bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of Ki67, topo IIa, MRP1, p53 and p-gp with chemo-responsiveness and survival in patients with hepatocellular carcinoma (HCC)
Authors: Yeo W. , Wong W. L. , Wong N. , To K. F. , Mo F. K. , Chan A. T. , Lai P. B. , Koh J. , Johnson P. J.
Published: March 2020

4139

Background: HCC is a common cause of cancer morbidity and mortality. For patients (pts) who are not candidate of curative surgery, chemotherapy (CT) is one of the main treatments but response has been poor due to drug resistance. In this study, using the pre-CT tumor biopsies of HCC pts who were entered into our recently reported phase III prospective randomized CT study (J Natl Cancer Inst 2005; 97(7): 536–539), we aimed to correlate selected biomarkers with CT responsiveness and survival. Methods: 188 HCC pts were entered into the CT study. They were separately consented for the present correlative study. CT response was based on WHO criteria. For the purpose of this study, pts were categorized into CT-‘responsive’ group (those who obtained clinical benefits and achieved CR, PR or SD) and CT-‘non-responsive’ group (those who developed PD). Immunohistochemical staining for Ki67, topo IIa, MRP1, p53 and p-gp were performed on the pre-CT tumor biopsies; findings of which were analyzed with conventional clinical variables to identify factors that influenced CT response and survival. Results: 149 pts had pre-CT tumor biopsies available and were thus included in the present analysis, 1 pt was not assessable for response; there were 75 pts in the CT-‘responsive’ group (23 PR and 52 SD) and 73 pts in the CT-‘non-responsive’ group. The overall median survival was 7.9 months. Using multivariate analysis, predictors of response to CT were Ki67 positivity (p = 0.0427; OR = 0.475), MRP1 positivity (p = 0.0323; OR = 0.429), age (p = 0.0027; OR = 1.056) and albumin level (p = 0.0130; OR = 1.108). Predictors of survival included Ki67 positivity (p = 0.0097; HR = 1.662), topo IIa positivity (p = 0.0358; HR = 1.566), total bilirubilin level (p = 0.0006; HR = 1.039) and ALT level (p = 0.0092; HR = 1.005). Conclusions: In addition to conventional factors, Ki67 and MRP1 positivity are predictors of response to CT, while Ki67 and topo IIa positivity are predictors of survival. The present study demonstrates that immunohistochemical staining of biomarkers can be instrumental in highlighting genes in the drug-resistant phenomenon of HCC. Acknowledgements: This study has been supported by the Direct Grant of Chinese University of Hong Kong, project no. 2041124.

No significant financial relationships to disclose.
Pemetrexed (A)/platinum for patients with advanced malignant peritoneal mesothelioma (AbM)—The Bielefeld experience
Authors: Karthaus M. , Frieler F. , Vasquez N. , Grader K. , Pfeil N. , Plahl A. , Tagizadeh K. , Trapp M. , Metzner D.
Published: March 2020

4151

Background: AbM is a very rare and aggressive neoplasm of the peritoneum. Treatment data of AbM are commonly case reports. A is approved for pleural mesothelioma (MPM) with rare data however regarding AbM. Methods: We evaluated efficacy and safety data of A (500 mg/m2) +DDP (75 mg/m2) or carboplatin (AUC 5) in AbM prospectively. Ctx was given d1 and repeated on d22 for 6 cycles or disease progression. Folic acid 400 μg po/d and vitamin B12 1000 μg i.m. qw 9 wks was administered to prevent AE . Study endpoints were best response (CR/PR), time to progression (TTP), survival and safety. Results: 89 consecutive mesothelioma pts were observed from 12/2002 until 12/2005 in a German single center institution. Four pts (1 AbM, 1 MPM, 2 MPM+AbM) were excluded due to renal impairment (n = 1) or death prior to Ctx (n = 3). AbM was diagnosed in 22 pts (16 epitholoid, 1 sarcomatoid, 5 other), while 5 additional pts had mesothelioma on both sites of the diaphragma. Efficacy data are available in 19 pts with AbM and 5 pts with AbM + MPM. Initial combination was with DDP in 21 pts treated with AbM. DDP was given in 3 and carboplatin combination in 2 pts with MPM + AbM. A was administered a median of 6 cycles in AbM (range 1–33). Toxicity (WHO > III/IV) was nausea (n = 4) and neutropenia (n = 4). Up to 12/05 death has been reported in 8 out of 22 pts with AbM, and in 3 of 5 pts with AbM + MPM. Mean survival was 13,65 months (range 1 to 35+ months) in AbM. Benefit for AbM was 77% with objective RR in 36%. Mean TTP was 11,54 months (range 0 to 35+) in AbM vs 15,4 months with MPM + AbM with a mean survival of 13,65 months (range 0 to 35+) and 22,3 months (range 0 to 35+) in the latter group. Conclusions: Pemetrexed with platinum is well tolerated and has substantial activity for malignant peritoneal mesothelioma. Further trials are warranted to prove this hopeful concept of pemetrexed based therapy for advanced AbM.

[Table: see text]

No significant financial relationships to disclose.
A retrospective review of anal squamous cell carcinoma in HIV positive and HIV negative patients
Authors: Grandhi J. , Philip P. A. , Washington T. , Shields A. F. , Vaishampayan U. , Heilburn L. K. , Venkatramanamoorthy R. , El-Rayes B. F.
Published: March 2020

4153

Background: The incidence of invasive anal cancer is 120 times higher in the HIV infected patients than in the general population. The outcome of anal cancer in HIV infected patients has not been evaluated in prospective trials and the published literature is limited to small retrospective case series. The aim of this study is to describe the outcome, tolerability, event free survival, and overall survival in patients with squamous cell carcinoma of anal canal (SCCAC) with and without HIV infection treated at Karmanos Cancer Institute/Wayne State University from 1991 to 2005. Methods: We performed a retrospective chart review. Patients were identified using the SEER database. We collected data regarding HIV status, demographics (age, gender, race), stage at diagnosis, treatment, response to treatment, toxicity and survival. Results: Forty patients with SCCAC were identified, of which 13 were HIV positive and 27 were HIV negative. The HIV-positive and HIV-negative groups differed by mean age (44 vs. 55 years), male gender (100 vs. 37 percent), and African American race (92 vs. 59 percent). There were no differences in stage at diagnosis, type of chemotherapy received. HIV positive population received reduced chemotherapy (67 vs. 8 percent), and RT (22 vs. 7 percent) dosage. The major toxicities observed in HIV positive and negative patients were mucositis (23% vs. 29%), neutropenia (8% vs. 33%) and skin toxicity (46% vs. 55%) secondary to radiotherapy. Only 61 percent of HIV-positive patients were disease free vs. 60 percent of HIV-negative patients. Conclusions: We found that HIV positive patients received lower doses of chemo-radiotherapy. Patients with HIV tolerated the lower dose chemoradiotherapy and had a similar toxicity profile to the HIV negative patients. No major difference in the risk of recurrence between HIV positive and negative patients was observed.

No significant financial relationships to disclose.
Annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: A randomized placebo-controlled trial
Authors: Michaelson M. D. , Lee H. , Kaufman D. S. , Kantoff P. W. , Finkelstein J. , Smith M. R.
Published: March 2020

4515

Background: Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Zoledronic acid (4 mg IV every 3 months) increases BMD in GnRH agonist treated men. Intermittent zoledronic acid (4 mg IV once annually) increases BMD in postmenopausal women with osteoporosis but the efficacy of the annual treatment schedule in hypogonadal men is unknown. Methods: In a 12-month open-label study, men with nonmetastatic prostate cancer (n = 44) who were receiving a GnRH agonist were assigned randomly to zoledronic acid (4 mg IV × 1) or placebo. BMD of the posteroanterior lumbar spine and total hip were measured by dual energy x-ray absorptiometry at baseline and month 12. Serum N-telopeptide, a marker of osteoclast activity, was measured every 3 months. Results: Mean (± SE) BMD of the posteroanterior lumbar spine increased by 4.0 ± 0.9 in men treated with zoledronic acid and decreased by 3.1 ± 0.9 percent in men who received placebo (P < 0.001 for between-group comparison). BMD of the total hip decreased by 0.7 ± 0.6 percent in men treated with zoledronic acid and decreased by 1.9 ± 0.7 percent in men who received placebo (P = 0.005). Compared to placebo, zoledronic acid significantly decreased serum N-telopeptide throughout the 12-month study (P < 0.05). Conclusions: In men receiving a GnRH agonist for prostate cancer, a single treatment of zoledronic acid significantly increased bone mineral density of the total hip and spine at 12 months. Annual zoledronic acid may provide a convenient and effective strategy to prevent bone loss in hypogonadal men. This study was supported in part by Novartis Oncology and by the Prostate Cancer Foundation.

[Table: see text]
Association of pain and quality of life (QOL) response with PSA response and survival of patients (pts) with metastatic hormone refractory prostate cancer (mHRPC) treated with docetaxel or mitoxantrone in the TAX-327 study
Authors: Berthold D. R. , Pond G. , De Wit R. , Eisenberger M. A. , Tannock I. F.
Published: March 2020

4516

Background: The TAX-327 study compared 3 weekly docetaxel (D3), weekly docetaxel (D1) or mitoxantrone (M), each with prednisone (P) for 1006 pts with mHRPC. Survival and symptom control were superior following D3+P as compared to M+P (Tannock et al, NEJM 2004;351;1502–12). Here we investigate associations between pain and QOL response with PSA response and survival. Methods: Pts were evaluated for pain, PSA and QOL at baseline and 3 weekly during treatment. Pain response (pts with initial pain) was defined by ≥ 2-point reduction in Present Pain Intensity (PPI) with no increase in analgesic score (AS) or ≥ 50% in AS with no increase in PPI. PSA response required ≥ 50% reduction in PSA from baseline. QOL response required ≥ 16-point reduction in FACT-P score (range: 0–156). Responses were confirmed ≥ 3 weeks later. Results: There were414 pts assessable for both pain and PSA response: PSA response was seen in 52.4% of 124 pts with pain response and 28.3% of 290 pts without pain response (p < 0.001). There were 704 pts evaluable for both QOL and PSA response: PSA response occurred in 56.5% of 147 pts with QOL response and 37.5% of 557 pts without QOL response (p < 0.001). The table shows associations of pain or QOL response and survival. Landmark analysis will be presented at the meeting. After adjustment for PSA and QOL response, pain response was an independent predictor of survival (HR = 0.47, p = 0.003). Conclusions: Pain and QOL response were associated with PSA response and pain response was an independent predictor of survival.

[Table: see text]

[Table: see text]
Prognostic factors for relapse in stage I seminoma managed by surveillance or adjuvant carboplatin: A multivariate analysis on 588 cases
Authors: Aparicio J. , Garcia-Puche J. , Lomas M. , Carabantes F. , Vazquez S. , Crespo C. , Climent M. , Murias A. , Oltra A. , Barrajon E.
Published: March 2020

4552

Background: The availability of reliable prognostic factors for relapse in stage I seminoma would allow a better patient stratification for individually tailored therapies. We performed a pooled analysis of patients included in two consecutive risk-adapted protocols. Methods: Between 1994 and 2004, 588 cases were prospectively registered. Median patient age was 33 years, median tumor size was 45 mm, serum BHCG levels were elevated preoperatively in 14.6%, and rete testis invasion was present in 26.9%. Three hundred and four patients (51.7%) with risk factors received two courses of adjuvant carboplatin, whereas 284 (48.3%) without these criteria were managed by surveillance. After a median follow-up of 48 months (range, 12–144), 43 relapses (7.3%) have occurred. Five-year disease-free survival was 92.3%. Univariate (log rank) and multivariate (Cox regression) analyses of prognostic factors for relapse were performed. Results: Relapses were less frequent after carboplatin treatment (3% vs 12%, p < 0.0001). Statistically significant, independent predictors of relapse were: 1) rete testis invasion and age (<30 years) in the whole series; 2) rete testis invasion for patients treated with adjuvant chemotherapy; and 3) tumor invasion beyond the albuginea and microvessel neoplastic invasion (defining 1997 AJCC pT2–4 staging) for patients managed by surveillance. In contrast, tumor size, histologic subtype (anaplastic), and serum preoperative BHCG levels were not associated with prognosis. Conclusions: Invasion of the rete testis and age (<30 years) represent high-risk factors for patients with clinical stage I testis seminoma, independently of the treatment selected. These two features, in combination with pathologic T2–4 staging, could improve patient selection for risk-adapted therapies.

No significant financial relationships to disclose.
Quality of life (QOL) of patients (pts) with metastatic hormone refractory prostate cancer (mHRPC) following treatment with docetaxel or mitoxantrone in the TAX-327 study
Authors: Pond G. R. , Berthold D. R. , Dewit R. , Eisenberger M. , Tannock I. F.
Published: March 2020

4557

Background: The TAX-327 study compared 3-weekly docetaxel (D3), weekly docetaxel (D1) or mitoxantrone (M), each with prednisone (P) for 1006 pts with mHRPC. Survival and symptom control were superior for treatment with D3+P as compared to M+P (Tannock et al, NEJM 2004;351;1502–12). Here we investigate QOL and its relation to pain, and effects of treatment on QOL in pts with minimal symptoms. Methods: Pts were assessable for pain response if Present Pain Intensity (PPI) ≥ 2 (range 0–5) or Analgesic Score (AS) ≥ 10. QOL was measured by the FACT-Prostate (FACT-P) self-report score (range 0–156, higher scores indicate better QOL). QOL response required a 16-point increase in FACT-P score maintained on 2 occasions; here deterioration of QOL was defined by a 16-point decrease from baseline in FACT-P score. Pts with minimal symptoms were defined at baseline by a FACT-P score > 128 or by PPI < 2 and AS < 10. Results: QOL was substantially impaired at baseline (FACT-P score ≤128) in 92% and 75% of pts who were and were not assessable for pain (p < 0.001). Correlation of FACT-P score with PPI and AS will be presented. QOL response and deterioration for all assessable pts, and for those with minimal symptoms are shown in the table (p-values compared with M+P). Time-dependent analysis of QOL and its relation to duration of treatment will be presented at the meeting. Conclusions: Most pts had impaired QOL at baseline regardless of pain. There was greater improvement in QOL following treatment with D+P compared to M+P for all pts and for pts with minimal symptoms. With the caveat that unequal withdrawal of pts might bias the data, there was greater probability of decline in QOL for pts receiving weekly docetaxel.

[Table: see text]

[Table: see text]
Phase II study of low dose (LD) and high dose (HD) premarin in androgen independent prostate cancer (AIPC)
Authors: Pomerantz M. , Manola J. , Taplin M. , Bubley G. , Inman M. , Lowell J. , Kantoff P. , Oh W. K.
Published: March 2020

4560

Background: Estrogens, including DES, transdermal estradiol, estramustine and PC-SPES, have shown antitumor activity in AIPC. We tested two doses of Premarin to determine efficacy and safety of this commonly available estrogen. Methods: Patients with progressive AIPC were eligible. Prior estrogen use, significant cardiac or thromboembolic disease, and concurrent steroids were not allowed. Patients were randomized to Premarin 1.25 mg once (LD) or 3 times (HD) daily. Prophylactic breast irradiation was encouraged and warfarin 1 mg daily was required, unless contraindicated. After the first stage of accrual, the LD arm was closed because of limited activity, while the HD arm continued to the 2nd stage. Results: 46 patients were enrolled; 17 patients were randomized to LD Premarin, 29 patients assigned to HD Premarin by randomization or direct assignment. One patient withdrew consent prior to therapy. Median follow up is 5.3 months. Median age was 69 years (range 52–86) and median PSA 84.6 ng/ml (range 2.5–794.1). 19 patients (41%) had measurable disease. PSA declines ≥ 50% were seen in 0% (95% C.I., 0–19.5) and 32.1% (95% C.I., 15.9–52.4) of patients treated with LD and HD premarin. 1 patient treated with HD Premarin had a partial measurable response (8.3%; 95% C.I., 0.2–38.5). Median time to progression was 3.3 and 3.2 months in the LD and HD arms, respectively. Premarin was well tolerated in 45 evaluable patients. One grade 4 toxicity was noted, a stroke in the LD arm. Grade 3 toxicity was rare with 1 allergic reaction, 2 DVTs and 3 episodes of GI toxicity in one patient. Two patients experienced grade 3 elevations in PT requiring modification of warfarin dose. No significant gynecomastia was reported. Analysis of serially drawn hormone levels and molecular correlates of treatment response is pending. Conclusions: HD Premarin is associated with a 32.1% PSA response rate, while no responses were seen with LD Premarin. A measurable response was noted in 1 of 12 patients treated with HD Premarin. Toxicity was modest, though thromboembolism was seen even with prophylactic warfarin. Ongoing studies are evaluating molecular and clinical predictors of response.

No significant financial relationships to disclose.
Salvage chemotherapy with paclitaxel, ifosfamide, and nedaplatin in patients with urothelial cancer who had received prior cisplatin-based therapy
Authors: Shinohara N. , Harabayashi T. , Suzuki S. , Nagao K. , Nagamori S. , Matsuyama H. , Naito K. , Nonomura K.
Published: March 2020

4579

Background: The combination chemotherapy of paclitaxel, ifosfamide, and nedaplatin (PIN regimen) has been shown to be effective in patients with advanced urothelial cancer. The aim of this presentation is to evaluate long-term followup outcomes in patients who had treated with standard cisplatin-based chemotherapy. Methods: The PIN regimen consisted of paclitaxel 175 mg/m2 on day 1, ifosfamide 4.5 g/m2 divided over days 1, 2 and 3, and nedaplatin 70 mg/m2 on day 1; PIN was given every 28 days. The doses of nedaplatin and ifosfamide were reduced according to the impairment of renal function (24h CCr) just before starting each cycle of PIN therapy Results: Thirty two patients who had previously undergone cisplatin-based chemotherapy were entered onto the study (median age, 66 years; median performance status, 1, median 24h CCr, 62ml/min [29–119ml/min] ). Metastatic sites at study entry included the lymph nodes (24), lung (6), bone (5), primary (5), soft tissue (3), and liver (2). Among the 32 assessable patients, there were 5 CRs (16%) and 19 PRs (59%) for an overall RR of 75 % (95% confidence interval [CI], 59–91 %). The median time to progression was 8 months (range, 0–50+ months) and the median survival was 22 months (range, 4–52+ months). Twelve patients received the full dose of PIN combination (median 5 cycles) and 20 patients required dose reduction (median 3 cycles). Nine of 12 (75%) patients who were treated with the full-dose PIN combination obtained a CR or PR, as did 15 of 20 (75%) patients who required dose reduction. Grades 3 and 4 neutropenia occurred in all patients. Febrile neutropenia occurred in 8 (25%) patients. Grades 3 and 4 thrombocytopenia occurred in 8 (25%) patients. Grades 3 and 4 anemia was observed in 6 (19%) patients. Grade 3 neuropathy occurred in 1 (3%) patient, who could not continue to receive additional cycles of PIN combination after 3 cycles. No patient experienced renal failure. There were no treatment-related deaths. Conclusions: The PIN combination was highly active and tolerable in patients who had previously treated with cisplatin-based chemotherapy, and might be suitable for those with mild to moderate renal insufficiency.

No significant financial relationships to disclose.
Thyroid function tests (TFTs) abnormalities in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib
Authors: Shaheen P. E. , Tamaskar I. R. , Salas R. N. , Rini B. I. , Garcia J. , Wood L. , Dreicer R. , Bukowski R. M.
Published: March 2020

4605

Background: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors. It has anti-tumor activity in mRCC pts with toxicity including fatigue. We investigated TFTs abnormalities and related signs and symptoms in pts with mRCC receiving sunitinib. Methods: The medical records of pts with mRCC enrolled in 4 ongoing clinical trials of sunitinib were reviewed. TFTs assessment (TSH, T3 and T4) was undertaken based on the clinical suspicion of treating physicians. Patient demographics, frequency and values of TFTs and any signs and symptoms of thyroid dysfunction were collected. Abnormal TFTs and treatment outcome were correlated. Results: Between 5/2004 and 12/2005, 62 pts (43 males, 19 females) were treated with sunitinib. The median age was 58 years (range, 23–72). Fifty-five pts had TFTs assessed while on treatment and 40 pts (65% of total) had one or more abnormality. Two pts had well-controlled hypothyroidism prior to initiation of sunitinib. TFTs abnormalities were consistent with hypothyroidism in all pts including one who initially developed transient hyperthyroidism. Signs and symptoms possibly related to hypothyroidism were found in 33 pts (53% of total) with abnormal TFTs and were initially attributed to sunitinib. Signs and symptoms included fatigue in 33 pts, anorexia in 20 pts, fluid retention in 17 pts, and skin/hair changes in 13 pts. Thyroid hormone replacement was undertaken in 12 pts and resulted in improvement of symptoms in 6 pts. Among the 40 pts with abnormal TFTs 29 pts had tumor evaluation; 13 had SD, 8 had PR, 2 had CR. There was no correlation between abnormal TFTs and treatment outcome. Conclusions: TFTs abnormalities are common in pts with mRCC treated with sunitinib. Thyroid hormone replacement is indicated in such pts to improve hypothyroidism-related symptoms and possibly to improve treatment tolerance.

[Table: see text]
Is physical function affected by androgen deprivation therapy (ADT) in men with non-metastatic prostate cancer?
Authors: Gogov S. , Hussain F. , Naglie G. , Tannock I. , Fleshner N. E. , Krahn M. D. , Duff Canning S. , Warde P. , Alibhai S. M.
Published: March 2020

4615

Background: Although prolonged use ofADT is hypothesized to adversely affect physical function, only a few small studies have examined this relationship and it remains unclear if self-reported weakness represents a decline in actual physical performance or is related to fatigue. Loss of physical function may be particularly important to older men who already have limited functional reserves. Methods: Men age 50 or older with non-metastatic prostate cancer who were starting continuous ADT were enrolled in this prospective longitudinal study. Physical function was tested using a Jamar dynamometer (grip strength), the Timed Up and Go (TUG) test, and the six-minute walk test (6MWT), representing upper extremity strength, lower extremity strength, and endurance, respectively. Assessments were done at baseline (prior to ADT), 3 months, 6 months, and 12 months. Results: 42 patients on ADT have been enrolled to date (mean age 74.8 y). There was a gradual but steady decline in grip strength from baseline (39.2 kg) to 3 months (38.1 kg), 6 months (37.9 kg), and 12 months (35.3 kg) (p < 0.05 for all comparisons). On average, patients took 7.3 seconds to complete the TUG and walked 1507 feet during the 6MWT at baseline. TUG and 6MWT scores did not worsen over time (p > 0.05). Conclusions: Preliminary data suggest that 3–12 months of ADT is associated with worsening upper extremity strength but lower extremity strength and endurance are relatively unaffected. A larger sample size is needed to determine if all aspects of physical function or only upper extremity strength deteriorate with ADT use. Additionally, most patients in our study reported excellent health and functional status at baseline and our results may not adequately reflect the impact of ADT in more frail older men.

No significant financial relationships to disclose.
Prostate specific antigen doubling time (PSA-DT) and velocity (PSA-V) provide independent prognostic information in androgen independent prostate cancer (AIPC) patients receiving chemotherapy
Authors: Daskivich T. J. , Regan M. M. , Kantoff P. W. , Oh W. K.
Published: March 2020

4616

Background: PSA-DT and PSA-V at AIPC have each demonstrated prognostic significance in retrospective studies. No study has compared PSA-DT and PSA-V at AIPC to determine if they are independent prognostic factors. Methods: PSA-DT and PSA-V were calculated in 91 AIPC patients treated with taxane chemotherapy. PSA-DT was calculated as log 2 divided by the slope of the linear regression of log PSA versus time, from the first rise above the PSA nadir on androgen deprivation therapy (ADT) until the start of the next treatment. PSA-V was calculated from the slope of the linear regression of the raw PSA values over time. PSA-DT and PSA-V were split into tertiles for analysis. The primary endpoint was overall survival (OS) from the date of AIPC. OS was analyzed using Cox proportional hazards regression. Results: In univariate analysis, shorter PSA-DT and higher PSA-V were associated with decreased OS. Also associated with decreased OS were: higher M stage at dx; PSA nadir on ADT >0.2; <12 wks to failure of ADT; presence of mets, bony mets, low Hb, high AP, and low albumin at AIPC; and type of chemotherapy. In multivariate analysis, PSA-DT ≤12 weeks (HR=3.2), PSA-V >10 ng/ml/yr (HR=2.8), PSA nadir >0.2 on ADT, low Hb, and type of taxane chemotherapy persisted as significant predictors of decreased OS (each p < 0.01). Rapid PSA-DT (≤12 wks) and high PSA-V (>10 ng/ml/yr) predicted the worst prognosis (25 mos median OS, unadjusted); slow PSA-DT (>12 wks) and low PSA-V (≤10 ng/ml/yr) the best prognosis (75 mos); and other combinations had intermediate prognoses (49 and 50 mos). Modifications of PSA-DT calculation such as nadir subtraction did not alter prognostic ability of either component. Conclusions: PSA-V at the start of AIPC contributes prognostic information independent of PSA-DT. Future studies should investigate the relative contribution of each of these factors in predicting survival.

No significant financial relationships to disclose.
A phase II study of a weekly schedule of BMS-247550 for patients with hormone-refractory prostate cancer: A trial of the Eastern Cooperative Oncology Group (E3803)
Authors: Liu G. , Wang W. , Dipaola R. , Carducci M. , Wilding G.
Published: March 2020

4618

Background: BMS-247550 (ixabepilone) is an epothilone B analogue with activity in taxane-resistent cancer cell lines. Ixabepilone has been administered using a q3wks schedule with significant neutropenia observed. Here we assess the activity and toxicity of ixabepilone, administered using a weekly schedule, in men with metastatic hormone-refractory prostate cancer. Methods: Patients with metastatic hormone-refractory prostate cancer (chemonaive and prior taxane) were treated with ixabepilone at 20 mg/m2 IV weekly × 3, in 4 wk cycles. This non-comparative study had a planned accrual of 29 chemonaive and 27 prior-taxane treated patients in order to detect a 50% PSA reduction using Consensus Criteria in at least 50% (91% power, α = 0.10) chemonaive and 30% (power 90%, α = 0.10) prior-taxane treated patients. Results: 32 pts with chemonaive and 37 pts with prior-taxane have been enrolled on this study. Median follow-up is 1.8 and 4.1 months respectively. Safety data is reported for the first 56 subjects (24 chemonaive and 32 prior taxane). Hematologic toxicity: Grade 3/4 neutropenia was seen in 10 pts (5 chemonaive, 5 prior-taxane). No significant thrombocytopenia was observed. Grade 3/4 neuropathy was seen in 7 pts (2 chemonaive, 5 prior-taxane). Grade 3 fatigue noted in 8 (3 chemonaive, 5 prior-taxane), grade 3 diarrhea in 5 (4 chemonaive, 1 prior-taxane), and grade 3 nausea in 3 subjects. Lastly, 2 subjects were reported to have developed a grade 3 ileus during therapy. Conclusions: In 56 subjects, BMS-247550 was found to have an acceptable toxicity profile when administered using a weekly schedule. Myelosuppression appeared to be improved, as compared to historical data with the q3wk schedule, using this dose and schedule. PSA/objective responses have been seen but at this time, no conclusion regarding its activity in the first or second-line setting can be made, as the response assessment is ongoing. Complete toxicity and response data will be presented for the entire group.

No significant financial relationships to disclose.
Pre-treatment PSA velocity (PSAV) is not predictive of outcomes after radical prostatectomy (RP) in a referral cohort
Authors: Hung A. , Depaula L. P. , Mongoue-Tchokote S. , Garzotto M.
Published: March 2020

4619

Background: PSA velocity has recently been reported as a significant predictor of prostate cancer-specific mortality in early-staged cancer patients selected from a large screening trial where the median PSA was 4.3ng/ml. In order to determine the broad applicability of these data to a more general population, we examined the effect of PSAV in a referral cohort. Methods: We analyzed over 643 prostate cancer cases diagnosed from 1995–2005. 196 patients underwent RP as definitive therapy. One patient received neoadjuvant hormonal therapy and was excluded. Our goal was to identify whether PSAV prior to RP was predictive of Relapse-Free Survival (RFS) and Overall Survival (OS). 156 patients had at least 2 pre-op PSA values available for the calculation of PSAV (median = 3 values/patient). PSAV was calculated by linear regression analysis using all pre-treatment PSA values available. Results: With a median f/u of 54 months, there were 14 deaths and 26 patients had biochemical relapse. At 5 years, OS was 93% and RFS was 91%. Surprisingly, no patients with biochemical relapse have died, and thus prostate cancer-specific mortality is 0%. In addition to the variables in the table below, seminal vesicle involvement (p = 0.015) and margin positivity (p=0.005) were also significantly associated with RFS confirming the expected prognostic factors in our cohort. On multivariate analysis, Gleason Grade was the only significant predictor of overall survival. For RFS, Gleason Grade, margin involvement, and pre-treatment PSAs were the only significant variables. Neither PSAV nor PSA Doubling Time were significantly associated with RFS or OS by univariate or multivariate analysis. Conclusions: Pre-treatment PSAV is not significantly associated with prostate cancer outcomes in a heterogenous population referred for an elevated PSA. Gleason Grade is still the most significant predictor of overall survival.

[Table: see text]

No significant financial relationships to disclose.
Five year follow up of a phase II study of cytotoxic immunotherapy combined with radiation in newly diagnosed prostate cancer
Authors: Aguilar L. K. , Teh B. , Mai W. , Caillouet J. , Ayala G. , Aguilar-Cordova E. , Butler E.
Published: March 2020

4635

Background: In the U.S. there are about 70,000 annual prostate cancer recurrences. The purpose of this study is to evaluate a product to decrease incidence of recurrence. This study is based on objective clinical responses in Phase I studies with AdV-tk (ProstAtak™, Advantagene, Inc) as monotherapy in recurrent disease and preclinical data demonstrating synergy between AdV-tk and radiation. AdV-tk is an adenoviral vector expressing the herpes thymidine kinase gene delivered to the prostate via TRUS-guided injection followed by 14 days of oral prodrug. The mechanisms of function involve direct tumor cytotoxicity, local elicitation of danger signals, recruitment and activation of antigen presenting cells and stimulation of systemic anti-tumor T-cell immunity. Method: AdV-tk was evaluated in combination with radiation in 66 newly diagnosed patients: 33 low risk (Arm A, PSA <10, Gleason <7, and T1c-T2a) and 33 intermediate-high risk (Arm B, PSA ≥10, Gleason ≥7, or T2b-T3). Arm A received two treatments with AdV-tk, immediately before and 14 days into radiation. Arm B received an additional treatment at initiation of androgen deprivation therapy. Results: Two surrogate and one definitive end-point were evaluated. Frequency of patients in Arm A with PSA nadir ≤0.2 ng/ml was 71% vs 56% in a control group of concurrent patients without AdV-tk. The two-year pathologic complete response (pCR) rate by sextant biopsy was 90% in Arm A and 94% in Arm B, compared to an expected range of 70–73%. Freedom from failure (FFF) after 60 month median follow up is 100% for Arm A and 90% for Arm B (95% for intermediate, 75% for high risk) vs best reported results of 79–90% for low risk and 48–79% for intermediate-high risk patients. The three failures in Arm B occurred within months after treatment leading to a Kaplan-Meier curve that plateaus at 90% beyond year 3. This is notably different than previous reports in which the curves continue to drop beyond year 5. Conclusion: These results suggest that AdV-tk combined with radiation therapy may significantly reduce the recurrence rate in patients with prostate cancer, particularly in patients with intermediate-high risk disease. A randomized controlled trial is warranted.

[Table: see text]
Gene profiling in transurethral resection samples of patients with hormone-refractory prostate cancer (HRPC)
Authors: Stoss O. , Albers P. , Werther M. , Zielinsky D. , Jost N. , Rueschoff J. , Henkel T.
Published: March 2020

4641

Background: Patients with metastatic carcinoma of the prostate (CaP) develop after a mean of 15 months resistance to hormone ablation therapy. However, the underlying molecular mechanisms are still unknown. Our goal was to identify the transcriptional changes that are characteristic for the transition to hormone resistant prostate cancer (HRPC) using oligonucleotide microarrays. Here, we report the attempt to profile fresh frozen tissue obtained by palliative transurethral resection (TUR) in patients with HRPC and concomittant urinary obstruction. Methods: Indications for palliative TUR were locally progressive tumors with obstruction and voiding problems. HRPC was defined according to the criteria of Scher et al. 1995. Samples of 8 HRPC patients were compared to tissues from 8 hormone-sensitive CaP patients including biological and technical replicates. All tissue samples had been pathologically evaluated. Only macrodissected prostate samples with at least 70% tumor content were used for RNA extraction. RNA quality was controlled using the Bioanalyzer Nanochip (Agilent Technologies, Palo Alto). Expression analysis was performed on Affymetrix oligonucleotide arrays. Results: We identified 323 genes being significantly deregulated (corrected p-value <0.05, false discovery rate <0.05). These genes were mapped to cellular pathways using the KEGG annotation and the most significantly deregulated pathways were identified. Deregulation of metabolic pathways included fatty acid metabolism as well as oxidative phosphorylation and ATP synthesis. Cell cycle control seems to be further suppressed by the downregulation of JNK-pathway via MEKK4 and JUND, the downregulation of p21 (CDKN1A) and the induction of Cylcin D1. We also present evidence for a significant downregulation of actin cyctoskeleton components. Deregulated genes likely to be specific for the transition from prostate carcinoma to HRPC will be presented. Conclusions: Gene expression profiling has been successfully standardised using fresh TUR material of HRPC patients. Deregulated genes have been mapped to specific signal transduction pathways. On this platform, clinical trials in patients with HRPC using specific inhibitors of cell signalling are being developed.

[Table: see text]
Androgen receptor (AR) modulation strategies for recurrent prostate cancer (PC) without androgen suppression
Authors: Ferrari A. C. , Wang L. , Liu X. , Liu X.
Published: March 2020

4657

Background: Prostate cancer (PC) progression is tightly linked to aberrant expression and activation of the androgen receptor (AR) gene and protein. Activation of AR is supported by increased/promiscuous ligand-binding to AR and cross-talk with activated growth factor receptor pathways and intracellular second messengers. Overexpression of AR mRNA has been linked to increased Sp1 and/or loss of AR suppressor protein (ARS) binding to the AR promoter (Oncogene, 2004). The purpose of this work was to test the hypothesis that down-regulation of AR levels and inhibition of ligand-dependent and ligand-independent activation can control androgen-dependent (AD) and -independent (AI) PC cells growth and sensitivity to apoptosis. Methods: AD and AI LNCaP cells treated with inhibitors of signal transduction pathways or inhibitors of Sp1, HDAC and/or DNA methylation were assessed for growth and apoptosis in the presence or absence of the anti-androgen bicalutamide. The combination index(CI)(CalcuSyn program) was used to measure activity: CI>1=antagonistic; CI=1, additive; CI<1,synergistic. Pertinent proteins were evaluated by Western blot. AR transactivation by transfection assays using AR and PSA reporter constructs. Results: Combinations of bicalutamide with inhibitors of Akt (Rapmycin), Sp1 (Mithramycin), HDAC (trichostatin A, Sodium butyrate) and DNA methylation (5’-Aza) were synergistic against AD and AI LNCaP cells while EGFR (Iressa) was additive. Decreased AR expression/phosphorylation and transactivation activity preceded the biologic effect. Some triplet combinations enhanced further AR modulation and biologic activity. Conclusion: a global strategy to simultaneously reduce AR levels and activation activity of downstream target genes might be an effective approach against androgen-dependent and androgen-independent clones present in recurrent, high-risk PC patients with potential to spare or postpone the need for castration.

No significant financial relationships to disclose.
Baseline quality of life (QOL) as a predictor of tolerance to intraperitoneal (IP) chemotherapy for advanced epithelial ovarian cancer (EOC): A Gynecologic Oncology Group (GOG) study
Authors: Wenzel L. B. , Huang H. Q. , Armstrong D. K. , Walker J. L. , Cella D.
Published: March 2020

5007

Background: A recent GOG randomized phase III trial demonstrated a 16 month improvement in survival for women with optimally debulked stage III EOC. Patients on the IP chemotherapy arm experienced a survival advantage but significantly worse toxicities, worse QOL during treatment, and more neurotoxicity (NTX) one year later, compared to those on the IV arm. We sought to determine whether baseline QOL and NTX and abdominal discomfort (AD) predict severity of IP treatment-related adverse effects and number of cycles completed. Methods: Three self-report QOL measures were utilized: the FACT-O (39 items), and FACT/GOG-NTX (11 items) and FACT/GOG-AD (4 items) subscales. Scoring was on a 5-point scale, with higher scores representing better QOL (FACT-O) whereas higher scores indicated worse symptoms (-NTX and -AD subscales). In addition to NTX and AD, we explored associations with fatigue. A logistic regression model was used for the analyses. Results: Of 205 patients randomly assigned to receive IP chemotherapy, 198 (97%) completed baseline QOL assessments, of whom 83 (42%) completed all 6 cycles and 16 (8%) completed none. Adjusting for age, performance status and residual disease, patients reporting higher baseline FACT-O and lower -NTX and -AD scores were more likely to complete more IP cycles. Categorizing FACT-O scores by quartiles (≤92, 93 to ≤108.8, 109 to ≤121.1, and >121.1), patients in the lowest quartile were significantly less likely to complete 6 cycles of IP therapy (odds ratio [OR] = 4.46; 95% CI: 1.95–10.21, p < 0.001). Higher FACT-O scores were also associated with less grade 3–4 fatigue (OR = 0.81 per 10 points; 95% CI: 0.67–0.99; p = 0.037); however, there was no relationship between baseline NTX and AD subscale scores and severity of physician-rated NTX and AD. Conclusions: Baseline patient-reported QOL and NTX and AD symptoms predict tolerance to IP chemotherapy. Patients with the poorest baseline QOL (FACT-O score <92) were least likely to complete IP therapy.

No significant financial relationships to disclose.
Pharmacokinetic analysis of an all intraperitoneal carboplatin and paclitaxel regimen in ovarian cancer patients demonstrates favorable systemic bioavailability of both agents
Authors: Krasner C. N. , Seiden M. V. , Fuller A. F. , Roche M. , Verrill C. L. , D’Amato F. , Tretyakov O. , Tyburski K. , Matulonis U. A. , Supko J. G.
Published: March 2020

5008

Background: A phase III trial (GOG172) demonstrated improved survival for patients with newly diagnosed and optimally debulked ovarian cancer treated with intraperitoneal (ip) cisplatin and paclitaxel (P), given both as a 24 h iv infusion and ip, as compared with standard iv dosing. Studies to further enhance efficacy and minimize toxicity of ip taxane/platinum regimens are needed. Because adequate systemic drug exposure is thought to be essential for maximum therapeutic benefit of ip chemotherapy, the pharmacokinetics (PK) and bioavailability of ip P and carboplatin (C) were determined in this pt population in a phase II trial to evaluate dosing by the ip route alone. Methods: P 60 mg/m2 once a week and C at an AUC 6 every weeks were infused over 1 h, iv in cycle 1 and ip in the 5 subsequent 21-day cycles. Plasma samples were collected during week 1 of cycles 1, 2 and 6. P was measured by LC/MS and free platinum (fPt) was determined by flameless atomic absorption. Results: PK data is available for 14 pts receiving at least 1 cycle of ip therapy and for 7 pts who received all 5 cycles. When given ip, P achieved a peak conc. in plasma (Cmax) of 0.086 ± 0.034 μM (mean ± SD) at 6.4 ± 2.2 h, 22-times lower than Cmax for iv infusion (1.92 ± 0.80 μM). Thereafter, P plasma levels were comparable for both routes and decayed at similar rates with a half-life of 13.9 ± 4.1 h for iv and 13.7 ± 2.2 h for ip dosing. The systemic bioavailability of ip P was 53 ± 19% for the initial dose and 46 ± 10% in cycle 6. P plasma levels exceeded 0.05 μM, the pharmacologic threshold conc., for >20 h upon ip dosing in 67% (10/15) and 71% (5/7) of pts in cycles 2 and 6, respectively. C was rapidly absorbed into systemic circulation when given ip with a Cmax of 83 ± 11 μM for fPt at 1.6 ± 0.2 h in cycle 2. Consistent with prior reports, systemic availability of fPt exceeded 100% (133 ± 22% in cycle 2; 142 ± 47% in cycle 6). Conclusions: Weekly ip P 60 mg/m2 with ip C (AUC 6) every 3 weeks achieved a potentially effective pattern of systemic exposure to both agents in a majority of pts. The cumulative time that P plasma levels are >0.05 μM per cycle of therapy is likely to be longer than provided by the iv/ip dosing regimen for P (135 mg/m2 24 h iv infusion day 1; 60 mg/m2 ip day 8) used in GOG172.

No significant financial relationships to disclose.
Efficacy of a quadrivalent HPV (types 6/11/16/18) L1 virus-like particle (VLP) vaccine against vaginal and vulvar pre-cancerous lesions: a combined analysis
Authors: Paavonen J.
Published: March 2020

5011

Background: In the US, 6000 cases of vulvar or vaginal cancer are diagnosed annually. HPV is detected in 75–100% of vulvar cancers in younger women. The most common HPV type detected is HPV 16, followed by HPV 18. These two types also cause a majority of HPV-related vaginal cancers. Treatment to prevent progression to vaginal/vulvar cancer is challenging. Here, we present a combined analysis of 3 randomized, placebo-controlled trials to evaluate the impact of a prophylactic quadrivalent HPV vaccine on the rates of HPV 16- and 18-related vulvar and vaginal neoplasia grade 2/3 (VIN 2/3 and VaIN 2/3). Methods: 18,150 women (16–26 yrs) from the Americas, Europe and Asia were enrolled in 1 of 3 trials. Subjects were randomized to either quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or placebo. For all trials, vaccination occurred at day 1, and months 2 and 6. Genital tract specimens were obtained at day 1 and at 6–12 month intervals thereafter for a maximum of 48 months. Colposcopy referral was algorithm-based. Biopsies were HPV-typed. Cytology, histology, and HPV detection were conducted centrally. Analyses were done per protocol (PP) (subjects received 3 doses, had no major protocol violations, were HPV 16 or 18 seronegative at Day 1 and HPV 16 or 18 DNA negative Day 1 through month 7) and modified intention to treat (MITT) (received ≥1 dose and were HPV 16 or 18 negative at Day 1 by serology and DNA). Endpoint counts began after Month 7 and Day 30 in the PP and MITT analyses, respectively. Results: In PP analysis, after an average of 18 months of follow-up, the vaccine was 100% effective (95% CI: 56–100%) in preventing HPV 16- or 18-related VIN 2/3 or VaIN 2/3. There were 10 cases in the placebo group and 0 cases in the vaccine group. In the MITT population, after an average of 2 years of follow-up, there were 24 histologically confirmed cases of HPV 16- or 18-related VIN 2/3 or VaIN 2/3, all in the placebo group (100% efficacy; 95% CI: 83–100%). Conclusions: Quadrivalent HPV VLP vaccine prevented HPV 16 and 18-related vaginal and vulvar high-grade precancerous lesions for at least 2 years post-immunization. This intervention is expected to greatly reduce the risk of vulvar and vaginal cancers.

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A multi-institutional evaluation of the safety and efficacy of bevacizumab for recurrent, platinum-resistant ovarian cancer
Authors: Wright J. D. , Alvarezsecord A. , Numnum T. M. , Rocconi R. P. , Powell M. A. , Berchuck A. , Alvarez R. D. , Trinkaus K. , Rader J. S. , Mutch D. G.
Published: March 2020

5019

Background: Bevacizumab has shown activity in recurrent ovarian cancer with an acceptable adverse event profile. However, the incidence of bowel perforation in a recent trial of heavily pretreated ovarian cancer patients was higher than expected from prior experience with bevacizumab. Whether the difference in the rate of bowel perforation was due to refractory disease, treatment history, disease burden, or location of tumor is uncertain. We sought to review our multi-institutional experience with bevacizumab in patients with recurrent ovarian cancer. Methods: A retrospective review of patients with recurrent ovarian cancer treated with single agent or combination bevacizumab therapy was undertaken. Toxicity was assessed using standard criteria. Response was determined radiographically and through serial CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. Results: Sixty-two eligible patients were identified. All had failed prior platinum-based therapy and had received a median of 5 prior chemotherapy regimens and 2 prior platinum-containing regimens. Single agent bevacizumab was administered to 12 (19%) women, while 50 (81%) received the drug in combination with a cytotoxic agent. The most common toxicities were myelosuppression (60%), proteinuria (19%) and hypertension (16%). Grade 3–5 toxicities occurred in 15 (24%) patients, including grade 3–4 hypertension in 4 (7%). Gastrointestinal perforations were identified in 4 (7%) subjects. Nine (15%) patients discontinued therapy due to toxicity. Fifty-eight patients were assessable for response. The overall response rate was 36% (4 CR, 17 PR) with stable disease in 40%. Clinical benefit (CR, PR, stable disease) was seen in 83% of patients treated with single agent therapy and 74% of those treated with bevacizumab-combination regimens. Conclusions: Bevacizumab demonstrates significant activity for recurrent, platinum-resistant ovarian cancer. Life threatening bowel perforations were noted in 7% of our subjects. The frequency of perforations in our cohort suggests that this complication is more likely to occur in heavily pretreated patients.

No significant financial relationships to disclose.