-3.1%]. The median time to progression was 7.9, and the months while median survival has not yet reached. The 1-year survival is 68.86%. Gr III-IV hematologic toxicity included neutropenia (61.5%), febrile neutropenia (11.5%), anemia (7.7%) and thrombocytopenia (7.6%). Non hematologic toxicity was mild (grade III vomiting and diarrhea in 7.7% and 3.8% of the pts, respectively). There was no neutropenic sepsis or toxic death. Conclusions: The sequential administration of cisplatin, gemcitabine and docetaxel is an active treatment for pts with advanced TCC. Toxicity is not manageable and this regimen warrants further investigation.

No significant financial relationships to disclose.
Results of a phase I trial administering Zyflamend to subjects with high-grade prostatic intraepithelial neoplasia
Authors: Katz A. E. , Pierorazio P. M. , Masson P. , Goluboff E. T. , Stone B. A. , McKiernan J. M. , Benson M. C. , Olsson C. A.
Published: March 2020

14575

Background: Subjects diagnosed with prostatic intraepithelial neoplasia (PIN) at prostate biopsy are at increased risk of developing prostate cancer on later biopsies. We initiated a phase I clinical trial to asses the safety and efficacy of the novel herbal anti-inflammatory, Zyflamend, to prevent prostate cancer in high-risk subjects with PIN. Methods: Men ages 40–75 diagnosed with high-grade PIN (without prostate cancer) on biopsy within the last six months were enrolled. Patients were assigned to one of eight treatment groups, with successive dose-escalation occurring in each group. Patients were evaluated every three months for 18 months; at which time they had a physical exam and blood samples drawn to monitor for toxicity, to check for fluctuations in PSA and testosterone, and monitor a battery of inflammatory serum. At 6, 12 and 18 months, 12-core transrectal ultrasound guided biopsy of the prostate was performed. Biopsy tissue was evaluated for the presence of PIN and/or prostate cancer then stained for inflammatory biomarkers. A NCI common terminology criteria for adverse events (v3.0) based questionnaire was used to monitor side effects. Endpoints are completion of the 18 month protocol without adenocarcinoma or diagnosis of adenocarcinoma prior to 18 months. Results: To date 25 patients have been enrolled; the expected closure date is March, 2006. The median patient age is 65.1 years with a median PSA level of 6.8. There have been no adverse events reported or toxicities apparent. Five patients (20%) have complained of grade I dyspepsia resolving spontaneously without intervention. Preliminary results include a total of 22 biopsies performed in 19 patients. 18 of the 22 biopsies were performed per protocol at scheduled visits, the remaining four were performed between scheduled visits. Of 22 biopsies completed seven returned positive for PIN (31.8%) and three have returned with adenocarcinoma (13.6%). Conclusions: The novel herbal anti-inflammatory, Zyflamend, appears to be associated with minimal toxicity and no serious adverse events when administered orally. Short term biopsy results indicate a low progression rate, although long-term efficacy awaits further studies.

No significant financial relationships to disclose.
Treatment of advanced renal cell carcinoma with tumor lysate pulsed IL-12 secreting autologous dendritic cells
Authors: Wimpissinger T. F. , Felzmann T. , Hügel H. , Funovics P. , Stackl W.
Published: March 2020

14585

Background: We have conducted a clinical phase I trial to evaluate feasibility and safety of dendritic cell-based immunotherapy in patients with advanced renal cell carcinoma (RCC). As opposed to previous cancer vaccination studies, dendritic cells were specifically enabled to secrete interleukin 12 (IL-12). Methods: Patients with advanced RCC (n = 11) received six weekly intranodal vaccinations with autologous monocyte-derived dendritic cells (mDCs). MDCs were loaded with autologous tumor cell lysate and were specifically stimulated to secrete IL-12 to polarize type-1 T-helper lymphocytes (Th1) and to directly present tumor antigens to cytotoxic T lymphocytes (CTL). Results: There was no significant treatment-related toxicity and no clinical evidence of autoimmunity. Vaccination was very well tolerated. Five patients had stable disease for at least five months, while four patients had progressive disease. Two patients with early clinically significant disease progression had to be excluded before completion of the treatment. In addition, we could detect enhanced anti-tumor immunity in vitro comparing immune response before versus after cancer vaccination. Conclusions: Our findings indicate that cancer vaccination with IL-12 secreting mDCs is well tolerated and has potential clinical and clear immunological effects in patients with advanced RCC.

No significant financial relationships to disclose.
A phase I/II study of docetaxel in combination with doxorubicin HCI liposome injection in advanced androgen-independent prostate cancer
Authors: Martin M. E. , Ferguson L. A. , Williams D. A. , Laber D. A.
Published: March 2020

14588

Background: There is no cure for men with AIPC. Recently two landmark studies demonstrated an improvement in survival for men with AIPC treated with docetaxel based chemotherapy. Doxorubicin is a very active agent against AIPC. Doxil is liposome-encapsulated doxorubicin with less toxicity. Methods: Objectives are to evaluate the efficacy and safety of DoxTax. A phase I dose escalation study was performed. Three cohorts according to the following dose escalation schedule were formed. In the absence of DLT, level 3 was the recommended dose for the phase II study. Response was assessed by size of measurable and non-measurable lesions (RECIST JNCI.2000), and PSA levels (JCO.1999). Toxicity was graded by the NCI CTCAE. Results: Eleven subjects with AIPC were enrolled and evaluated for toxicity and response. Total number of cycles administered: 59, median of 5.5 cycles/patient. Patient characteristics: Median age 67 years (53–81); prior hormonal manipulations 2 (1–2); prior chemotherapy 1 (0–2); ECOG performance status 1 (1–2); and median PSA 78 ng/ml (8.73–783). Objective response: Out of 11 subjects, four men (36%) achieved a reduction in PSA of > 50%, while one (9%) achieved a >80% PSA reduction, for an overall PSA response of 45%. Seven patients had measurable lesions. Using RECIST criteria, five of seven subjects maintained (SD). Palliative response: Nine subjects (82%) improved their ECOG performance status. Additionally, 8 men (73%) had decreased level of pain. Toxicity: No dose limiting toxicity occurred. One patient had grade 3 generalized weakness related to disease progression. Grade 1–2 adverse events were not related to the dose and included: 64% fatigue, 45% anemia, 18% neutropenia, alopecia, anorexia, vomiting, 9% each for nausea, thrombocytopenia, weakness, hand/foot, and neuropathy. Conclusions: DoxTax is a well-tolerated, easy to administer and effective therapy for patients with metastatic AIPC. Accrual to the phase II trial is ongoing. [Table: see text]

[Table: see text]
Identification of urinary markers using proteomics analysis of urine in patients with bladder cancer
Authors: Nabi G. , Cash P. , N’Dow J.
Published: March 2020

14605

Background: The discovery of new urinary markers for non-invasive detection and surveillance of bladder carcinoma remains an active field of current research with an aim to replace invasive investigations such as cystoscopy. We have analysed the urinary proteomes of patients with bladder tumor and compared them the urinary proteomes of a healthy volunteer control group to detect putative, tumour specific urinary markers for bladder tumor. Methods: 24 hour and midstream samples were collected from healthy volunteers and patients with newly diagnosed bladder tumours. Urinary proteins were isolated by a technique previously described by our group (Nabi G, N’Dow J, Hasan ST, Boot IR, Cash P. Proteomic analysis of urine in patients with intestinal segments transposed into the urinary tract. Proteomics. 2005 Apr;5(6):1729–33.)1. Proteins were resolved by 1-dimenional (1-DE) and two dimensional gel electrophoresis (2-DE). The proteins that differed when analysed by either 1-DE or 2-DE between patients and controls were identified using peptide mass mapping. Results: Six patients with newly diagnosed bladder cancer and 5 healthy volunteers were recruited into this study. All patients were found to have superficial transitional cell carcinoma with high grade (3 with grade 3, 3 with grade 2) on subsequent histopathological examination. For the same individual no detectable differences were observed in the protein profiles of midstream and 24 hour urinary samples when analysed by either 1DE or 2-DE. However, between patient and controls a number of proteins differed in abundance and these were identified. Proteins that were present in patients, but absent in controls, included FK506 binding protein 6 isoform, apolipoprotein A-IV, paraliprotein and lipid binding protein. Conclusions: The present study identified some of the novel urinary biomarkers in present with bladder cancer. Some of these have been shown to change their expression with deeper invasion of disease and might be useful in predicting behaviour of superficial bladder cancer.

No significant financial relationships to disclose.
A randomised phase II trial assessing the impact of the addition of gefitinib to the combination of radiotherapy and short-term maximal androgen blockage in high-risk localised prostate cancer: Safety evaluation
Authors: Thirion P.
Published: March 2020

14613

Background: Given the in-vitro evidence of potential increase in tumour radiosensitisation and hormonal deprivation-related tumour growth inhibiting effect by the addition of EGFR inhibitors, a randomised unblinded phase II trial was initiated to evaluate the impact of the addition of gefitinib to a combination of radiotherapy (RT) and maximal androgen blockage (MAB) in patients (pts) with high-risk localised prostate cancer. Methods: Eligible pts had biopsy proven localised prostate carcinoma Gleason score ≥7 and/or cT3 stage and/or initial PSA ≥ 20; without nodal and distant metastases. All pts were treated by 8 months MAB using LH-RH agonist (Zoladex 3.6 mg/month) and peripheral anti-androgen (Casodex 50 mg/day), and localised Conformal RT (Prostate + Seminal Vesicles, 75.6 Gy/42 daily fractions), initiated after 4 months of MAB. Pts were randomised to receive or not gefitinib 250 mg/day concomitantly for 8 months. The planned accrual was 98 pts. The end-points were ASTRO defined PSA-relapse-free survival at 18 months and toxicity. A safety evaluation was performed mid 2005. Results: 20 pts (10 per arm) were included from 10/2003 to 02/2005. No significant difference in RT or MAB-related toxicity was seen between the 2 arms. The addition of gefitinib significantly increased the frequency and intensity of reversible skin toxicity events (Rash-CTC grade 3–4: 4 pts Vs O pts, p = 0.04), with a trend for reversible transaminase enzymes elevation (TEE) (CTC grade 3–4: 2 pts Vs 0 pts). No treatment interruption was reported in the control arm. In the experimental arm, 3 pts completed treatment, 3 pts had a temporary (<10 days) gefitinib discontinuation (reversible asthenia and skin rash) and 4 pts had a permanent gefitinib discontinuation for reversible CTC grade 3 toxicity (skin rash: 2 pts, TEE: 2 pts). Conclusions: Gefitinib-related toxicity led to treatment discontinuation in 4 out of 10 patients. The trial is under review. This trial was supported by AstraZeneca.

No significant financial relationships to disclose.
Preclinical and clinical investigation of histone deacetylase inhibitor valproic acid given orally in androgen independent prostate cancer
Authors: Sharma S. , Vogelzang N. , Wong B. , Adams C. , Manno P. , Welborne K. , Giraud Y.
Published: March 2020

14614

Background: Considerable preclinical data suggests that histone deacetylase inhibitors (HDAIs) can cause differentiation and apoptosis of prostate cancer cell lines and inhibit prostate cancer xenografts in vivo. There is evidence that valproic acid (VPA) is a HDAI and can be administered safely to cancer patients intravenously (Atmaca et al J Clin Oncol 2004). Methods: In the current investigation, 6 cell lines of a variety of solid tumors including prostate cancers were treated with escalating concentrations of VPA (0.5, 1, 2 and 4 mM) over 24–144 hours. Cell growth inhibition was studied by a modified MTS assay. Simultaneously, patients with androgen independent prostate cancers were treated with dose escalations of oral VPA every week or as tolerated (10, 15, 20, 25 mg/kg). Weekly total and free serum VPA, PSA and serum testosterone levels were obtained. In addition, lymphocytes were collected for histone H3 acetylation. Results: VPA inhibited all solid tumor cell lines in a dose-dependent and time-dependent fashion. Optimal (>50% over control) inhibition of most cell lines required 2–4 mM exposure over at least 72–96 hours. Prostate and lung cancer lines were more sensitive to inhibition after VPA administration. A total of 5 patients (Median age 71, Range 48–78) were treated with VPA. Major adverse events included Gr 1 confusion (1 pt), Gr 1 fatigue (3 pts), Gr 1 Dizziness (2 patients) and Gr 1 nausea and vomiting (1 pt). When PSA levels were normalized for simultaneously drawn serum testosterone (Median 20, Range 16–281 ng/dl), all patients had transient drops in PSA. In 3 of 4 evaluable patients, normalized PSA increased after patients were discontinued from VPA because of side effects or co-morbid conditions. In 1 patient, normalized PSA declined after re-challenge with VPA. Conclusions: In this study, VPA has demonstrable activity in cell lines and in patients as measured by lowered PSA levels. Normalization of PSA to serum testosterone might be important to detect clinical effects of HDAIs. Updated clinical data and a correlation between PSA, serum levels of VPA and histone acetylation will be presented.

No significant financial relationships to disclose.
Treg depletion with denileukin difititox (DD) enhances lymphocytosis and eosinphilia in patients treated with high-dose IL-2 (HDIL-2) for metastatic renal cell cancer (MRCC)
Authors: Gidron A. , Eklund J. , Mortone B. , Rademaker A. W. , Goolsby C. , Kuzel T.
Published: March 2020

14627

Background: CD4+CD25+ T cells (Treg) play a suppressive role in immune regulation. DD is an IL-2 receptor specific cytotoxin. We postulated depletion of Treg with DD may enhance immune effector cell populations during HDIL-2 tx, including eosinophilia which was reported to be involved in immune response to neoplasm (Mattes et al. J Exp Med 197: 387, 2003). Methods: Seven pts (5 male, median age 58 yrs) with MRCC were tx’d with HDIL-2 and DD in different schedules to determine safety and effect on immune response as manifested by changes in Treg, lymphocyte, and peak eosinophil counts. Pts were tx’d with IL-2 600,000 IU/kg Q8H on days (d) 1–5 and 15–19. Three (group A) and 2 (group B) pts were given 6 and 9 ug/kg daily on d 8–10 respectively, while 2 (group C) pts received 9 ug/kg of DD on d -4- -2. Four (group D) pts with metastatic melanoma who received HDIL-2 as above but without DD were included as controls. Flow cytometry was done on days -4, 1,8,10,15 for group C and on days 1, 8, 10, 15, 22 for groups A, B, and D. CBC was obtained within 24 hours of flow cytometry. Results: After DD Treg increased in group A (mean change in absolute T-reg count of 16%) and decreased in groups B and C (34.5 and 20% respectively) compared to baseline. Group C trended toward a greater lymphocytosis at day 8 compared to all other groups (mean increase of 8.6 vs. 3.3 K/ul p = 0.059). A higher peak level of eosinophilia was noted in group C compared with groups A, B and D combined (mean increase of 9.9 vs. 3.0 k/ul p = 0.03). Group C demonstrated a higher mean % change in absolute number of CD8+ T-cells between onset of therapy and Day 8 compared to groups A, B, D combined (increase of 1095% vs. 496% respectively, p = 0.35). Toxicity was similar to that expected with HDIL-2. Conclusions: Administration of DD in conjunction with HDIL-2 was associated with a decrease in Treg that may be schedule and dose dependent. The results suggest an enhanced immune stimulatory effect as manifested by lymphocytosis and peak eosinophilia and CD8+ T-cells in group C. Despite small pt numbers, results suggest that pre-treatment with DD may confer an advantage. It is too early to know if laboratory results correlate to clinical benefit.

[Table: see text]