bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II trial of 17-allylamino-17-demethoxygeldanamycin (17-AAG) in patients with hormone-refractory metastatic prostate cancer
Authors: Heath E. I. , Hillman D. , Vaishampayan U. , Sheng S. , Sarkar F. H. , Gaskins M. , Pitot H. C. , Tan W. , Ivy P. , Pili R.
Published: March 2020

15553

Background: 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with anti- proliferative activity in several mouse xenograft models including prostate cancer models. Serum IL-6, IL-8, and maspin are potentially important markers of prostate cancer biology. Methods: Patients (pts) with metastatic, hormone-refractory prostate cancer progressing on at least one prior systemic therapy with rising PSA were eligible. All pts received 17-AAG at a dose of 300 mg/m2 IV weekly for three out of four weeks. Primary objective was to assess the PSA response (50% decrease in PSA). Secondary objectives included Adverse Events (AEs) and correlative serum markers including IL-6, IL-8 and maspin levels. A Simon two-stage design required a total of 25 pts with early termination if < 2 responses occurred among the 1st 16 eligible patients. Results: Seventeen pts were enrolled of which 15 were deemed eligible. Median age was 68 and median PSA was 252 ng/mL. Pts received 17-AAG for a median number of 2 cycles. No pt had a PSA response. No grade 4/5 AEs occurred. Grade 3 AEs included fatigue (4 pts), lymphopenia (2 pts) and back pain (2 pts). The median PSA progression free survival was 1.8 months (95% CI: 1.3–3.4 months). The six-month overall survival was 61% (95% CI: 37%-100%). Due to the lack of PSA response, accrual was stopped per study design. At day 15, the median IL-6 and IL-8 increase from baseline was 0.4 pg/ml (p=0.57) and 3 pg/ml (p=0.73), respectively. Maspin levels had day 15 increase of 6-fold (p=0.44). At treatment failure (TF), the median IL-6 increase from baseline was 4.47 pg/ml (p=0.03) and IL-8 decrease was 1.8 pg/ml (p=0.31). Maspin levels had a 29-fold increase at TF (p=0.09). Conclusions: 17-AAG did not show any activity with regards to PSA response. Serum IL-6 was significantly increased at the time of TF. Further evaluation of 17-AAG at a dose of 300 mg/m2 IV weekly in this patient population is not warranted.

No significant financial relationships to disclose.
Titration of dosage of the protective effect of zoledronic acid in patients submitted to androgen-deprivation therapy due to CaP
Authors: Rodrigues P. , Hering F. , Bruna P. , Meler A. E.
Published: March 2020

15561

Background: Androgen-deprivation therapy is gold-standard treatment for advanced CaP. Zoledronic acid has become a new adjuvant drug for osteoporosis prevention and pain control in patients submitted to androgen-deprivation therapy but regimen of administration is not consensual. Many off-label regimens are used on different occasions. Methods: 64 patients (mean age: 71.7 y-o) after being diagnosed with non-intended to cure therapy were initiated with androgen-deprivation with LHRH agonists at the same time they initiated no treatment (control-16 cases) or monthly (12), bi- monhtly (10), tri-monthly (14) or semestral (12) zoledronic acid infusions for 24 months. Lumbar BMD were evaluated periodically with dual- energy X-ray absorptiometry with densitometry in L2-L4 at 6-month intervals. Tuckey-Kramer and Scheffe`s tests were used for statistical significance of 0.05. Results: Control patients revealed a subgroup showing progressive diminishing BMD along the studied period while another sub-group remained stable. Patients receiving treatment with zoledronic acid showed increasing BMD at the lumbar area (p <0.05) for the 4 treated groups. The protective effects of lumbar BMD were remarkable starting at 18 months in the 4 treated groups with progressive increase of BMD with no clear advantage to any particular regimen (p >0.05). Bone protection could be achieved in the 4 treated groups with no differences for the monthly, bimestral, trimestral or semestral infusions. Conclusions: Zoledronic acid is effective in decreasing bone loss after androgen-deprivation therapy compared to no treatment for osteoporosis. Titration of the dosage regimen of the infusions showed no statistical advantage for any temporal regimen. Reasons for that can only be speculative at this time.

[Table: see text]

No significant financial relationships to disclose.
Minimal invasive perineal radical prostatectomy
Authors: Albers P. , Schaefers S. , Löhmer H. , De Geeter P.
Published: March 2020

15566

Background: Radical perineal prostatectomy (RPP) has experienced a reappraisal as excellent surgical treatment option for patients with localized prostate cancer which is competing well with the retropubic (RRP), endoscopic and robotic approaches. Herein we report a new and improved minimal invasive technique of an intrafascial, nerve-sparing and seminal vesical sparing RPP. Methods: From July 2003 to July 2006, 507 radical prostatectomies (317 RPP, 190 RRP) have been performed by 3 surgeons. RPP selection criteria: PSA ≤ 10 ng/ml, Gleason sum ≤ 7, volume ≤ 50 ml. A minimal invasive technique (MI-RPP) was used in 146 of 317 RPP (46%) in order to potentially improve on the results of classical RPP. “Minimal invasive” was defined as an approach with reduced mobilisation of the rectum, intended bilateral nerve-sparing with intrafascial preparation and leaving the seminal vesicals in situ. This approach was compared to classical RPP and to RRP. Perioperative and follow-up data using validated questionnaires were centrally registered using an on-line internet-based prostate cancer data bank provided by the Tumorzentrum Berlin. Results: With a median follow-up of 12 months (0–24), the oncological outcome of patients with MI-RPP was not different to RPP or RRP (comparable T-stages). PSA relapse in MI-RPP, RPP, and RRP in pT2R0 was seen in 10.2%, 14.7%, and 9.7% respectively (n.s.). Continence rates (0–1 pad/d) at 4 weeks were 61.7%, 45.0%, and 43.8%, respectively. This improved at 12 months to 96.3%, 85.7%, and 85.6%, respectively (p < 0,023; p < 0,005). MI-RPP, RPP, and RRP showed pT2 in 70.5, 69.6, and 57.3% with R1pT2 in 1.9, 6.7, and 9.2%, resp. Nerve-sparing was performed in 90.4, 62.0, and 57.4% with median OR times of 90, 141, and 163 min. Catheter removal after more than 13 d was seen in 6.6, 13.6, and 33.3%, resp. Conclusions: MI-RPP represents an improved perineal technique regarding intraoperative and postoperative complications maintaining comparable oncological outcome to RPP and RRP. Leaving seminal vesicals in place did not increase PSA relapse rates. Since OR time is significantly less and early recovery is superior, MI-RPP should be the recommended first-line perineal approach to patients with low risk prostate cancer. At the time of the meeting, data of more than 600 patients will be presented.

No significant financial relationships to disclose.
Combined treatment image guided-intensity modulated radiotherapy (IG-IMRT) plus high-dose rate brachytherapy (HDR) and hormonotherapy (HT) as treatment for high-risk prostate cancer: Five-year result of a phase II study
Authors: Guix B. , Bartrina J. , Henriquez I. , Serrate R. , Palombo P. , Vendrell J. , Tello J.
Published: March 2020

15571

Background: To report early and late toxicity and preliminary biochemical outcome in 345 patients with high-risk (Gleason >=7; PSA>20 or T2c-T3) clinically localized prostate cancer treated with combined high-dose-rate brachytherapy and IMRT (IMRT-HDR) to the prostate and seminal vesicles with 24–36 months of hormononal treatment (goserelin+bicalutamide) (HT). Methods: Between 12/1999 and 10/2003, 345 patients with PSA>20, Gleason score>6 and/or T2c-T3 N0 M0 prostate cancer were treated with IG-IMRT followed by HDR implant to the prostate and HT. Patients were randomly assigned to receive HT for 24 (group 1, 172 patients) or 36 months (group 2, 173 patients). Acute and late toxicities were scored by the EORTC/RTOG morbidity grading scales. Special attention to local, regional or distant recurrence, survival, late effects, PSA and testosterone levels and quality of life was done. PSA failure was defined as nadir +2.0 ng/ml. Results: All patients completed treatment. One patient included in the group 1 and none of the group 2 experienced grade 3 rectal toxicity (rectal ulcer). Seven patients in each group (4.0%) developed acute Grade 2 urinary symptoms, and none experienced urinary retention. No patient (0%) developed Grade 4 rectal complications or grade 3 or 4 urinary complications. With a median follow-up of 44 months, the 5-year actuarial PSA relapse-free survival rates for the whole group of patients was 95.7 %. No statistical differences between group 1 and 2 patients were found. Conclusions: High-dose IG-IMRT+HDR and HT was a safe and effective method of escalating the dose to the prostate without increasing the risk of late effects. Acute and late rectal and urinary complications were significantly low, compared with what has been observed with high-dose conventional, 3D-conformal or IMRT-only. Short-term PSA control rates seem to be at least comparable to those achieved with 3D-EBRT or IMRT. Both treatment regimes were very effective. Longer follow-up is needed to know if better PSA control rate are achieved with longer HT.

No significant financial relationships to disclose.
Do patients with larger prostates have greater toxicity after external beam radiotherapy for localized prostate cancer?
Authors: Pinkawa M. , Fischedick K. , Asadpour B. , Piroth M. D. , Gagel B. , Krenkel B. , Klotz J. , Eble M. J.
Published: March 2020

15577

Background: To aim of the study was to assess the impact of prostate volume (PV) on health-related quality of life (HRQOL) before and at different points in time after conformal radiotherapy for prostate cancer. Methods: A group of 180 patients has been surveyed prospectively before (time A), at the last day (B), two months after (C) and sixteen months (median) after (D) radiotherapy (70.2- 72Gy) using a validated questionnaire (Expanded Prostate Cancer Index Composite). Patients in this analysis (n=165) met the prerequisite of responding to the first and last questionnaire. The multi-item scale scores were transformed lineary to a 0–100 scale, with higher scores representing better HRQOL. The group has been divided into a subgroup with a small PV (median 32cc; range 11–45; 83 patients) and a subgroup with a large PV (median 59cc; range 46–151; 82 patients). Results: Treatment plans for large prostates implied a larger planning target volume (averagely 396 vs. 305cc; p<0.01) with a significantly larger dose to the bladder and rectum at all volume levels. Patients with large prostates presented with lower urinary bother (averagely 76 vs. 83; p=0.04), but higher bowel bother scores (averagely 95 vs. 90; p<0.01) before the beginning of treatment. At time B, urinary bother scores decreased stronger for patients with large prostates (averagely 22 vs. 16 points). Comparing posttreatment scores to baseline scores, no significant decrease resulted for urinary function or bother scores for both groups at time C and D. At time D, urinary function scores even increased significantly for patients with large prostates (averagely 4 points). Bowel function and bother scores were still significantly lower for both groups at time C and D (averagely 3–8 points). HRQOL scores did not differ significantly between both patient groups at time D. Conclusions: In spite of a higher dose-load to the organs at risk, lower urinary bother scores before treatment and a higher decrease of urinary scores at the end of radiotherapy for patients with larger prostates, long-term HRQOL scores did not differ significantly between patients with large and small prostates. An improvement of urinary function suggests a regression of hyperplastic prostatic tissue.

No significant financial relationships to disclose.
The impact of primary Gleason pattern on survival following brachytherapy for Gleason score 7 prostate cancer
Authors: Adamovich E. , Merrick G. S. , Galbreath R. , Butler W. , Wallner K. , Allen Z. , Gutman S.
Published: March 2020

15588

Background: A recent radical prostatectomy series reported lower rates of biochemical control and cause-specific survival in Gleason score 7 patients with primary Gleason pattern 4. In this study, we evaluated the impact of Gleason 4+3 versus 3+4 on cause-specific, biochemical progression-free and overall survival in patients managed with permanent prostate brachytherapy. Methods: From April 1995 to June 2003, 530 prostate cancer patients underwent brachytherapy for clinical stage T1b-T3c (2002 AJCC) prostate cancer with Gleason score 3+4 (n=300) or Gleason score 4+3 (n=230) histology. All patients underwent brachytherapy more than three years prior to analysis. The mean and median follow-up was 6.0 and 5.7 years, respectively (range 3.2–11.2 years). Of the evaluated cohort, 412 (77.7%) received supplemental XRT and 177 (33.4%) received androgen deprivation therapy. No statistical differences were discerned between the use of XRT, however, Gleason 4+3 patients were more likely (37.4% versus 30.3%, p=0.002) to receive ADT. Multiple clinical, treatment and dosimetric parameters were evaluated as predictors of cause-specific, biochemical progression-free and overall survival. Results: At 10 years, primary Gleason 3+4 versus 4+3 did not predict for cause-specific survival (96.7% versus 93.3%, p=0.506), biochemical progression-free (97.0 versus 92.9%, p=0.085) or overall survival (77.0% versus 78.0%, p=0.9333). Cox linear regression analysis demonstrated no significant predictors for cause-specific survival while pre-treatment PSA, prostate volume and clinical stage predicted for biochemical progression-free survival. Patient age, tobacco use and diabetes were the strongest predictor for overall survival. To date, 57 patients have died (25 with Gleason 4+3 and 32 with Gleason 3+4). Of the deaths, 76% were due to cardiovascular events or second malignancies. To date, 4 patients (2 in each cohort) have died of metastatic prostate cancer. Conclusions: Following brachytherapy, the primary Gleason pattern did not impact cause-specific, biochemical progression-free or overall survival in Gleason score 7 prostate cancer. Cardiovascular disease and second malignancies were responsible for 9 times more deaths than prostate cancer.

No significant financial relationships to disclose.
The effect of androgen deprivation on mini-mental status examination in patients with biochemical recurrence of prostate cancer
Authors: Tan W. , Wehle M. , Graff-Radfford N. , Buskirk S.
Published: March 2020

15592

Background: Androgen deprivation (AD) is a common treatment option for asymptomatic patients with biochemical recurrence of prostate cancer. Side effects such as sexual dysfunction, hot flashes, fatigue and gynecosmastia have been well documented. However, some of the side effects such as osteoporosis, insulin resistance, hyperglycemia, and anemia have only been recently recognized. The effects of AD on memory are not known. Aim: To determine if there is a decline in cognitive function(CF) in patients on AD using the modified MiniMental Status examination (MMSE). This test was chosen because it was simple, easy to administer and reproducible. Methods: We prospectively enrolled men with biochemical recurrence of prostate cancer prior to initiation of AD and monitored their MMSE at baseline, 2 ,and 4 months and while on AD (Mayo Clinic Jacksonville 8/2004- 9/2006). Results: 38 men were enrolled,however, only 20 men had at least 3 MMSE testing done. (5 withdrew consent, 13 had missing MMSE or lost to followup). The mean age was 68 years, mean baseline MMSE score was 27 and none had a clinical diagnosis of dementia or depression. Comparing the first MMSE and the 2nd MMSE score 19/20 patients had no decline of CF except for one patient who had a transient decline of 5 points in his MMSE score during a period of depression ,however, he had subsequent recovery of his score back to his normal baseline 27. Comparing the first and third MMSE score 20/20 patients had no decline of CF. The mean score change in MMSE score was -1 in 3 patients, 0 in 9 patients, +1 in 4 patients, +2 in 2 patients and +3 in 2 patients. There was no decline of 3 or more points in the mean score in any patient. Interestingly, 2 patients had an 3 point improvement of their MMSE score. We felt that it was secondary to being more familiar to the test process and not due to AD. Conclusions: There is no significant decline in MMSE score in men on AD at 2 and 4 months. MMSE might not be able to detect subtle changes in memory therefore, further study with more sensitive test to discriminate CF decline would be warranted and with longer followup cognitive impairement may be more evident.

No significant financial relationships to disclose.
Side effects of sunitinib malate (SM) treatment for patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: Cartenì G. G. , Montano M. , Perrotta E. , Otero M. , Guida T. , Ragone G. , Aurilio G. , Maiorino L. , Stavolo C. , Panza N.
Published: March 2020

15617

Background: SM is a tyrosine kinase inhibitor recently approved for treatment of mRCC. Side effects of treatment have been investigated in 51 pts with mRCC and 35 out 51 enrolled pts resulted evaluable for response. Methods: Pts were clinically evaluated before therapy and each month during SM treatment; haematological and biochemical parameters were measured after each cycle. Thyroid function was also evaluated measuring thyroid-stimulating-hormone (TSH), serum free thyroxine (FT4) and triiodothyronine (FT3), before the start and after 6 months of treatment. Results: Toxicity was evaluated according to NCI-CTC. Neutropenia grade 3 was observed in 7 pts (13,7%), grade 2 in 13 (25%); anemia grade 3 was found in 3 pts (5,8%) and grade 2 in 6 (11,7%); thrombocytopenia grade 3 was found in 6 pts (11,7%), grade 2 in 5 (9,8%). Mucositis resulted a frequent side effect. In fact, 4 (7,8%) pts showed a grade 3 toxicity, 16 (31,3%) grade 2 and 10 (19,8%) grade 1 Among 29 out 35 (82,8%) pts who responded to therapy, 3 had mucositis grade 3, 15 grade 2, 9 grade 1. Conversely, among 6 out 35 (17,1%) pts who had progressive disease during treatment, mucositis was observed in only 2 pts. 24 pts out 35 who received 6 months SM treatment were reevalueted for thyroid function. No patient had thyroid dysfunction before treatment. Conversely, 8 pts showed severe ipothyroidism (TSH, FT3 and FT4 out of the normal range) and 6 others intermediate ipothyroidism (only TSH increased over 20 μU/ml) after at least 6 cycles of therapy. Conclusions: SM therapy represents a new interesting approach to the treatment of mRCC, but shows noteworthy side effects. Regular monitoring of thyroid function with administration of levothyroxin substitutive treatment at the appearance of the thyroid disfunction is required. A direct correlation between grade 2–3 mucositis and clinical response to treatment could be postulated on the basis of our data, although a statistical analysis on a greater cohort of subjects is required to confirm this observation.

No significant financial relationships to disclose.
Clinical activity of transdermal estradiol in patients with hormone and chemotherapy refractory prostate cancer
Authors: Chhabra S. , Doyle-Lindrud S. , Jeyamohan C. , Metzger D. , Todd M. B. , DiPaola R. S. , Goodin S. , Stein M. N.
Published: March 2020

15619

Background: Oral estrogens are an effective treatment for metastatic hormone refractory prostate cancer but are not used because of an increased cardiovascular risk, particularly thromboembolism. Use of alternative formulations that bypass first pass metabolism may be safer and more effective. Therefore, we evaluated the anticancer safety and efficacy of transdermal estradiol (TDE) in patients with hormone refractory prostate cancer. Methods: Patients with metastatic prostate cancer who had progressed on hormonal therapy and at least one chemotherapy regimen that included docetaxel (median of 2 prior regimens, range 1–5) were treated with four TDE 0.1 mg/24 hour patches which were changed every 7 days until disease progression or unacceptable toxicity occurred. Serum prostate- specific antigen (PSA) levels were followed at regular intervals. End-points included PSA response, measurable disease response, time-to- progression (TTP), toxicity and quality of life. Results: In this ongoing trial, two patients out of eleven had a PSA response (confirmed PSA decline by = 50%). In five of the nine patients who did not have a ≥ 50% biochemical response to therapy, the PSA level declined between 2.1% and 25.4%, with a median of 19.9%. Two of the eleven patients have continued on study and are on week 9 and week 14, respectively. For the remaining nine patients who are now of study, the TTP ranged from 4 to 19 weeks, with a median duration of 8 weeks. Treatment toxicity included grade 1 nausea, breast enlargement/ tenderness and/or leg edema in six patients. No thromboembolic or cardiovascular events occurred. Conclusions: Early analysis of this ongoing study reveals modest antitumor activity of TDE with minimal toxicity in heavily pretreated patients with hormone refractory prostate cancer.

No significant financial relationships to disclose.
Statin use and inflammation in prostate biopsy tissue
Authors: Shannon J. , Collins L. , Adams G. , Luhr G. , Garzotto M.
Published: March 2020

15624

Background: The statin class of drugs has been shown to affect tumors through a number of mechanisms including inhibiting tissue inflammation. Inflammation is a common finding in men undergoing a prostate biopsy and may play a role in prostatic tumorigenesis. We set out to determine whether the use of statin drugs was associated with altered tissue inflammation on prostate biopsy. Methods: Data were collected on all men with a PSA </= 10 ng/ml that underwent a prostate biopsy. A urinalysis to rule out the presence of infection was carried out in all men. The presence or absence of cancer and/or inflammation was determined by pathology report review. Statin data were recorded from the VA electronic pharmacy database. Statin duration and intensity variables were calculated for each subject based on total days used for each statin at each prescribed dose. Only men with a negative biopsy were considered in our analyses. Odds ratios (OR) as estimates of the relative risk for prostate inflammation associated with each level of statin use and 95 percent confidence intervals (CI) were obtained using pooled conditional logistic regression stratified on year of biopsy. Results: Out of 1,482 men with data available on inflammation, family history of prostate cancer, age and race; 436 were found to have prostatic inflammation. In final adjusted models stratified on year of biopsy (prior to 1997, 1997–2001, 2001 -2006) we found no association between any statin use (OR=0.88, 95% CI (0.70–1.11)), intensity of use (OR=0.93, 95% CI (0.86–1.01)), or duration of use (OR=0.932, 95% CI (0.86–1.01). These results did not change when individual statin types were analyzed. Conclusions: Statin use was not associated with a reduction in tissue inflammation in men undergoing a prostate biopsy. If statin use affects prostatic carcinogenesis, it is unlikely to do so by affecting tissue inflammatory networks.

No significant financial relationships to disclose.
Variance in physician attitudes toward androgen deprivation therapy initiation for biochemical cancer recurrence
Authors: Hemmerich J. A. , Ahmed F. , Bylow K. , Stadler W. , Dale W.
Published: March 2020

15626

Background: The optimal timing for starting Androgen Deprivation Therapy (ADT) for patients with recurrent prostate cancer (PCa) remains uncertain. In 2004, the American Society of Clinical Oncology deemed the evidence insufficient to recommend early ADT initiation. Recent evidence shows a slight survival benefit to recurrent PCa patients with high risk features; however, early initiation can prematurely reduce patients’ quality of life without providing benefit. This pilot study surveys physician attitudes and practices regarding ADT initiation at a single institution. Methods: Physicians (n=20), including 7 attendings and 13 fellows, who treated biochemically- recurrent PCa patients enrolled in a companion study completed a survey about clinical experience, knowledge of recommendations, and attitudes regarding decisions to start ADT. They also rated the importance of sixteen factors potentially contributing to the decision. Results: Consistent with the ASTRO definition, forty-five percent answered, that three consecutive PSA-rising tests constitute recurrence. For patients with high risk features (Gleason > 7, doubling time < 10 months), 55% said ADT should be started immediately, while only 15% noted that the literature remains unresolved on this issue. For patients without high risk features, 100% would defer ADT. The two factors rated most important in determining ADT initiation timing were PSA doubling time (100%) and patient preferences (95%). Conclusions: Our preliminary data suggest that even within one institution, there is variance in physicians’ definitions of PCa recurrence and the correct treatment strategy. Despite the lack of definitive data on the benefit of early ADT initiation even for high risk patients, over 50% said such patients should start immediately.

No significant financial relationships to disclose.
Expression of EGFR, HER-2 and p53 predictive of prognosis in muscle-invasive bladder cancer
Authors: Sakr W. , Marur S. , Che M. , Heilbrun L. , Smith D. , Powell I. , Pontes E. , Cher M. , Vaishampayan U.
Published: March 2020

15637

Background: The significance of over expression of Erb-1 (epidermal growth factor receptor/ EGFR) and Erb-2 (Her-2) has been reported in various tumors. The aim of this study was to investigate the correlation of the expression of EGFR, Her-2 and p53 with relapse free survival (RFS) and over all survival (OS) in patients with muscle invasive bladder cancer Methods: All patients with muscle invasive bladder cancer diagnosed at our institution between1993and 2004 were considered for the study. Immunohistochemical staining for EGFR, Her2 and p53 performed on formalin-fixed paraffin-embedded archival tissue was evaluated as positive or negative without knowledge of clinical outcome. Survival data determined by reviewing patients medical records were correlated with the staining results. Results: Of the 46 patients who qualified for the study, 40 had slides interpretable for Her 2 and p 53 staining and 38 had slides interpretable for EGFR staining. 35 of 38 were EGFR +ve, 22/40 were Her-2 +ve and 12/40 were p53+ve. The median age of the 46 patients was 67.5 years with a male/female ratio of 60% and 40%. 83% had clinical Stage 2; of those 42%, 23%, and 35% had pathological stages T2, T3 and T4 respectively. Six of 46 (13%), received adjuvant therapy. Tumor histology was pure transitional carcinoma in 56%, or with other components (squamous or adenocarcinoma) in 44%. Median follow-up was 48.8 months for RFS and 44.9 months for OS. Patients with positive EGFR had a median RFS of 34.8 months and median OS of 59.8 months. In patients with negative EGFR, median RFS and OS were not yet reached. Her 2 positive patients had median RFS of 19.2 months compared to 63.8 months in Her-2 negative patients. Her-2 negative patients had median OS of 59.7 months while median was not reached in Her 2 positive patients. Conclusions: While the differences are not statistically significant, the trends observed warrant prospective investigation of the prognostic significance of these markers in a larger population of muscle invasive bladder cancer patients.

No significant financial relationships to disclose.
Monotherapy with a tumor-targeting mutant of S. typhimurium cures orthotopic metastatic mouse models of human prostate cancer
Authors: Hoffman R. M. , Zhao M. , Geller J. , Ma H. , Yang M.
Published: March 2020

15641

Background: The evidence that bacteria have a therapeutic effect on tumors has been accumulating since the 19th century. In recent years, there has been renewed interest to develop bacteria that target necrotic tumor areas. However, this approach requires combination with cytotoxic chemotherapy for efficacy. Toward the goal of effective tumor-targeting bacteria as monotherapy, we have developed Salmonella typhimurium leu-arg auxotrophs (A1-R), which enable the bacteria to grow in viable as well as necrotic areas of tumors but not in normal tissue. Methods: In the current study, we determined the efficacy of A1-R on metastatic PC-3 human prostate tumors orthotopically implanted in nude mice. Ten of 20 orthotopically-implanted nude mice served as untreated controls and were followed until death. Ten mice were given the S. typhimurium A1-R weekly intravenously, beginning at 2 weeks when the tumor was first externally visible due to expression of green fluorescent protein. Survival time was compared to the untreated mice. 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. Four A1-R-treated mice remain alive and well 6 months following implantation. Ten additional non-tumor-bearing mice were used to determine toxicity of S. typhimurium A1-R which were injected weekly. No toxic effects were observed. Conclusions: The approach described here, where bacterial monotherapy could cure metastatic prostate tumors, is a significant improvement over other bacterial tumor-therapy strategies that require combination with toxic chemotherapy. The results also suggest the clinical potential of tumor-targeting bacteria that can grow in the viable as well as necrotic areas of the tumor. 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.
Treatment of metastatic papillary renal cell carcinoma with immunochemotherapy with interleukin-2, interferon-alpha and 5- fluorouracil
Authors: Herrmann E. , Brinkmann O. A. , Bode M. E. , Bierer S. , Köpke T. , Hertle L. , Wülfing C.
Published: March 2020

15644

Background: Combined immunochemotherapy with interleukin-2 (IL-2), interferon-alpha (IFN-a) and 5-fluorouracil (5-FU) is an established first-line therapy for metastatic renal cell carcinoma (RCC). However, data on histologic parameters predictive of clinical benefit are rare. Methods: Treatment courses of 164 patients consisted of IFN-a at 9 x 106 IU on day 1 of weeks 1 and 4 and days 1, 3, 5 of weeks 2 and 3; and at 18 x 106 IU on days 1, 3, 5 of weeks 5–8. Interleukin-2 was administrated at 18 x 106 IU twice daily on days 3–5 of weeks 1 and 4; and at 9 x 106 IU on days 1, 3, 5 of weeks 2 and 3. Additionally, patients received 5-FU at 750 mg m-2 on day 1 of weeks 5–8. In 153 patients, radical nephrectomy had revealed 22 cases of papillary RCC (pRCC, 13.4%) and 131 cases of clear cell RCC (ccRCC, 79.9%). In the remaining 11 (6.7%) their disease was inoperable. The overall response rates were evaluated according to WHO criteria. Results: For ccRCC and inoperable disease, responses of 34.4% and 27.3% after one cycle and 28.8% and 16.7% after two cycles, respectively, were noted. In contrast, no patient with pRCC showed any response after two cycles of combined immunochemotherapy. Conclusions: No objective response was seen in patients with pRCC. Hence, immunotherapeutic agents must be questioned in this histologic subtype.

No significant financial relationships to disclose.
Clinical outcome of patients (pts) with taxane-resistant (TR) hormone-refractory prostate cancer (HRPC) treated with second-line cyclophosphamide (CP) -based metronomic chemotherapy
Authors: Nelius T. , Klatte T. , de Riese W. , Filleur S.
Published: March 2020

15647

Background: For pts with TR HRPC no standard chemotherapeutic treatment exist. In this study we evaluate the efficacy of CP-based metronomic chemotherapy in this pt population. Methods: Pts with metastatic HRPC with disease progression under docetaxel-based chemotherapy were eligible. The primary endpoint was PSA response. Secondary endpoints were time to progression (TTP), survival and toxicity. Low dose CP (50 mg/d) and dexamethasone (1 mg/d) were administered orally in a metronomic manner. Treatment was continued until disease progression. Results: Between February 2005 and May 2006 17 pts were enrolled in this study. The median follow-up was 12 weeks (range: 4–60). Median Age was 68 years (range: 42–85). Median PSA at study entry was 134 ng/ml (range: 46.0–6554). 9 pts had a PSA response (medium 44.4%), 4 pts = 50% and 5 pts < 50%. 8 pts had a PSA progression. The medium time to maximal response was 12 weeks (range: 4–36). TTP/survival for pts with PSA response and PSA progression was 24/60 weeks and 4/4 weeks, respectively. 3 pts of the progression group showed a decrease in PSA doubling time. 5 pts reported a decrease in bone pain after 4 weeks treatment. No grade 3 and 4 toxicities were noted. Conclusions: In this study, low-dose metronomic administered CP demonstrated efficacy as second line treatment in pts with TR HRPC. The treatment was well tolerated and almost without toxicity. The mechanism of action of low dose CP involves inhibition of tumor angiogenesis secondary to inhibition of dividing endothelial cells in tumor associated blood vessels. Dexamethasone may also have antiangiogenic properties by inhibiting the production of vascular endothelial growth factor. Further investigation regarding an antiangiogenic treatment strategy for HRPC are therefore of great interest.

No significant financial relationships to disclose.
Long-term survival in patients with para-aortic lymph node metastasis with systematic retroperitoneal lymphadenectomy followed by adjuvant chemotherapy in endometrial carcinoma
Authors: Hiura M. , Nogawa T. , Matsumoto T. , Yokoyama T. , Shiroyama Y. , Wroblewski J. , Hirata E.
Published: March 2020

16011

Background: The purpose of this study was to assess modified radical hysterectomy including systematic pelvic and para- aortic lymphadenectomy followed by adjuvant chemotherapy in patients with para-aortic lymph node metastasis in endometrial carcinoma and to identify the multivariate independent prognostic factors for a long-term survival over the past 10 years. Methods: Between December 1987 and December 2002, we performed modified radical hysterectomy with bilateral salpingo-oophorectomy including systematic pelvic and para-aortic lymphadenectomy, and peritoneal cytology in 284 endometrial carcinoma patients who gave an informed consent at the Department of Gynecologic Oncology of Shikoku Cancer Center. The patients with a tumor confined to the uterus (stage Ic and II) were treated by 3 courses of CEP (cyclophosphamide 750 mg/m2, epirubicin 50 mg/m2, cisplatin 75 mg/m2) regimen 3–4weeks apart, extrauterine lesions involving adnexa and/or pelvic lymph node (PLN), and para-aortic lymph node (PAN) metastasis were treated by 5 and 10 courses, respectively. Multivariate analysis was performed for the prognostic factors and actuarial technique for the survival rate. Results: PLN and PAN metastasis were 9.2% (26/284) and 7.4% (21/284), respectively. The univariate analysis of prognostic factors revealed that FIGO clinical stage, histology, myometrial invasion, adnexal metastasis, lymphvascular space invasion, tumor diameter, peritoneal cytology and retroperitoneal lymph node (RLN) metastasis were significantly associated with 10-year overall survival. A multivariate analysis showed that adnexal metastasis (p=0.0418) and lymphvascular space invasion (p=0.0214) were significantly associated with 10-year overall survival. The 5- and 10-year survival in patients with negative and positive para-aortic lymph node were 96%, 72% and 93%, 62%, respectively (p=0.006). Conclusions: We conclude that surgery with systematic pelvic and para-aortic lymphadenectomy followed by adjuvant chemotherapy might improve a long-term survival in patients with PAN metastasis in endometrial carcinoma.

No significant financial relationships to disclose.
Evaluation of gemcitabine versus cisplatinum as an adjunct to radiotherapy in locally advanced carcinoma uterine cervix
Authors: Bhatt M. L. , Matin A. , Srivastava M. , Pant M. C. , Srivastava K. , Gupta S. , Rastogi M. , Singh U. , Chhavi D.
Published: March 2020

16012

Background: Locally advanced carcinoma cervix patients are treated by a combination of external beam radiation and brachytherapy. Concurrent chemo-radiotherapy has been an active area of investigation in such patients. In this present study, we have compared two chemotherapy drugs- cisplatinum vs gemcitabine along with radiotherapy in loco-regionally advanced carcinoma cervix with the purpose of evaluating loco-regional disease control and tolerability of these combinations. Methods: This study was undertaken on 65 biopsy-proven patients with stage IIb- IIIb carcinoma cervix. All patients were treated with 50 Gy of external beam radiation with 2 Gy per fraction, 5 days a week followed by intra-cavitary radiotherapy (ICRT). Dose of ICRT delivered by high dose rate brachytherapy was 18 Gy by either of the two schedules, viz. 3 fractions of 6 Gy at weekly interval or 2 fractions of 9 Gy each at one week apart. The concurrent chemotherapy was either inj. Cisplatinum 35 mg/m2 IVI weekly (control group), or inj. gemcitabine 150 mg/m2 IVI weekly (Study group). Results: A total of 65 age and stage matched patients were recruited in the two arms of the study. We analyzed sixty patients who completed the above treatment protocol with 32 patients in control group and 28 in study group. Eighty-nine percent patients in study group had complete response (CR) to the above combination treatment vs. 72% CR in control arm (p< 0.05). However, overall response rate (CR+ PR) was similar in both the groups (96% in study group vs. 100% in control group). No patient in both the groups had grade IV skin reaction with only one patient in study group developing grade III skin toxicity. Grade III gastrointestinal (GI) toxicity was higher in study group as compared to controls (14% vs. 3%) with none of the patients experiencing grade IV GI toxicity. No other significant toxicity was encountered in this study. Conclusions: We can conclude that synchronous chemo-radiotherapy using either gemcitabine or cisplatinum as radiation sensitizer is feasible in locally advanced carcinoma cervix with similar overall response rate and acute toxicity profile with a significantly higher complete response rate when gemcitabine is used as a chemotherapeutic drug.

No significant financial relationships to disclose.
Persistence of EpCAM-positive disseminated tumor cells after platinum-based chemotherapy in the bone marrow of patients with primary ovarian cancer
Authors: Wimberger P. , Heubner M. , Kimmig R. , Scheulen M. E. , Kasimir-Bauer S.
Published: March 2020

16023

Background: The impact of chemotherapy on disseminated tumor cells (DTC) in ovarian cancer is still unknown. Therefore we evaluated in 30 patients with primary ovarian cancer, undergoing radical tumor debulking surgery, (1) the influence of first-line chemotherapy with carboplatinum and paclitaxel on DTC elimination in bone marrow (BM) and peripheral blood (PB), (2) the coexpression of the epitelial antigen EpCAM on DTC and (3) the impact on progression free survival (PFS). Methods: DTC were detected in PB (20ml) and bilateral BM aspirates (10ml) using density gradient centrifugation and immunocytochemistry, applying the anti-cytokeratin antibody A45-B/B3. EpCAM-positive DTC were analyzed by using the antibodies HEA-125-FITC and Ber-EP4-FITC. PFS was estimated using the Kaplan-Meier method and statistically evaluated using a two-sided log-rank test. A significant increase or decrease of DTC was assessed if the difference was = 2 DTC. Results: Before chemotherapy, we identified DTC in 16% of PB samples with a mean number of 2 cells (range 1–3) and in 50% of BM samples with a mean number of 3 cells/9x10E6 BM cells (range 1–8). After chemotherapy, DTC were detected in PB in only one patient but still in 50% of BM samples with a with a mean number of 17 cells/9x10E6 BM cells (range 1–100). In BM, chemotherapy completely eliminated DTC in 30% of the patients, no significant change was documented in 47% and a significant enhancement of DTC was shown in 33%, including 8 patients (27%) who had no DTC before chemotherapy. In case of significant increase of DTC, patients showed a trend for reduced PFS (12.8 months ± 0.7; mean PFS ± SEM) in comparison to patients with no increase (19.3 months ± 1.4) or decrease of DTC (p=0.07). DTC, persisting after chemotherapy, co-expressed EpCAM. Conclusions: It has to be considered, whether these patients with persisting EpCAM-positive DTC in BM might profit from an additive immunotherapy e.g. by the intraperitoneal application of a trifunctional antibody targeting EpCAM, CD3 and accessory cells.

No significant financial relationships to disclose.
A phase I study of imatinib mesylate and paclitaxel in patients with advanced (stage IIIC/IV) or recurrent uterine papillary serous carcinoma (UPSC)
Authors: Slomovitz B. M. , Ramondetta L. M. , Johnston T. , Lu K. H. , Broaddus R. R. , Muller P. , Iyer R. B. , Burke T. W. , Gershenson D. M. , Wolf J.
Published: March 2020

16025

Background: Uterine serous carcinoma (USC) is a rare, aggressive uterine tumor biologically distinct from typical endometrial cancers. Imatinib mesylate (IM)-associated kinases (kit, abl, PDGFR-B) are overexpressed and activated in most tumors from patients (pts) with USC. Single agent paclitaxel (TAX) has a good response rate but short duration of response in pts with USC. The purpose of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of escalated doses of IM with a fixed dose of TAX. Methods: Pts with newly diagnosed (stage IIIC/IV) or recurrent USC were eligible (pts were required to have tumors that expressed at least one of the IM-targeted kinases by immunohistochemistry). Measurable disease was not required. TAX was administered at 175 mg/m2 every three weeks. One dose reduction to 135 mg/m2 was allowed. IM was given daily (400 mg, 500 mg or 600 mg). A 3+3 design was implemented. Pts with measurable disease were treated until progression or treatment associated toxicity. Pts with no measurable disease were treated for six cycles. Results: 11 pts were enrolled. The median age was 62 years (47–79). A total of 50 cycles were administered. Three pts were treated at the first dose level (400 mg), 6 pts treated at the second dose level (500 mg), and 2 pts were treated at the highest dose level (600 mg). Three DLTs were observed (1 at 500 mg level and 2 at 600 mg level) including: rash, neutropenia, and fatigue. IM 500 mg daily and TAX 175 mg/m2 every three weeks was the MTD. There were 3 serious adverse events not related to treatment (infection, dyspnea, pain). Neutropenia was the most common grade 3 or 4 toxicity but only one patient required TAX dose reduction. 8 pts were evaluated for efficacy (2 with measurable disease, 6 with no measurable disease). 1 (of 2) pts with measurable disease had a partial response and was treated for 13 cycles. Of the 6 pts with no measurable disease, 2 recurred (5 and 10 months). The median disease free interval for the pts without recurrent disease was 22 months (6–30). Conclusion: Combination therapy of IM and TAX is well tolerated with minimal side effects in pts with advanced or recurrent USC. Initiation of the phase II component of this study is warranted to better evaluate efficacy.

No significant financial relationships to disclose.
ErbB3 protein expression in serous ovarian carcinomas of elderly women
Authors: Hirsch M. S. , Liu J. , Drapkin R. , Lee H. , Matulonis U. A.
Published: March 2020

16026

Background: Ovarian carcinoma is the leading cause of death due to gynecologic malignancies, and older age at the time of diagnosis has been suggested to correlate with poorer outcome. Recent studies suggest that expression of ErbB3, a member of the epidermal growth factor receptor family, is associated with decreased survival. The goal of this study was to examine ErbB3 protein expression with a tissue microarray (TMA) comprised of advanced papillary serous (PS) ovarian carcinomas, and to correlate results with clinical information to evaluate for expression differences in younger and older women. Methods: A high density TMA (with 4 cores per primary tumor) was constructed by retrospective review of PS ovarian carcinoma cases seen between 1999 and 2005. Patients were divided into 2 cohorts based on age (=65 and =55 at diagnosis). Only cases of stage III or IV disease were included, and patients with BRCA mutations were excluded. Clinical data were obtained by chart and database review. TMA sections were immunostained for ErbB3, and expression was correlated with age, stage, and overall survival. Results: 136 primary tumors were available: 72 in the =65 group, 64 in the =55 group. Tumors from the =65 cohort were significantly less likely to express ErbB3 (16.7%) when compared to the ≤55 cohort (51.6%) (p<0.0001). Patients whose tumors expressed ErbB3 had decreased median survival (33.6 months) compared to ErbB3 negative cases (47.3 months), but these results were not statistically significant (p=0.10). ErbB3 expression correlated in a borderline significant manner with stage (dichotomized as IIIa/IIIb vs. IIIc/IV) at the time of diagnosis (stage IIIa/b 11.8%+ vs. stage IIIc/IV 36.1%+; p=0.055). Multivariate analysis with respect to age, stage, and ErbB3 status did not reveal ErbB3 to be a statistically significant predictor of poor outcome in this data set. Conclusions: These results demonstrate that PS ovarian carcinomas in patients aged =65 at the time of diagnosis are significantly less likely to express ErbB3 than those ≤55. Correlation between ErbB3 expression and more advanced stage at the time of diagnosis bordered on significance. There was a non-significant trend towards decreased overall survival in both univariate and multivariate analyses in patients whose tumors exhibited ErbB3 expression.

No significant financial relationships to disclose.
Post-treatment [18F] fluorodeoxyglucose positron emission tomography as a prognostic tool for progression-free survival in epithelial ovarian cancer
Authors: Chung H. , Kim J. , Park N. , Song Y. , Kang S. , Lee H.
Published: March 2020

16029

Background: The aim of this study was to evaluate response to therapy using post-treatment molecular imaging with [18F] fluorodeoxyglucose (FDG), and to compare the response with outcome in patients with epithelial ovarian cancer (EOC). Methods: This was a retrospective medical record review of 179 patients with EOC. All patients underwent post-treatment whole-body positron emission tomography (PET) imaging scan with [18F] FDG from August 1998 to April 2005. Patients were treated with surgical staging procedure followed by platinum-based combination chemotherapy at least 3 cycles. Post-treatment whole-body FDG-PET was performed 1 to 7 months (median, 3 months) after completion of treatment. Results: One hundred fourteen patients showed no abnormal FDG uptake while 65 patients had abnormal FDG uptake at the scan. One hundred thirteen patients experienced recurrence or metastasis during follow-up. Median progression-free survival (PFS) was 44 (range 2–83) months, and 5-year PFS rate was 34.3%. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of [18F] FDG PET images in the diagnosis of ovarian cancer recurrence or metastases were 46.1%, 82.8%, 59.2%, 82.8%, and 46.1%, respectively. A Cox proportional hazards model of survival outcome indicated that abnormal post-treatment FDG uptake (persistent or new) was the most significant prognostic factor for developing metastatic disease and death from EOC (hazard ratio, 0.432; 95% CI 0.296 to 0.630; P <.0001). However, there was no relation between the maximal standardized uptake value (SUVmax) and the PFS. Conclusion: Post-treatment abnormal FDG uptake (persistent or new) detected by whole-body PET measures tumor response and might be predictive of poor prognostic ourtcome from EOC.

No significant financial relationships to disclose.