bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/II study of docetaxel and atrasentan in men with metastatic hormone-refractory prostate cancer (HRPC)
Authors: Moore C. N. , Creel P. , Petros W. P. , Torain T. , Yenser S. , Gockerman J. , Hurwitz H. , Garcia Turner A. , Sleep D. J. , George D. J.
Published: March 2020

14504

Background: Docetaxel is first-line standard treatment for metastatic HRPC. New combinations with targeted therapies may improve clinical responses. . Atrasentan is an endothelin receptor A (ETA) inhibitor with an IC50 in the pM range. Clinical studies suggest atrasentan delays time to disease progression, bone turnover markers and PSA kinetics. Methods: We conducted a Phase I/II trial of docetaxel and atrasentan to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and treatment response of this regimen. Patients were treated with docetaxel IV every 3 weeks at doses ranging from 60 to 75 mg/m2. Atrasentan was given orally at 10 mg daily starting on Day 3 and continuously thereafter. Initially, we defined DLT as grade IV neutropenia, but subsequently amended the protocol to redefine DLT as grade IV neutropenia lasting ≥ 7 days. Plasma PK evaluations were conducted for each drug when administered alone (Cycle 1 Day 1, 21) and together (Cycle 2 Day 1). Serial samples were evaluated by LC-MS and data were modeled using a standard, two-stage approach. Results: 18 patients were enrolled over 3 dose levels (9 at 60 mg/m2; 6 at 70 mg/m2 and 3 at 75 mg/m2) in the phase I portion and to date 9 more patients have been enrolled in a dose expansion cohort at a docetaxel dose of 70 mg/m2. Patient demographics include median age 69, PSA level 87.3 ng/ml, hemoglobin 12.7 g/dl, and KPS 90%. DLT, initially any grade IV neutropenia, was seen at every dose level, however no grade IV neutropenia has lasted ≥ 7 days and no MTD has been defined to date. Drug-related grade III/IV toxicities included only neutropenia (42%); grade I-II toxicities included fatigue, peripheral edema, and nausea. To date, 5 of 15 evaluable patients who have been treated with 70–75 mg/m2 of docetaxel and 10 mg of atrasentan demonstrate a sustained PSA response. Preliminary PK data in 11 patients show a mean docetaxel terminal half-life of 46 hr and systemic clearance of 55 L/hr. The median difference in systemic clearance between the cycles was 18% with values increasing in 67% of subjects. Conclusions: The combination of docetaxel and atrasentan appears to be well tolerated to date. The study is ongoing to more accurately determine safety, response and potential pharmacokinetic interactions.

[Table: see text]
Tumor location does not impact return of renal function following partial nephrectomy
Authors: Pettus J. , Sharp D. , Ofer Y. , Bach A. , Russo P.
Published: March 2020

14511

Background: To study the impact of tumor location on the glomerular filtration rate (GFR) changes following partial nephrectomy. Methods: We reviewed our institutional database to identify patients who underwent partial nephrectomy between 1/1995 and 7/2005. Preoperative CT and/or MRI studies were reviewed to characterize tumors as either central or peripheral. Central tumors were defined as those involving the collecting system or renal sinus; all others were categorized as peripheral. We used the Abbreviated Modification of Diet in Renal Disease study equation to estimate GFR preoperatively, in the early postoperative hospital stay, and at 1 and 12 months after surgery. Multivariate models were fit to determine the association of tumor location with changes in GFR at each time period after controlling for age, sex, tumor size, American Society of Anesthesia Score, ischemic time, operative time, and blood loss. Results: A total of 616 patients (265 central and 351 peripheral tumors) were available for analysis. Patients with central tumors were younger compared to those with peripheral tumors (62 vs. 59, p = 0.014), had longer intraoperative renal ischemia (40 vs. 30 min, respectively, p < 0.001), and had longer operations (201 vs. 184 min, respectively, p = 0.01). Although baseline GFR did not differ between the groups, a significantly larger decrease in GFR was found in patients with central compared to peripheral tumors in the early postoperative period (−16 vs. −11 cc/min/1.73 m2, p = 0.013) and 1-month follow-up (−10 vs. −6 cc/min/1.73 m2, p = 0.017). The GFR change was similar at 1-year follow-up, −10 and −11 cc/min/1.73m2 (p = 0.586) for central and peripheral tumors, respectively. On multivariate analysis, tumor location was not significantly associated with the change in GFR at any of the time intervals after adjusting for size, ischemic time, operative time, age, sex and comorbidity. Conclusions: Patients with centrally located tumors have a more pronounced short-term decrease in GFR, which reflects a longer operative time and ischemia duration. Tumor location does not appear to impact the long-term renal function. This suggests that renal sparing surgery should not be withheld from this subset of patients.

No significant financial relationships to disclose.
A phase I/II trial of RAD 001 with gefitinib in patients with castrate metastatic prostate cancer and glioblastoma multiforme
Authors: Shaffer D. R. , Abrey L. E. , Beekman K. , Eicher C. , Morris M. , Slovin S. , Feldstein J. , Larson S. , Rosen N. , Scher H. I.
Published: March 2020

14520

Background: Inactivation of the Pten tumor suppressor gene, leading to constitutive activation of the PI3K/AKT/mTOR pathway, is correlated with resistance to EGFR-targeted therapies. This trial tested the concept that inhibition of mTOR by RAD 001 (NOVARTIS) will restore sensitivity to EGFR inhibition by gefitinib (ASTRA ZENECA), in patients with progressive PC and GBM. Methods: Phase I was designed to determine a safe and tolerable dose and the pharmacokinetics (PK) of RAD (30/ 50/ 70 mg po weekly) with a fixed dose of gefitinib (250 mg po qd) in patients with PC and GBM. Phase II evaluated the proportion of PC patients with no change or a decline in PSA at 12 weeks, without clinical or radiographic progression. FDG PET imaging and immunohistochemistry were included as correlative studies. Results: 12 patients (2 GBM, 10 PC) were treated in Phase I, and 22 of 27 PC patients have been treated in Phase II. (The GBM Phase II results are reported separately). 20/32 (63%) of PC patients had received prior chemotherapy. No dose limiting toxicities were observed in Phase I, and 70 mg of RAD 001 weekly with gefitinib 250 mg qd was studied as the Phase II dose. PK parameters estimated during a 3 week single agent lead-in phase and during subsequent combined therapy suggested no clinically relevant PK interactions between RAD and gefitinib. The most common drug-related grade 3/4 toxicities were lymphopenia (28%) and elevated ALT (7%). Serial FDG PET scans showed > 25% decline in SUV uptake in 9/23 evaluable patients during the first week of treatment; of these, 3 patients showed no progression at 12 weeks. Overall, 5/29 PC patients showed no progression at 12 weeks, 3 (60%) of whom had received prior chemotherapy. Conclusions: Combination therapy with RAD 70 mg weekly and gefitinib 250 mg daily appears to be safe and is associated with modest activity in metastatic prostate cancer. Support: Novartis Pharmaceuticals, Astra Zeneca Pharmaceuticals.

[Table: see text]
Matrix metalloproteinase type 2 (MMP2) is selective expressed in adrenocortical carcinoma but not in adrenal adenoma: An immunohistochemical study
Authors: Sperone P. , Volante M. , Berruti A. , Bollito E. , Frangipane E. , Daffara F. , Terzolo M. , Gorzegno G. , Dogliotti L. , Papotti M.
Published: March 2020

14534

Background: Adrenocortical carcinoma (ACC) is a very rare disease which account for no more than 0.2% of all malignancies, and its differential diagnosis from adrenocortical adenomas (ACA) is based on the application of different scoring systems, which, however, lack a sensitivity and specificity of 100%. Little is known on the mechanisms leading to the malignant phenotype in adrenocortical tumors; among alternative mechanisms, metalloproteinases (MMPs) have been demonstrated in solid tumors, including endocrine ones, to be implicated in malignant progression and metastatization. Our aim was to investigate metalloproteinase 2 (MMP2) expression in adrenocortical tumors. Methods: A series of 33 ACC and 23 ACA was retrospectively collected from a large series of adrenocortical lesions, and the diagnosis was reviewed independently by three investigators (MV, EB, MP) according to the Weiss histological criteria. MMP2 was determined by immunohistochemistry and the results scored by semi-quantitative analysis, based on the intensity of the staining and the percentage of tumor cells positive. Immunohistochemical results were compared to clinico-pathological parameters, such as sex, age, hormonal secretion, and outcome. Results: MMP2 expression was detected in 1/23 ACA (4%), and in 25/33 ACC (76%) (X-square test p < 0.001). MMP2 immunohistochemical pattern in ACC was focal to moderate to strong in 10, 12 and 3 cases, respectively. In addition, moderate to strong MMP2 expression, as compared to low or negative immunostaining, correlated with shorter disease-free survival (p = 0.012) and poor outcome (p = 0.07). No correlation were found comparing MMP2 expression and other clinico-pathological parameters. Conclusions: As reported in a variety of solid tumors, our data indicates a possible role of MMP2 in the malignant evolution of adrenocortical tumors, and its immunohistochemical localization may be a potential useful tool in the differential diagnosis of benign versus malignant adrenocortical lesions. In addition, a strong immunohistochemical MMP2 expression seems to be related to a poor prognosis in ACC.

No significant financial relationships to disclose.
Altered expression of β-catenin and UDP-glucose dehydrogenase in normal appearing acini of cancer-bearing prostate glands, detected by quantitative fluorescence imaging analysis
Authors: Huang D. , Casale G. P. , Wehbi N. K. , Tian J. , Hemstreet G. P.
Published: March 2020

14540

Background: Expression of β-catenin and UDP-glucose dehydrogenase (UGDH) is markedly altered in prostate adenocarcinomas. The objective of this work was to evaluate expression of these proteins in normal appearing acini (NAA) of cancer-bearing prostate glands, as potential biomarkers of PC field disease. Methods: Archived core biopsies of 42 pairs of PC cases and controls were labeled for β-Catenin, and a tissue microarray of 10 prostatectomy specimens of cancer cases and controls were labeled for UGDH. A fluorophore-conjugated secondary antibody was incorporated into the staining protocol. Fluorescence in prostatic acini was measured with an automated Leica microscope and Image Pro Plus software and expressed as mean pixel intensity (MPI) per acinus and average MPI (AMPI) per case or control. Results: Mean AMPI of β-catenin in NAA of 33 cases (545 ± 93) was lower (p < 0.01) than that of normal acini (NA) in age-matched controls (684 ± 90), whereas mean AMPI of NAA in the remaining 9 cases (712 ± 111) was higher (p = 0.003) than that of the matched controls (634 ± 95). Twelve cases under-expressing β-catenin in NAA had AMPIs below the lowest AMPI (506 ± 83) of all controls. Mean AMPI of UGDH in NAA of 7 cases (372 ± 169) was lower (p < 0.05) in comparison to both NA (558 ± 119) and cancerous acini (CA) (645 ± 88). The difference between CA and NA did not achieve statistical significance. Conclusions: Reduced expression of β-catenin is a cancer-associated event in NAA. A cut-off AMPI (506) for β-catenin detected 29% of PC cases with 100% specificity. Altered expression of UGDH in NAA is a potential biomarker of PC. Funded by DoD grant DAMD17–02–1-0121.

No significant financial relationships to disclose.
Permanent 125I prostate brachytherapy outcome in patients younger than 60
Authors: Linstadt D. E. , Logsdon M. , Stickney D. , Chabra D. , Russo M. , Workman S.
Published: March 2020

14553

Background: Permanent 125I prostate brachytherapy (PB) has been shown to be an effective form of treatment for men with clinically localized prostate cancer. However, the efficacy of PB in younger men is not well established, and many urologists and oncologists have been reluctant to recommend PB to younger men, since most reported PB outcome has been based on men implanted in their late 60s and 70s. Methods: Between 1/1/98 and 6/30/01, 100 consecutive men aged 49–59 (median 56) underwent PB. All had either low- or intermediate-risk disease. PB was performed without combined external beam irradiation or post-PB androgen deprivation. The prescribed radiation dose=144–145Gy, the median implant activity=38mCi, median prostate volume=36 ml. Mean day-30 post-PB CT-based implant dosimetry values were V100=94%; V150=60%; D90=160 Gy. The primary endpoint for this analysis was the 5-year biochemical no evidence of disease rate (bNED) defined by the ASTRO consensus definition. Secondary endpoints were disease-specific survival (DSS); freedom from salvage therapy (FSRx), and overall survival (OS). Median PSA followup was 59 months (maximum 93 months). Actuarial results were calculated using the Kaplan-Meier method. Results: The 5-year bNED rate was 92%. 8 patients developed biochemical failure, and 6 went on to salvage treatment with hormonal therapy. There were 2 biopsy-proven local recurrences: one in a patient with previously diagnosed bony metastases, and one with isolated seminal vesicle recurrence (prostate biopsies negative). 3 other patients with biochemical failure had negative re-biopsies at 24, 64, and 66 months post-PB. No patient received local salvage therapy. One patient died from a second malignancy (colon CA diagnosed after PB). The 5-year DSS rate = 100%; FSRx = 93%, and OS = 99%. There were 2 Grade 3 GU complications (urethral strictures) (2%) and one Grade 4 GU complication (TURP) (1%). There were no Grade 3 or 4 GI complications. Conclusions: PB is an effective treatment modality for men younger than 60, with 5 year results comparable to those reported with prostatectomy and external beam irradiation. Given that most men who fail PB do so within 5 years of the implant, there appears to be no compelling scientific reason to advise against PB in men younger than 60 solely based on their age.

No significant financial relationships to disclose.
Phase II study of FK228 in patients with hormone refractory prostate cancer (HRPC)
Authors: Molife R. , Patterson S. , Riggs C. , Higano C. , Stadler W. M. , Dearnaley D. , Parker C. , McCulloch W. , Shalaurov A. , De-Bono J. S.
Published: March 2020

14554

Background: FK228 is a bicyclic depsipeptide that inhibits histone deacetylase (HDAC). HDAC inhibition results in accumulation of hyperacetylated histone proteins resulting in G1 and G2/M arrest, differentiation of transformed cells and apoptosis. FK228 can also inhibit HSP90, ablating androgen receptor expression. Methods: FK228 was administered intravenously at 13mg/m2 on days 1, 8 and 15 of a 28-day schedule for up to 6 cycles. Sixteen patients were treated in stage 1. If ≥ 1 response was seen, an additional 9 patients were to be recruited. Eligibility criteria included: no prior chemotherapy, metastatic disease, ≤3 lines of hormonal therapy, QTcB <500 msec, Karnofsky PS ≥80. The primary endpoint was to measure rate of disease control (complete response [CR], partial response [PR], stable disease [SD] for 6 months). Secondary endpoints were PSA response rate, time to PSA and objective disease progression, safety profile, effect on disease related symptoms and pharmacokinetics (PK) of FK228. Results: Interim results are available after 16 patients were enrolled in stage 1 and 5 patients in stage 2. Median age (n = 21): 65 years (range 43–77). 3 patients have completed 6 cycles of treatment, 4 are ongoing and 14 have discontinued. 16 patients are evaluable for radiological response and 18 for PSA response: 1 has achieved a confirmed radiological PR (6 months [m]), and 6 have confirmed SD (2 for 6m, 1 for 5 m, 1 for 4 m+, 1 for 3 m+). 2 of 18 have had a 50% fall in PSA (6 m, 4 m+) and another a 40% fall (5m). Most common drug related adverse events are (grade [gr],%): fatigue (gr 1–2, 88%), nausea (gr 1–2, 77%; gr 3, 10%), anorexia (gr 1–2, 72%), vomiting (gr 1–2, 55%; gr 3, 10%), non-specific asymptomatic ECG changes (gr 1–3, 44%), diarrhoea (gr 1–2, 38%), thrombocytopaenia (gr 1–2, 33%) and weight loss (gr 1, 20%). Conclusions: Interim results of treatment with FK228 suggest clinically relevant antitumor activity with an 18% disease control rate and a 11% PSA response rate. Toxicity is manageable. Accrual into the study continues.

[Table: see text]
Salvage radiotherapy (SR) in patients (pts) with prostate cancer (PC) and rising prostate specific antigen (PSA) after radical prostatectomy (RP): Results from a single-center study
Authors: Wiegel T. , Lohm G. , Hoecht S. , Bottke D. , Neumann K. , Hinkelbein W.
Published: March 2020

14556

Background: In pts with PC and biochemical relapse after RP SR is well established. However, the significance of pre-radiotherapeutic variables for guidance of treatment decisions is less clear. We analyzed prognostic factors in a large cohort of pts treated with SR after RP. Methods: 163 pts with PC and persisting PSA-levels (n = 60) or PSA-elevation following undetectable PSA-levels (n = 103) after RP received three-dimensional conformal radiotherapy (RT). None received androgen depriving therapy between prostatectomy and start of RT. We evaluated the impact of age, stage, surgical margin status (SMS), Gleason score and PSA-kinetics by survival and regression analysis. Biochemical progression (BP) was defined as PSA-increases at 3 consecutive time points after the post RT nadir. To detect thresholds for significant prognostic variables, we calculated receiver operating characteristic (ROC) curves. Results: Medians for pre-RT variables were: 11.97 ng/ml for pre-prostatectomy PSA (Pre-OP PSA), 5.4 months for PSA doubling time (PSADT) and 0.339 ng/ml for pre-radiotherapy PSA (Pre-RT PSA). Probability for a projected 4-year PFS was 50% (median follow-up: 33.5 months). Logistic regression revealed a significant impact on the probability of BP for Pre-OP PSA (p = 0.036), PSADT (p = 0.024) and tumor-stage (p = 0.043), whereas Pre-RT PSA and SMS had a significant impact on achievement of undetectable post-RT PSA (p = 0.009 and p = 0.028 respectively). Analysis of ROC-curves for Pre-OP PSA, Pre-RT PSA, PSADT revealed an area under the curve not exceeding 0.704 for any of these parameters. Conclusions: By analyzing ROC-curves we could not detect clear thresholds for PSA kinetic variables. In accordance with recently published data we found similar independent significant variables predicting a therapeutic success. However, we observed a lower median Pre-RT PSA and a higher probability of PFS in our patient cohort. This suggests, that early radiotherapeutic intervention improves PFS.

No significant financial relationships to disclose.
Diagnosis of local relapse after radical radiotherapy (RRTH) of prostate cancer by biochemical PSA kinetics and transrectal ultrasonography (TRUS) verified by prostate biopsy
Authors: Nietupski K. E. , Demkow T. , Skoneczna I. , Pilichowska M. , Peczkowski P. , Kraszewska E. , Ligaj M. , Poniatowska G. , Sieczych A. , Chaladaj-Kujawska A. , Sikora B.
Published: March 2020

14631

Background: Patients (pts) with the cancer of the prostate after radical radiotherapy (RRTH) are followed by clinical examination, periodical measurements of PSA level, bone scan, bone x-ray examinations, CT of abdomen and pelvis. The biochemical progression (according ASTRO Consensus Panel) is not always equal the clinical progression. The next step in all cases of rising PSA is to diagnose or to exclude the local progression, which has to be distinguished from systemic progression. Methods: Prospective evaluation of effectiveness of the biochemical indicators as predictors of local relapse after RRTH and probability of positive tru-cut biopsy outcome in case of positive TRUS result. 51 pts with prostatic adenocarcinoma after RRTH, who experienced biochemical (PSA) progression were included. All of them had a negative bone scan results, negative abdomen-pelvis CT scan or ultrasonography and no clinical evidence of distant metastases. All pts underwent a tru-cut biopsy guided by TRUS. Each of them were eligible to local salvage procedures. The TRUS-guided tru-cut biopsy were performed in all pts. Results: The median observation time (between RRTH and biopsy) was 34 mo (11–78). The median PSA level at the biopsy was 2.46 ng/ml (0,69–11,26). TRUS was positive in 20/51 pts. In 31 pts, there was no evidence of local progression in TRUS. TRUS specificity was 62.02% (95% CI 48.75–75.39%) and sensitivity 40.91% (95% CI 27.42%–54.40). The biopsy outcome was positive in 22/51 pts (43%). The biopsy was positive in 58% (25/26) in subgroup with PSA level lower than 2.46 ng/ml and 27% (7/25) in group with PSA upper to this value. There were no significant associations between positive biopsy outcome and PSA velocity. Conclusions: In pts with suspicion of local relapse we observed the low predictive value of PSA level at biopsy (area under ROC curve = 0.6113). There were no associations between positive biopsy outcome and PSADT (PSA doubling time) which could help in better selection for invasive procedure.

No significant financial relationships to disclose.
Fixed infusion rate (FIR) gemcitabine (G) based treatment for advanced renal cell carcinoma (ARCC): Efficacy and toxicity data from a phase II study
Authors: Zustovich F. , Cartei G. , Ceravolo R. , Salmaso F. , Zovato S. , Artioli G. , Cingarlini S. , Binato S. , Pastorelli D.
Published: March 2020

14632

Background: ARCC is still an untreatable disease because high dose IL2 therapy is feasible and effective only in a small percentage of patients (pts). Standard dose IL2 is palliative as well as every other treatment. G is a well tolerated agent, even in aged pts and is moderately effective in ARCC. FIR of 10 mg/m2/min increases intracellular G active metabolites and may enhance therapeutic and toxic effect. Aim of study was to evaluate the FIR-G effectiveness in ARCC. Methods: G was administered IV at 10 mg/m2/min FIR for 50 to 1250 min according to age and PS on day 1,8,15 every 28. Immunotherapy (IT) was IL2 3MU subcutaneously daily for 5 days a week or Alfa-INF 3MU three days a week, chronically given. Results: We enrolled 23 pts; 5 female; median age 59 years (29–75), all stage IV disease, all nephrectomized with histologically confirmed clear cell carcinoma; median Fhurman’s grade was 3 (1–4); median PS was 2 (0–3); 9 pts had bone mets; prior treatments: IT, mostly low doses IL2, in 12 pts; chemotherapy in 7 pts and palliative radiotherapy in 9 pts. 125 cycles (median of 5, range 1–35) were administered with a median G dose of 1050 mg/m2 over 105’. 13 Pts received IT (11 pts were IT naïve and received IL2 and 2 pts previously treated with IL2 received Alfa-INF). In the 22 pts valuable for toxicity grade 1–2/#pts was: granulocytopenia/5, anemia/2, nausea/5, vomiting/2, constipation/1, mucositis/1, fever/1, infection/1, fatigue/2, cutaneous/5, peripheral edema/4; grade 3–4 was: anemia/3, nausea/1, fatigue/3, cutaneous/1, vascular venous/1, peripheral edema/1. 26 cycles had to be delayed due to side effects. In the 22 valuable pts we reported 3 PR with a RR of 14% and 11 pts (50%) had SD. All pts were valuable for TTP with a median of 5.6 months (1–35). Data on OS are still immature with a median of 15+ (3–55+). Conclusions: FIR-G ± IT is safe and moderately effective against ARCC. Due to the small number of pts no separate analysis is possible between G ± IT or prognostic factors groups. Nevertheless our TTP and OS data are promising considering the detrimental prognostic factors in the treated population. Present work was part of studies program of, and partly supported by, AOI (Associazione Oncologia Italiana), Padova, Italy.

No significant financial relationships to disclose.
Oral bisphosphonates fail to prevent bone loss from androgen deprivation therapy in men with prostate cancer
Authors: Lam R. Y. , Scholz M. , Guess B. , Trilling T.
Published: March 2020

14643

Background: Androgen deprivation therapy (ADT) is a widely administered treatment for prostate cancer. However, ADT is associated with accelerated bone loss, osteoporosis, and fractures (Shahinian, NEJM 2005; 352:154). According to Smith et al, annual bone loss on ADT approaches 9% (Smith, NEJM 2001;345:948), using QCT densitometry, a highly sensitive test for the detection of osteoporosis in men. Intravenous bisphosphonates (pamidronate, zolendronate) have been shown to prevent ADT-related bone loss in randomized phase III trials. We performed a retrospective analysis to determine if oral bisphosphonates effectively prevent bone loss in men receiving ADT. Methods: Twenty two men, ages 60–80, were placed on alendronate or risendronate at the initiation of ADT. Baseline and follow-up bone mineral densitometry (BMD) studies were performed with QCT densitometry. Repeat BMD was performed 12- 27 months (mean = 17mo) after the baseline BMD. Percentage change in bone density was annualized. Within each treatment group, the hypothesis of no mean change from baseline was analyzed using a paired t test. Results: Mean baseline bone density was 122.6mg/cc. Mean follow-up bone density was 112.7mg/cc. For the whole group, the annualized mean change in BMD was negative 7.77%/yr (p = 0.0003). Of note, 9/22 men maintained or gained bone density (-1.26% to +5.95%). 13/22 men lost at least 6.03% (-6.03% to -23.2%). There was no unexpected toxicity or fractures. Conclusions: In this retrospective study, prophylactic oral bisphosphonates do not protect against accelerated ADT-induced bone loss in men with prostate cancer.

No significant financial relationships to disclose.
Talactoferrin alfa is an anti-cancer agent with activity in renal cell cancer (RCC) patients and a novel immunomodulatory mechanism of action
Authors: Varadhachary A. , Spadaro M. , Engelmayer J. , Blezinger P. , Valli T. , Petrak K. , Pericle F. , Mokyr M. B. , Forni G. , Hayes T. G.
Published: March 2020

14648

Background: Talactoferrin alfa (talactoferrin) is a novel, orally administered immunomodulatory protein with demonstrated anti-cancer activity in preclinical experiments. Methods: Talactoferrin’s safety and efficacy in cancer patients was evaluated in a Phase I/II trial. Patients with metastatic disease who had failed standard therapy were treated with single-agent oral talactoferrin. Tumors were measured by CT scan using RECIST criteria. Talactoferrin’s mechanism of action was evaluated in preclinical experiments in tumor-bearing immunocompetent BALB/c and knockout mice. Cytokine levels were measured by ELISA. Cellular changes were measured by FACS analysis and immunofluorescence. Results: Seven patients with metastatic RCC who had failed previous systemic therapy were treated with oral, single-agent talactoferrin. Talactoferrin was safe and very well tolerated without a single drug-related SAE. All seven patients achieved at least Stable Disease, with one patient showing a deep and sustained partial response (71% shrinkage by RECIST two years after start of therapy). There was an apparent increase in median PFS to 7.3 months, with two patients still progression free after two years. Median OS has not yet been reached. In experiments conducted to define its anti-cancer mechanism, orally administered talactoferrin was found to act at the gut and the Gut Associated Lymphoid Tissue (GALT). Talactoferrin induced the chemotaxis of immune cells to intestinal Peyer’s Patches in mice, initiating an immunostimulatory cascade in the GALT and activating both innate and adaptive immunity. We observed significantly increased numbers of Dendritic Cells, NK-T cells and CD8+ T-lymphocytes in small intestinal Peyer’s patches, a systemic increase in Natural Killer (NK) and Cytotoxic T-lymphocyte (CTL) activity, activation of tumor draining lymph nodes, and cellular infiltration of distant tumors. The critical role of NK-T and CD8+ cells was demonstrated in knockout and depletion experiments. Conclusions: Talactoferrin, a first-in-class molecule with apparent clinical anti-cancer activity in RCC, acts through a novel immunomodulatory mechanism of action.

[Table: see text]
Genetically altered Salmonella typhimurium profoundly increases survival in nude mice with metastatic PC-3 prostate tumors
Authors: Hoffman R. M. , Zhao M. , Geller J. , Yang M. , Ma H. , Tan X. , Li X.
Published: March 2020

14653

Background: We previously published that a genetically-altered Salmonella typhimurium, expressing GFP, could completely destroy subcutaneously-implanted PC-3 tumors in nude mice when injected locally or intravenously (PNAS 102, 755–60, 2005). The bacteria are leu-arg auxotrophs which enable the bacteria to grow in PC-3 tumors but not in normal tissue. Methods: In the current study, we explore the effect of this bacteria, termed S. typhimurium A1, on metastatic PC-3 tumors orthotopically implanted in nude mice. PC-3 is a non-hormone-dependent prostate cancer. In this study, 20 mice were implanted orthotopically with PC-3 tumors expressing GFP. Approximately 2 weeks following implantation, the tumors were externally imageable. Ten of the 20 mice served as controls and followed until death without treatment. Ten mice were given the S. typhimurium A1 weekly intravenously, beginning at 2 weeks when the tumor GFP was first externally visible, and survival time was compared to the untreated mice. Ten additional non-tumor-bearing mice served as controls for the possible toxicity of S. typhimurium A1 and were also injected weekly with the bacteria intravenously. Results: Of the 10 mice with the PC-3 tumors injected weekly with S. typhimurium A1, 7 were alive and well at the time the last untreated mouse died. Currently, 4 treated mice remain alive and well 17 weeks following implantation. 3 of these 4 mice had no external fluorescence for the past 5 weeks despite discontinuing S. typhimurium A1. One mouse shows a progressive decrease in fluorescence, only a tiny spot if left. This mouse continues on S. typhimurium injection weekly. Conclusions: Injection of genetically-altered leu-arg-auxotrophic S. typhimurium into mice with metastatic PC-3 tumors has resulted in more than the tripling of lifespan of 4 of the mice. Three of the mice appear “cured” and have not external fluorescence despite discontinuing S. typhimurium treatment for the past 5 weeks. One mouse continues on weekly injections of S. typhimurium and is well with decreasing fluorescence. Since human prostate cancer eventually becomes non-androgen-dependent similar to PC-3 tumors, genetically-altered bacteria represent a novel potential treatment for this disease.

No significant financial relationships to disclose.
Chemotherapy with a combination of consecutive low-dose cisplatin with ifosfamide and epirubicin (CLD-IEP) in sarcoma uteri
Authors: Shimizu Y. , Katase K. , Ishiya T. , Takahashi Y. , Yamada M. , Umezawa S. , Utsugi K.
Published: March 2020

15016

Background: To evaluate the efficacy and toxicity of CLD-IEP for patients (pts) with sarcoma uteri. Methods: Eligible criteria were: a histologic proof of advanced or recurrent sarcoma uteri; measurable lesions; age between 18 and 75 yrs; WHO PS 0–3; WBC ≥ 3,000/μL; platelet count ≥ 100,000/μL; hemoglobin level ≥ 9 g/dL; adequate liver function; C-Cr ≥ 40 mL/min; no lung, heart, or brain disease; no previous neoplastic disease; no prior chemotherapy; and informed consent. The CLD-IEP regimen was ifosfamide 700 mg/m2 infused over 2 hrs days 1 through 4; epirubicin 50 mg/m2 bolus day 7; and cisplatin 15 mg/m2 infused over 2 hrs days 1 through 5. The treatment was repeated at 4-week intervals. Results: To date, thirty-eight eligible pts (17 leiomyosarcoma [LMS], 4 endometrial stromal sarcoma, and 17 carcinosarcoma) were enrolled in this study and all pts were assessable for response, toxicity, and survival. The median age was 53 yrs (range, 37–77). Twelve pts received CLD-IEP in the neoadjuvant setting. Nine pts had prior radiotherapy. After a median of 4 cycles (range, 2–13), we observed objective responses in 22 pts (58%), with 5 (13%) CRs and 17 (45%) PRs (95% CI, 40% to 76%, 4% to 22%, 27% to 63%, respectively). Of 17 pts with LMS, 1 CR and 7 PRs (1 pt with good PR surviving more than 48 months after the start of CLD-IEP) were observed. Median overall survival time (MOS) after the start of CLD-IEP for all 38 pts was 17.5 months (range, 2.7 to 61.5). MOS was 20.8 months in the responders versus 9.9 months in the non-responders (Log-rank, p = 0.023). The median progression-free survival time of the responders was 10.5 months. NCI-CTC grade 3 or 4 leucopoenia, neutropenia, thrombocytopenia, and anemia occurred in 63%, 75%, 12%, and 18%, respectively. There was no significant nausea/vomiting, nephrotoxicity, or CNS toxicity. Conclusion: CLD-IEP regimen has significant to moderate anti-tumor activity with acceptable toxicity in pts with sarcoma uteri including LMS.

No significant financial relationships to disclose.
Residual tumor status in clinical trials of advanced ovarian cancer: A systematic review
Authors: Beltrán M. , Hernández X. , Abal C. , Velasco M. , Rubio J. , Colomer R.
Published: March 2020

15024

Background: To determine whether the proportion of optimal disease status after surgery has changed along a defined period (the platinum era) on the setting of randomized clinical trials (RCT) in advanced ovarian cancer ( AOC). Methods: All RCT of chemotherapy for AOC in the platinum era (accrual period from 1980 to 2002) were searched. Studies were identified in an intensive review in MEDLINE, EMBASE and Cochrane Database, plus bibliographic references in the articles. We included those studies reporting stage, residual disease status and accruing both optimal and suboptimal disease. Simple linear regression models (slrm) were generated to evaluate the proportion of optimal disease status and of FIGO stages over time. Results are reported as two-side p values and 95% confidence intervals. Results: Seventy-five randomized studies, including 20,981 patients, fulfilled the inclusion criteria. Forty-two % of cases had optimal disease after surgery. Stage distribution was as follows: stage I-II, 7.5%, stage III, 72%, stage IV, 20%. Optimal disease status after surgery increased steadily over time, with larger proportions in more recent studies (r=.55; p < .005). Although there was a significant increase in stage I-II cases (r=.41; p < .005), inclusion of patients with stage III and stage IV did not change over time. Conclusions: Reported randomized clinical trials of chemotherapy for advanced ovarian cancer from 1980 to 2002 show a significant trend towards better postsurgical status of residual disease, with a larger proportion of patients with optimal disease in the more recent trials. This is marginally influenced by FIGO stage and therefore, occurs more likely from more extensive surgical debulking procedures. These changes in surgical approach result in an improvement of outcome, that may be independent of the postsurgical treatment used.

No significant financial relationships to disclose.
Early evaluation of response to neoadjuvant chemotherapy in stage IIIC-IV epithelial ovarian cancer patients by 18FDG-PET and CA 125: Preliminary findings from the Arianna Project 02
Authors: Cacciari N. , Fanti S. , Zamagni C. , Rosati M. , Massari F. , Musto A. , Rosati F. , De Iaco P. , Melotti B. , Martoni A.
Published: March 2020

15039

Background: Early evaluation of response to primary chemotherapy (PSC) in epithelial ovarian cancer (EOC) pts could allow to administer a proper number of cycles in order to obtain optimal results. Arianna Project 02 is aimed to investigate early tumor response to PSC correlating a set of routine and experimental hystological, biological and gene-expression profile data with clinical data before, during and after PSC. Methods: Stage III-IV EOC received 6 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m2 and are evaluated at baseline and before each cycle by 18FDG-PET, CA 125, circulating tumor cells and experimental circulating bio-markers. Ultrasounds, CT scan and pelvic MRI are done at baseline and every other cycle. This preliminary report is focused on the correlation between changes of PET and CA 125 serum levels and pathological response. Results: Up to now 6 out of 11 pts completed PSC and surgery. Baseline tumoral 18FDG uptake expressed as Standardized Uptake Value (SUV) and CA125 were abnormal in all pts (SUVmax range: 12.1–20; CA 125 range: 416–2026 U/ml, upper normal limit 35 U/ml). One complete and 4 partial pathological remissions > 90% and one no change were observed. Mean (with range) SUVmax and CA125 decrease (Δ SUV and Δ CA125) measured after the 1st, 2nd, 3rd and last cycle of PSC in the 5 responders are similar (table). In the non-responder SUV decreased by 63% after the 1st cycle of PSC, but increased to baseline value after the 2nd cycle and remained unchanged until surgery, while CA 125 progressively decreased from 416 U/ml to 47 U/ml. Conclusions: These preliminary findings indicate that the behaviour of PET and CA 125 in responders are similar. More data are necessary to define the role of PET in the early evaluation of response to PSC in EOC pts. The study is still ongoing and the relationship between evaluation performed by PET and CA125 and by CT scan, ultrasound and pelvic MRI will be presented at ASCO meeting.

[Table: see text]

No significant financial relationships to disclose.
Is there a CA-125 level that predicts negative second look surgery (SLS) in patients with advanced epithelail ovarian cancer (EOC)?
Authors: Sharma S. , Singhal P. , Odunsi K. , Lele S.
Published: March 2020

15042

Background: The value of second look surgery (SLS) in advanced epithelial ovarian cancer (EOC) has been has been questioned because performing this procedure has not been associated with a clear survival advantage.However, SLS continues to be the most accurate means of documenting the response to chemotherapy, and therfore still used in investigational protocols. The primary purpose of this study was to assess the levels of CA 125 after treatment, that could predict absence of disease at SLS. Methods: Between 1998 and 2003, 98 stage III EOC patients who underwent optimal cytoreductive surgery, completed 6 cycles of platinum/paclitaxel chemotherapy, and were NED (no evidence of disease: normal CA 125, normal physical and radiological examination) were included in this study. SLS was performed at 6–8 weeks from completion of primary therapy. Patients with disease present at SLS were considered to have persistent disease and received second line chemotherapy. Patient demographics, surgical and chemotherapy treatments, and CA 125 levels prior to start and at completion of primary treatment were collected retrospectively. Survival was estimated by the Kaplan-Meier method. Results: Forty seven out of 98 (48%) of optimally debulked patients who were NED at completion of primary therapy underwent SLS. Twenty-five out of 47 patients (53%) had evidence of disease at SLS and 22 out of 47 patients (47%) were NED at SLS. The median disease free survival was 42 months (95% CI 16, 81) in patients with negative SLS compared with 17 months (95% CI 9, 45) in patients who did not undergo SLS (p = 0.03). Estimated 5-year survival in patients with negative SLS was 90% compared to 50% in patients who did not undergo SLS (p = 0.05). CA 125 levels of ≤ 10 after completion of primary therapy was predictive of negative SLS (p < 0.05). Conclusions: SLS evaluation of disease status appears to be a more accurate than standard clinical evaluation in patients who are NED at completion of their primary therapy. Negative SLS also appears to be a predictor of improved disease free and overall survival. Furthermore, CA 125 ≤ 10 is predictive of negative SLS in patients who are NED after completion of primary therapy.

No significant financial relationships to disclose.
Maintenance therapy in epithelial ovarian cancer (EOC): Could EGFR inhibitor- gefitinib be a candidate drug? A pilot study
Authors: Hariprasad R. , Kumar L. , Patnaik R. , Gupta A. , Kumar S.
Published: March 2020

15046

Background: We aimed to evaluate the role of EGFR inhibitor, gefitinib among patients with advanced & recurrent EOC to prolong progression-free survival (PFS). Methods: Between Nov. 2004 and Dec. 2005, 32 patients (median age 45 years, range 33 to 63) have been recruited. The study subjects were - (i) eleven patients with EOC stage IIIC-IV who had gross residual disease (≥1 cm) after primary debulking surgery and had achieved complete response (CR) following six cycles of paclitaxel and carboplatin (Group-I) (ii) Group II - includes 21 patients who achieved CR following salvage chemotherapy for relapsed EOC (1st relapse- 8, 2nd- 8, 3rd -3 & 4th relapse in 2 patients). All Patients received gefitinib 250 mg once daily till evidence of relapse. Patients were examined every month and toxicity (CTC version II) was recorded. Serum CA-125 was done once in 2 months and CAT scan of abdomen & pelvis at 6 monthly interval. The study was approved by Institute Ethics Committee and informed written consent was obtained from each patient before starting Gefitinib. Results: The mean duration of treatment is -5.6 months (Gp-I: 7.7 months, Gp-II: 4.5 months). Toxicity was mild, mainly in the form of skin rash & diarrhoea. Skin rash occurred in 10 patients (31.3%); Group I - 8 patients (grade IV-2, III-2, I-4) & in 2 patients in group II (grade III-1, II-1). Diarrhoea occurred in 7 patients (22%); Group I-1, group II-6) all grade I. No pulmonary or hematological toxicity was observed. Currently, 18/32 patients are on Gefitinib (mean duration of treatment 6.1 months); in 12 patients gefitinib has been discontinued due to relapse (group I- 4, Group II-10). Among 10 patients with skin toxicity (Gp I-8, Gp II-2), 6 continue to be disease-free (Group I- 5, Group II-1) compared to 12 of 22 without skin toxicity. Conclusions: Toxicity to gefitinib was mild, and limited to skin and GIT. Correlation between EGFR expression vs. response can help in identifying patients who possibly might benefit with gefitinib therapy.

No significant financial relationships to disclose.
Efficacy of pegylated liposomal doxorubicin (PLD) and oxaliplatin (OX) in pre-treated advanced epithelial ovarian cancer (EOC) and relation to p53 status
Authors: Nicoletto M. O. , Donach M. E. , Borgato L. , Angelini F. , Artioli G. , Azzoni P. , Perin A. , Barile C. , Bertorelle R. , Cecchetto A. , Cartei G.
Published: March 2020

15054

Background: The efficacy of PLD+Ox in pre-treated advanced EOC in third and fourth line suggests that the elevated survival in these patients might activate the p53 pathway. Methods: Inclusion criteria: Performance Status≤2, relapse or progression after 1–3 lines of therapy; ≤4 prior antiblastic drugs; life expectancy >3 months; LVEF >50%.Treatment consisted of 1 hr infusion of PLD 30–35 mg/m2 on day 1 and 70 mg/m2 of Ox in 2 hrs on day 2 for 8 cycles, then 2 cycles of PLD alone. Clinical response was evaluated by CT scan every 3 cycles. Primary endpoints were overall survival and its correlation with p53. Results: From June 2000, 65 pre-treated pts were enrolled. They were divided according to platinum sensitivity into sens, part-sens and res (time to progression after platinum therapy of ≥12, ≥6 or <6 months). Median age = 65 yrs, range 41–84, (23 pts >70 yrs). 56 pts were evaluable for response: 28 sens with an ORR = 79%, 15 part-sens ORR = 47%, and 12 res ORR = 50%. 445 cycles were administered (median = 6 cycles/pt). Median survival from 1st cycle was 19 months, 10 and 8 months in sens and part-sens and res groups respectively (p = 0.00021). Major (G3–4) toxicities were: neutropenia (6 episodes), gastrointestinal (3 episodes). G1–2 neurosensorial toxicity was seen in 18 pts and PPE in 10 pts. 1 toxic-related death was recorded. Median LVEF showed no significant changes during treatment. There is no clear correlation between OS and amount of Platinum/Taxol administered previously. p53 was analyzed for expression and mutations. Mutations were sought in exons 5, 6, 7 and 8. Immunohistochemistry of 11 amplified samples showed p53 overexpression in 8 pts, of these 7/11 had a CR and/or PR (64%). The analysis is ongoing. The 5-yr survival after first relapse is 64%, 24% and 0% for sens, part-sens and res respectively. 6/6 (100%) evaluable patients with BRCA mutations responded to therapy (5 BRCA1 pts, 1 BRCA2 pt): 4 CR and 2 PR, presently all living. Conclusions: The therapy is effective in increasing OS in Platinum-sensitive patients after re-exposure to Carboplatin and Taxol and may be effective in p53+/mutated pts and for pts with BRCA mutation. For Pt-refractory and Pt-partially-sensitive pts an optimized use of this treatment must be identified.

No significant financial relationships to disclose.
Topotecan therapy as salvage in heavily pretreated ovarian cancer patients (hpocp)
Authors: Wcislo G. B. , Bodnar L. , Nasilowska A. , Szarlej-Wcislo K. , Szczylik C.
Published: March 2020

15057

Background: Topotecan is utilized as to a second-line chemotherapy agent in ovarian cancer. The third or more line of chemotherapy is possibly to use against ovarian cancer which is chemosensitive even when this malignancy progressed. Methods: Prior chemotherapy with platinum compounds, paclitaxel, doxorubicin was used. Topotecan was given as 30-minute infusion at the dose of 1.5 mg/m2 through 5 consecutive days every 21 days. Toxicity profile was assessed according to NCI CTC and response was measured while met RECIST and CA-125 criteria described by Rustin et al. Results: Between 2001 and 2005, 22 hpocop were enrolled onto the study and received at least two cycles of topotecan salvage, median 6 (range 2–6). The patients were previously treated with chemotherapy and characterised 37% (8/22) as platinum-sensitive, 9% (2/22) as partial platinum- sensitive, 27% (6/22) as platinum-resistant and 27% (6/22) as platinum-refractory. Twenty hpocp of the total number of 22 were monitored after chemotherapy through fulfilling RECIST criteria: 7/20 (35%) -PR, 7/20 (35%)-NC, 8/20 (40%)-PD. The clinical response rate in 20 patients with assessable CA 125 levels was 30% (6/20) with 75% response, and 15% (3/20) with 50% response by Rustin et al. criteria. Time to progression of ovarian cancer was median 5,0 months, SD ± 2.0 (range from 2 to 7) and median survival 8 months, SD ± 21 (range from 2 to 39). Toxicity profile was recorded as following: neutropenia 3/4th grade in 8/22 (36%), anaemia 3/4th grade in 9/22 (41%), thrombocytopenia 4th grade in 6/22 (27%), and non-hematologic toxicity relied on alopecia 7/22 (32%). We have not observed fatal outcome after topo salvage therapy. Conclusions: Topotecan could be involved in therapy of patients with ovarian cancer previously heavily pretreated. It offers clinical benefits in ovarian cancer course as to be a stabilised disease despite prior chemotherapy but reliable management alleviates hematologic toxicity.

No significant financial relationships to disclose.