bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of poor-risk metastatic renal carcinoma patients with combination gemcitabine, capecitabine, and bevacizumab at a tertiary cancer center
Authors: Miller L. , Lal L. S. , Tannir N. M. , DaCosta Byfield S. , Atkinson B. , Feng C. , Lau J. K. , Yin L. , Jonasch E.
Published: August 2020

e16112

Background: Treatment of poor risk metastatic renal carcinoma (mRCC) is challenging, and empiric combinations may be attempted in practice once conventional therapies fail. These combinations may lead to formal clinical trials. Evaluation of mRCC patients given an empiric combination of gemcitabine (gem) capecitabine (cap), and bevacizumab (bev) at a tertiary care center was performed. Methods: After obtaining IRB approval, non investigational use of gem in combination with cap and bev in mRCC patients was identified using institutional databases. Collected data included demographics, previous therapies, number of metastatic sites, MSKCC risk stratification variables, prior nephrectomy status, drug therapy duration, and progression-free survival (PFS). Descriptive statistics were employed for data analysis. Results: Thirty-six patients were included in the analysis, with a median age of 55.5 years. Seventeen patients (47%) had previously received a tyrosine kinase inhibitor (TKI). Twenty-two patients (61%) had clear cell histology, 13 patients (36%) had sarcomatoid features, 20 patients (56%) had undergone previous nephrectomy, 20 patients (56%) had four or more sites of metastasis and 27 patients (75%) were diagnosed within 1 year of therapy. Initial treatment consisted of gem (908.61 mg/m2) every 2 weeks, cap (2.75 grams/day), and bev (828.82 mg) every 2 weeks. The median PFS for the study population was 5.83 months. The subset of TKI patients had a median PFS of 5.4 months. Therapy was relatively well tolerated with only 3 patients discontinuing one or more of the drugs due to adverse reactions. Thirteen of the patients started a TKI post discontinuation of the triple therapy. Conclusions: The triple therapy combination in this retrospective evaluation provides promising efficacy and acceptable tolerability in patients with poor prognosis mRCC. Based on these observations, a phase II is now underway assessing gemcitabine, capecitabine and becacizumab in patients with sarcomatoid RCC.

[Table: see text]
Phase II study of 2-methoxyestradiol NanoCrystal dispersion (2ME2) alone and in combination with sunitinib (SU) in patients with metastatic renal cell carcinoma (mRCC) progressing on SU
Authors: Harrison M. R. , Pili R. , Logan T. , Wilding G. , Eickhoff J. , Sidor C. , Staab M. , Arnott J. , Liu G.
Published: August 2020

e16116

Background: Panzem NCD (2ME2) is a non-estrogenic derivative of estradiol with antiproliferative and antiangiogenic activity that downregulates HIF-1α. One mechanism of VEGFR TKI failure may be upregulation of HIF-1α. We hypothesized that 2ME2 may have single-agent activity in pts who previously progressed on SU and that addition of 2ME2 may restore response in pts progressing on SU. Methods: Pts with clear cell mRCC who had previously received or were currently receiving SU with disease progression were eligible. Pts who had previously received SU were treated with 2ME2 alone (arm A). Pts currently on SU continued on the 4:2 schedule, with the addition of 2ME2 (arm B). All pts received 2ME2 at 1,500 mg PO TID, repeated in 6 wk cycles. The primary endpoint was objective response (OR) rate by RECIST. An exploratory endpoint was metabolic response on FDG-PET. Simon optimal 2-stage design was used with plans to enroll 21 pts/arm, and if activity was seen to continue enrollment for a total of 41 pts/arm. Results: 17 pts were enrolled (A: 10; B: 7). Median number of cycles on study was 1 (range <1 to 5). A pt remains on study in cycle 8. Adverse events (AE) of grade 3 or greater occurred in 4 pts (29%). Most frequent AE were: fatigue (71%), diarrhea (50%), dysgeusia (29%), anemia or decreased hemoglobin (29%), and anorexia (21%). Reasons for treatment discontinuation include: disease progression (7), pt/doctor discretion (3), AE (3), and noncompliance (1). No ORs by RECIST were seen. Conclusions: 2ME2 appears to have some single-agent activity, with an MR in a pt removed from study due to AE and a metabolic PR (ΔSUVmax -84%) in a pt with SD by RECIST. With 6/17 pts discontinuing therapy before meeting any OR endpoint, 2ME2 was not tolerable in this population. The study was closed to accrual knowing that a more promising 2ME2 analog is currently under development for oncologic use. The rationale to target HIF-1α after (and during) SU therapy remains of interest. This study design provides a unique way to assess both single-agent and rational combination strategies in pts with mRCC and should be utilized with other agents to seek evidence for clinical activity.

[Table: see text]
Inhibitor of differentiation-1 (Id1) characterization in poor-prognosis (PP) human bladder cancer (BCa) primary tumors and matched metastases (MTS) using a new monoclonal antibody (MoAb)
Authors: Ponz-Sarvisé M. , Calvo A. , Redrado M. , Nguewa P. A. , Abella L. , Catena R. , García-Foncillas J. , Panizo A. , Gil- Bazo I.
Published: August 2020

e16119

Background: Id1, involved in cell differentiation, proliferation, tumor angiogenesis and metastasis, has recently showed to mediate lung MTS from breast cancer (PNAS 2007). The expression of Id1 in human cancer has been related to poor prognosis breast, prostate (Gil-Bazo, Amer Soc Clin Oncol GU. 2009) and other non-adenocarcinoma tumors. To date one study showed remarkable Id1 expression (exp.) in 28% of unselected human BCa using a new MoAb (195–14) for immunohistochemistry (IHC) analysis. Our aim is to study Id1 exp. in a group of PP BCa and their matched MTS using this MoAb (195–14). Methods: We selected 22 patients (pts) treated in our institution. Formalin-fixed and paraffin- embedded bladder biopsy samples of each patient and matched MTS samples of 9 of them were stained and scored for tumor and endothelial Id1 exp. Anti-human Id1 rabbit MoAb 195–14 (1:500), (Biocheck), was used for IHC. Results: 90% of pts were males; median age was 61. Most pts had PP advanced (22,7 % stage III; 68,2% stage IV) BCa. Primary tumor samples and additional 9 matched MTS biopsy samples were analyzed. In contrast with the previous data 80% of primary invasive BCa and more than 75% of MTS showed tumor cell Id1 exp. As previously reported Id1 exp. in tumor samples endothelial cells reached 70%. We also observed Id1 exp. in tumor in situ areas near the invasive carcinoma in 16 out of 20 pts expressing Id1 in the primary tumor. Conclusions: For the first time using a MoAb against Id1 and in accord with our previous observations in prostate cancer the selection of PP pts increases tumor cell Id1 exp. from 28 up to 80%. Interestingly we show BCa MTS to express Id1 with a similar exp. pattern than primary tumors. Id1 exp. profile in PP and metastatic initiation of BCa needs further research. Id1 exp. in tumor in situ areas suggests Id1 as an initial factor in the BCa carcinogenic process and in the case of being confirmed Id1 could represent a target in BCa prophylaxis.

No significant financial relationships to disclose.
Acupuncture for hot flashes for prostate cancer patients
Authors: Hayes M. , Reeder C. , Beer T. M.
Published: August 2020

e16125

Background: Hot flashes are a common adverse effect of androgen suppression therapy (AST) for prostate cancer. We sought to determine the effect of acupuncture on hot flash frequency and intensity, quality of life, sleep quality, and biomarkers. Methods: Men on AST who had a hot flash score (HFS) (J Clin Oncol. 2001;19:4280–4290) > 4 were treated with acupuncture with electro-stimulation twice weekly for 4 weeks and once per week for an additional 6 weeks. The treatment plan included the following points: bilateral gallbladder 34, bladder 15, 23, and 32 and unilateral governing vessel 20, heart 7, pericardium 6, liver 2, and spleen 6. Continuous low intensity electro-stimulation at 2 Hz was used to connect bladder 23 inferiorly to bladder 32. Needles were retained for 30 minutes with manual stimulation at 10-minute intervals. The primary endpoint was a 50% reduction in the HFS after 4 weeks of therapy. Hot Flash Related Daily Interference Scale (HFRDIS) (J Pain Symptom Manage. 2001;22:979–989), Pittsburgh Sleep Quality Index (PSQI) (Psychiatry Res. 1989;28:193–213), Short Form Health Survey-36 (SF-36) (Med Care. 1992;30:473–483), blood serotonin, plasma CGRP, and urinary 5-HIAA were also examined. Results: 22 men were enrolled between September 2003 and April 2007 and were eligible and evaluable. After 4 weeks of therapy, 9 of 22 patients (41%, 95%CI 21 to 64%) had > 50% reduction in hot flashes. 12 of 22 patients (55%, 95%CI 32 to 76%) met this response definition after 7 weeks of treatment. No patients had a significant increase in the HFS on therapy. Hot flash related quality of life, measured by HFDIS, improved in all patients and sleep quality, measured by PSQI, improved in hot flash responders. Hot flash related biomarkers including serotonin, 5-HIAA, and CGRP were examined before and after treatment. Conclusions: Multiple placebo-controlled trials have demonstrated that 25% of patients respond to placebo treatment for hot flashes. 41% of patients responded by week 4 and 55% by week 7 in this pilot study providing evidence of a potentially meaningful benefit with acupuncture therapy. Hot flash-related quality of life was also significantly improved with acupuncture treatment. Further studies of acupuncture for hot flashes in men undergoing hormonal treatment for prostate cancer are warranted.

No significant financial relationships to disclose.
bcl-2 expression and possibility of bladder preservation using combined modality treatment in muscle-invasive transtional cell carcinoma
Authors: Gaffar H. A. , Elfayomy A. , Elmaghraby A. , Elnemr M. M. , Elsawy W. H.
Published: August 2020

e16133

Background: whether combined chemoradiotherapeutic approaches can obtain the same local control as radical surgery, reducing the rate of distant metastases and improving survival with preservation of bladder for carefully selected patients. The BCL2 inhibits apoptosis. The apoptosis inhibiting action of BCL2 confirms a poor prognosis by current treatment modalities. To evaluate the combined modality treatment and selective bladder preservation and to evaluate BCL-2 expression that may predict treatment response and survival. Methods: 66 eligible patients with T2–4a NxM0 transitional cell carcinoma received two courses of gemcitabine and cisplatin followed by 45 Gy of pelvic radiotherapy in 1.8 Gy fractions with concomitant cisplatin. Tumor response was evaluated by cystoscopy and biopsy. Those responding completely were given 20 Gy bladder boost; patients with residual tumor were assigned to immediate cystectomy. Immunohistochemistry was used to assess the tumor cell expression of BCL-2. Results: After neoadjuvant chemotherapy, a complete response (CR) observed in 14 patients, a partial response (PR) in 26 and no change (NC) in 26. At cystoscopy after the pelvic irradiation with 45 Gy plus cisplatin, a CR was achieved in 33 patients, a PR in 14 and NC in 19. Immediate cystectomy was performed in 21 patients with PR or NC after neoadjuvant chemoradiotherapy. Bcl-2 was expressed in 35 (53%) of the patients. Bcl-2 immunoreactivity was inversely correlated with of histological grade (p = 0.0232) and was not correlated with gender distribution (p = 0.4666), the clinical stage (T) (p = 0.4325) or response to treatment (p = 0.6234). No significant difference was noted between the cause-specific survival rate of patients with positive Bcl-2 expression and those with negative BCL-2 expression. Conclusions: this combined approach of chemotherapy and radiation therapy with bladder preservation should be considered as an option for muscle-invasive transitional cell carcinoma of bladder. Initial results suggest the possibility of retaining a functioning bladder in many patients, without compromising survival. Assessment of Bcl-2 protein expression may be used to predict a clinical response to this combined modality approach.

No significant financial relationships to disclose.
Staging with 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) for nonseminomatous germ cell tumor (NSGCT): The Peter MacCallum Cancer Centre experience
Authors: Pezaro C. J. , Toner G. C. , Hicks R.
Published: August 2020

e16140

Background: We retrospectively evaluated our single institution experience using FDG-PET as part of initial assessment of stage I/II NSGCT. Previous studies by de Wit et al and the TE22 trial concluded that there was a very limited role for PET staging in NSGCT. Despite these results, PET continues to be utilised in our center. Methods: With local ethics approval, the PET center database at Peter MacCallum Cancer Centre (PMCC) was used to identify a series of 26 patients with NSGCT who underwent FDG-PET as part of staging investigations between 1998 and 2008. Demographic and clinical information was collected using electronic and paper medical records. Histological samples were reviewed if additional information was required. Results: Lymphovascular invasion (LVI) was present in 10 (38%) of orchiectomy specimens. 15 patients had stage I disease on both CT and PET. PET upstaged 7 patients from stage I to stage II disease, and all upstaged patients received systemic chemotherapy (3 cycles BEP). 1 patient with stage I disease on PET and CT received adjuvant chemotherapy (2 cycles EP). 3 patients with LVI and stage 1 disease on CT and PET underwent surveillance. With median follow-up of 33 months (range 1–94), all patients were alive without disease recurrence, although 1 patient was treated for a second primary NSGCT. Conclusions: Using PET images, we were able to identify patients with low volume metastatic disease and achieve 100% relapse-free survival rates. Despite the small sample size, these results are promising and are better than expected based on published data. This might be explained by the quality of the PET imaging, including attenuation correction and combined CT/PET for enhanced sensitivity interpreting retroperitoneal disease. Further evaluation of PET is warranted, particularly in patients with equivocal CTs or with the high-risk feature of LVI. [Table: see text]

No significant financial relationships to disclose.
Complete androgen blockade as second-line hormone manipulation and delay of chemotherapy in metastatic prostate cancer
Authors: Kaliks-Guendelmann R. , Santi P. , Cardoso A. , Del Giglio A.
Published: August 2020

e16141

Background: Complete androgen blockade (CAB) after failure of castration or androgen receptor blocker (ARB) has not shown to prolong survival in patients with metastatic prostate cancer, unlike docetaxel-based chemotherapy. The widely variable clinical benefit seen with CAB as second-line hormone manipulation still justifies the identification of the patients to whom it should be offered. Objective: to evaluate progression-free survival (PFS) and overall survival (OS) in patients treated with CAB after failure of castration or ARB and to identify clinical predictors of benefit. Methods: We performed a retrospective analysis of all patients with metastatic prostate cancer treated with CAB as second-line hormone manipulation in a single institution after September 2005. OS and PFS were estimated using Kaplan-Meyer plots. We identified 78 patients and evaluated correlations of prostate specific antigen (PSA), Gleason scores, age, type and length of first-line hormone manipulation with OS and PFS during CAB. Fifty-four patients had failed castration and 24 had failed ARB. Forty-four patients received chemotherapy after failing CAB. Results: With a median follow-up of 21 months, median PFS with CAB was 12 months (CI 6.8–17.2). We did not find any correlation of PFS with type of first-line hormone manipulation (castration vs ARB, p = 0.10), age group (≤70 or >70 years old, p = 0.10), level of PSA at diagnosis (≤50 or >50 ng/mL, p = 0.17) or length of first-line hormone manipulation (≤14m vs >14 m, p = 0.78). There was no significant correlation between PFS and Gleason score at diagnosis (score ≤7 or >7, p = 0.25), nor between the level of testosterone at the beginning of CAB and PFS. Median OS for patients on CAB after failing castration was 36 months (CI 24–48), and median OS of patients on chemotherapy was not reached at 9.5 months follow-up. Conclusions: Based on a PFS of 12 months, OS of 36 months and good patient tolerance, we believe CAB should still be used in CRPC, prior to initiation of chemotherapy. Predictors of clinical benefit are still to be identified.

No significant financial relationships to disclose.
Clinical experience with oral vinorelbine (NVB) plus prednisone as first- or second-line chemotherapy of metastatic hormone- refractory prostate cancer (HRPC)
Authors: Cervera J. M. , Garcia-Carbonero I. , Girones R. , Beltran M. , Calderero V. , Gonzalvez M. L. , Domenech M. , Diaz N. , Jimenez-Lacave P. , Gonzalez A.
Published: August 2020

e16151

Background: IV NVB plus hydrocortisone (HC) compared with HC alone resulted in improved clinical benefit, progression-free survival (PFS) and PSA response rate in HRPC. The oral formulation of NVB avoids the side effects associated with the IV injection, may reduce administration and toxicity-related costs and is easy to administer. Due to these advantages, single agent oral NVB treatment could be considered as an optimal option for patients (p) with HRPC previously treated with a taxane or as first-line treatment when a taxane is not indicated. We retrospectively evaluated efficacy and toxicity or oral NVB administered as single agent as first or second-line chemotherapy of metastatic HRPC. Methods: Retrospectively data was collected from p with metastatic HRPC treated with oral NVB 80 mg/m2 days 1 and 8, with a prior test of myelosensitivity at 60 mg/m2 for the first cycle, plus prednisone 10 mg/day. Patients had received a taxane as first-line treatment or had a documented contraindication to receiving docetaxel. 1 cycle was equivalent to a 3-week period. Results: Data on 55 p treated in 11 Spanish centres were included for assessment. Median age was 72.5 years (range 54–86). ECOG PS 0, 17%; 1, 66%; 2, 17%. Median PSA 75 ng/mL. Prior taxane chemotherapy, 87%. Median number of cycles was 4 (range 1–6). 53.8% of p could escalate oral NVB to 80 mg/m2. 221 cycles were performed, 4.1% were delayed and 3.2% had a dose reduction. Grade 3–4 events were infrequent and mainly haematological: neutropenia (5.5% of p), anemia (3.6%), pain (3.6%), infection (1.8%), asthenia (1.8%), respiratory (1.8%). No febrile neutropenia was reported. 49 p were evaluable for PSA response rate; complete plus partial response was observed in 20.4% (95% CI: 10.2% - 34.3%) and PSA stable was reported in 40.8%. 29 p were evaluable for measurable disease; among them, 20.7% presented partial response and 44.8% stable disease. Median follow-up was 4.3 months. Survival status: 49 p (89.1%) are alive and 6 p (10.9%) died. Conclusions: Oral NVB is a safe and active regimen in previous chemotherapy treated HRPC. For those p who can not receive a taxane as first-line therapy, oral NVB can also be considered as an effective first-line treatment.

No significant financial relationships to disclose.
Percutaneous orchiectomy: A noninvasive method of castration beyond percutaneous testicular sclerosis
Authors: Nepomuceno E. C. , Quintiliano F. , Lima F. S. , Café E. , Boente P.
Published: August 2020

e16153

Background: Surgical castration is the gold standard for hormonal deprivation in metastatic prostate cancer, nevertheless this simple procedure may involve on psychological consequences. According to many studies, it's possible to achieve ischemic lesion in liver tissue beyond sclerosants agents (like alcohol or glycerol), however there are very few reports about the effects of such agents in testicles. These study objectives evaluating histological and morphological characteristics of rat testicles submitted to percutaneous administration of sclerosants agents and also, to compare serum testosterone levels between rats submitted to a surgical orchiectomy or percutaneous injection. Methods: Twenty four rats have been shared in four groups with eight animals each. In group O, rats were submitted to bilateral orchiectomy. In the other groups, rats were submitted to percutaneous administration of a sclerosant agent and orquiectomy after thirty days as follows: Group A, Alcohol injection; Group G - Glycerol; Group S - Saline solution (control group). Serum testosterone level was measured after 15 and 30 days in each animal. Results: There is no complication or death in this series. Rats of groups A and G comparing to control group (group S) had smaller testicular weight (0,8±0,1g; 1±0,2g versus 3,15±0,1g p<0,0000001) and smaller testicular volume (0,16±0,05mL; 0,23±0,11mL versus 2,38±0,05mL p<0,0000001). Testosterone serum levels were as similar in groups A and G (sclerosis) as in group O (orchiectomy). After 15 days testosterone levels were A=2,9±0,74 ng\dL; G=2,8±0,39 ng\dL versus O=2,91±1,46ng\dL p=0,99; and after 30 days were A=2,58±0,4ng\mL, G=2,78±0,3ng\mL versus O=2,7±0,95ng\mL p=0,895). Histological findings show extensive necrosis beyond macrophagic infiltration and no Leydig cells visualized.There is no significantly statistical difference between Alcohol and Glycerol groups. Conclusions: Percutaneous administration of alcohol or glycerol in rats testicles causes atrophy and reduces testosterone serum levels like it occurs after surgical castration. More studies are necessary to evaluate if this minimally invasive procedure may be an alternative to surgical orchiectomy in advanced prostate cancer.

No significant financial relationships to disclose.
Phase I study of extended field intensity modulated radiation therapy (EF-IMRT) and docetaxel in patients with node-positive prostate cancer
Authors: Hauke R. J. , Enke C.
Published: August 2020

e16154

Background: Treatment for patients with node positive prostate cancer remains challenging. With hormonal ablation therapy (HAT), conventional radiation doses to the lymph nodes produces few cures or long-term remissions, likely due to suboptimal doses and/or fields of radiation. Docetaxel has radiosensitizing properties. We conducted a phase I study combining HAT with EF-IMRT and concurrent docetaxel in men with biopsy-proven node positive prostate cancer. Methods: Eligible patients had biopsy proven N1M0 disease and adequate hematologic and hepatic function. All subjects received neoadjuvant HAT (bicalutamide 50 mg/d with an LHRH agonist) for at least 2 months but less than 13 months prior to EF-IMRT and continued for 2 years after completion of radiation (bicalutamide discontinued at the end of radiation). EF-IMRT target doses: prostate 81.0 Gy/45 fractions; intraprostatic target 81.0 - 84.6 Gy/45 fractions; pathologically involved lymph node 72 Gy/43 fractions; pelvic lymph nodes 54.0 Gy to 70.2 Gy/43 fractions. Ultrasound targeting and a water filled rectal catheter balloon were used daily to minimize movement and locate the prostate. Weekly docetaxel was administered during radiation at 5, 10 or 17 mg/m2. The primary endpoint was determining grade III/IV toxicity. Results: Nine patients have been treated. No grade III/IV toxicities occurred within the defined observation period. All subjects received their prescribed radiation and chemotherapy doses. One patient developed an anal fissure and one patient had tachyarrhythmias about 6 months after radiation. Seven of 9 patients are now beyond the 2 year post-radiation period; 4 patients remain in remission; one patient developed primary lung cancer; another was lost to follow up at 1 year post-radiation and 3 had relapsed disease within the 2 year post-radiation window. Conclusions: The addition of weekly docetaxel to EF-IMRT along with HAT is well tolerated in patients with node positive prostate cancer. Phase II studies are warranted based on these results.

[Table: see text]
What is the optimum number of beams and energy for IMRT boost in prostate cancer? A plan comparison study
Authors: Kunhiparambath H. , Prabhakar R. , Rath G. K. , Sharma D. N. , Heera P. , Julka P. K.
Published: August 2020

e16158

Background: Intensity Modulated Radiotherapy (IMRT) is used in carcinoma prostate to achieve better target coverage with less dose to critical organs thereby permitting dose escalation and eventually better therapeutic ratio. There is scarcity of literature evaluating beam number and energy in prostate cancer treated by IMRT. Aim of our study is to identify the optimal number of beams and energy in the boost treatment of prostate cancer by IMRT. Methods: Ten patients were included in this study. Initially a dose of 45 Gy in 25 fractions was delivered to the prostate, seminal vesicles and the nodes by 3DCRT. A boost dose of 27 Gy in 15 fractions was planned to the prostate and the seminal vesicles by sliding window IMRT. Four different sets of IMRT plans: 5, 7 and 9 field with 6 MV; 7 field with 15 MV were generated. The dose constraints to the critical structures and the target volume were based on standard guidelines. The mean dose, maximum dose, volume receiving the prescribed dose (V100), volume receiving > 107% and <95% of the prescribed dose were analyzed for CTV and planning target volume (PTV). The mean dose, volume receiving 100%, 50% and 30% of the prescribed dose were analyzed for the bladder and the rectum. Similarly, the mean dose and the maximum dose to the right and left femoral heads, monitor units (MU) and the integral dose were analyzed. SPSS V10.0 software was used for statistical analysis. Results: The seven beam plan provide better dose homogeneity to PTV and lesser doses to critical structures like bladder, rectum and femoral heads when 6 MV photon is used. 15 MV photons further improve the dose homogeneity and decrease the dose to critical structures. The Monitoring Units required to deliver the treatment and the Integral dose is significantly reduced by using 15 MV compared to 6 MV. Conclusions: The optimal IMRT plan for boost planning in carcinoma prostate is that uses 7 beams and higher energy. This yields lesser dose to surrounding critical structures with better target conformity. [Table: see text]

No significant financial relationships to disclose.
Metastatic prostate cancer at diagnosis: Clinical presentation in the post-PSA era
Authors: Dickstein R. J. , Kreshover J. E. , Milose J. C. , Gignac G. A.
Published: August 2020

e16159

Background: Prostate cancer (CaP) has varying biologic behavior. Prostate-specific antigen (PSA) screening dramatically diminished the presentation of patients (pts) with metastatic CaP from 5.6% in 1990 to 1.5% in 2003 as evidenced by the CaPSURE database. Our institution has a uniquely diverse demographic and socioeconomic population and we sought to identify pts with metastatic CaP at diagnosis to evaluate contributing factors. Methods: We retrospectively reviewed all pts charts diagnosed with CaP as identified by ICD-9 code (185) between January 1st 2003 and October 31st 2008 after cross referencing with the term metastatic. Pts progressing from localized disease were excluded. Data was collected on pts initially presenting with metastases. Results: Sixty-one pts presented initially with metastatic CaP at a median age of 68 years old (45 –90) and a median PSA of 92 ng/mL (4.4 –3463). Digital rectal exam was normal in 8 pts (13%) and abnormal in 43 (70%). Median body mass index was 27.2 (16.9 –46.7) with 26 pts (42%) being smokers and 20 (32%) non-smokers. Thirty-six pts (59%) had a Charlson Comorbidity Index score of 0, 10 (16%) a score of 1, 10 (16%) a score of 2, and 5 (8%) a score of ≥ 3. Fifteen pts (24%) were Caucasian, 42 (68%) black [24 (39%) African American, 10 (16%) Caribbean, 8 (13%) African], 1 (1%) Hispanic, 1 (1%) Asian, 1 (1%) Albanian, and 1 (1%) Indian. Presenting symptoms were comprised of 32 pts (52%) with lower urinary tract symptoms including hematuria, urinary retention, and hydronephrosis, 21 (34%) with bone pain, 3 (4%) with neurologic deficits, and 17 (27%) were asymptomatic. Forty-seven pts (77%) underwent prostate biopsy of which 33 (70%) had high grade (Gleason ≥ 8) tumor. Conclusions: CaP initially presenting as metastatic disease is a rare event in the post-PSA era, but may result from lacking primary health care screening, poor patient compliance, or inherent predisposing factors of tumor biology. Our analysis identifies a predominantly non-Caucasian population of patients, contrasting the CaPSURE database, who are otherwise healthy. We plan on performing comprehensive analyses on all patients with metastatic CaP at Boston Medical Center.

No significant financial relationships to disclose.
Does the day or season of operation predict biochemical recurrence after radical prostatectomy?
Authors: Hirsh A. L. , Lee D. J. , Hruby G. , Benson M. C. , McKiernan J. M.
Published: August 2020

e16162

Background: Outcomes in hospital based medicine are associated with the experience and availability of the medical staff, as mortality and morbidity rates increase each summer with new medical graduates. Hospital staff members are thought to be more fatigued and less available towards the end of the week and on weekends. However it is not known if there is a difference of outcomes based on the season or day of the week. We sought to identify if different seasons or surgical days of the week can predict poor outcomes and biochemical recurrence (BCR) in radical prostatectomy (RP). Methods: A retrospective analysis of the Columbia Urologic Oncology database was performed. 1865 consecutive men underwent RP from 1991 to 2008 by three surgeons. Data was collected in an institutional review board approved registry, with median follow up of 36 months. BCR was defined as two consecutive PSA levels > 0.2 ng/ml. Stratified cox regression methods were used to model the relationship between surgeon, preoperative variables, season, day of the week, and BCR. Winter was defined as December through February, spring as March through May, summer as June through August, and fall as September through November. Results: The mean age of the men undergoing RP was 61.2 years (37–79), with a mean preoperative PSA of 8.12. 424 men (22.7%) had positive surgical margins, and the mean estimated blood loss (EBL) was 1119cc. Patient age (p=0.68), preoperative PSA (p=0.32), EBL (p=0.51), and positive surgical margin rate (p=0.78) were not significantly different between each day. Men undergoing RP did not have different rates of BCR according to the day of the operation (p=0.58) or season (p=0.997). The particular season and day of the operation were not significantly associated with BCR, and were not independent predictors of BCR in a multivariable model after adjusting for preoperative PSA, Gleason sum, tumor stage, and surgeon. Conclusions: Patient surgical outcomes and BCR rates after RP are not associated with the particular season or day of the week of the procedure. These findings suggest that men undergoing RP do not need to be concerned about the particular season or day when scheduling the procedure.

No significant financial relationships to disclose.
Potential therapeutic activity of adecatumumab (MT201), a fully human monoclonal antibody, against epithelial cell adhesion molecule (EpCAM) in uterine serous papillary carcinoma
Authors: Santin A. , Bellone S. , El-Sahwi K. , Buza N. , Tavassoli F. A. , Silasi D. , Azodi M. , Schwartz P. E. , Rutherford T. J. , Pecorelli S.
Published: August 2020

e16502

Background: Uterine serous papillary carcinoma (USPC) represents a variant of endometrial cancer characterized by a highly aggressive biologic behavior and inborn resistance to chemotherapy. MT201 is a fully human monoclonal antibody recently developed against epithelial cell adhesion molecule (EpCAM). In this study we have evaluated the potential of MT201 as a novel therapeutic strategy against USPC. Methods: EpCAM expression was evaluated by real time-PCR and immunohistochemistry (IHC) in a total of 54 USPC fresh-frozen biopsies and paraffin embedded tissues. EpCAM surface expression was evaluated by flow cytometry in 6 freshly established USPC cell lines derived from advanced stage USPC patients. Sensitivity to MT201 antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) was tested in standard 4-hour chromium (51Cr) release cytotoxicity assays. Results: EpCAM transcript was significantly overexpressed in fresh frozen USPC when compared to fresh-frozen normal endometrial cells (NEC) [i.e., mean (minimum-maximum) copy number of 515.4 (31.5–1568.3) in tumor samples versus 8.1 (1.0–25.5) in flash-frozen NEC (p < 0.001)]. By IHC, EpCAM protein expression was found in 96% (26 out of 27) USPC samples and this expression was significantly higher when compared to normal endometrial cells (p < 0.01). High surface expression of EpCAM by flow cytometry was found in 83% (5 out of 6) of the primary USPC cell lines available to this study. Importantly, while primary USPC cell lines were highly resistant to natural killer dependent cytotoxicity in vitro, EpCAM positive cell lines were found highly sensitive to MT201-mediated ADCC. Human serum IgG did inhibit MT201-mediated cytotoxicity against USPC in vitro. Conclusions: These results demonstrate for the first time high EpCAM expression in uterine serous carcinoma at mRNA and protein levels and high sensitivity to MT201-mediated cytotoxicity in vitro by primary USPC cell lines. MT201 might be a novel and attractive therapeutic strategy in patients harboring advanced, recurrent or metastatic USPC refractory to standard treatment modalities.

No significant financial relationships to disclose.
Population profiles of extra-ovarian and ovarian serous adenocarcinomas: Comparisons with grade stratification
Authors: Grimley P. M. , Matsuno R. , Anderson W. F.
Published: August 2020

e16506

Background: Molecular studies of ovarian serous adenocarcinomas (OSC) have linked distinct patterns of gene expression or mutations to high or low tumor grade. This heterogeneity appears to be mirrored in two population subgroups delineated by age-specific incidence rates (ASIR) stratified by grade. We aimed to determine whether serous adenocarcinomas of the peritoneum (PSC) or fallopian tubes (FSC) comprised grade-related subgroups comparable to OSC. Methods: Data for women with invasive OSC (25,997 cases), PSC (2,157), and/or FSC (618) registered in the NCI's Surveillance, Epidemiology, and End Results program (1976–2005) were analyzed. Incidence rates (IR) stratified by grade were compared by year or age of diagnosis. Descriptive analyses were supplemented with tests for trend or age interaction by grade. Cancer-specific survival also was compared by grade (Kaplan-Meier estimator). Results: We observed trend interactions by grade for OSC, PSC, and FSC (p < 0.001); age-adjusted incidence rates rose more rapidly for high than low grade tumors over time. ASIR for OSC/PSC were higher for low than high grade tumors prior to age 40 years, after which rates became higher for high grade (p < 0.001 for age interaction by grade). ASIR were similar for FSC but interpretation was limited by small sample sizes. Unilateral carcinomas were far more common for FSC than OSC (90.9% versus 40.6%). Actuarial cancer-specific cumulative survival was worse for high than low grade tumors (all anatomic sites). Conclusions: Trend and survival analyses both were consistent with a biologically significant high/low grade stratification of OSC, PSC, and FSC. For PSC, significant correlations to ASIR by high/low grade were consistent with two population subgroups as defined for OSC; and also appeared congruent with molecular models that project dual pathways of carcinogenesis. For FSC, definitive correlations will require larger sample sizes.

No significant financial relationships to disclose.
A phase II evaluation of pemetrexed (ALIMTA, LY231514, IND#40061) in the treatment of recurrent or persistent endometrial carcinoma: A phase II study of the Gynecologic Oncology Group
Authors: Miller D. S. , Blessing J. A. , Krasner C. N. , Drake R. D. , Higgins R. , McMeekin D. S. , Puneky L. V.
Published: August 2020

e16507

Background: To estimate the anti-tumor activity of pemetrexed in patients with advanced or recurrent carcinoma of the endometrium that failed on higher priority treatment protocols and to determine the nature and degree of toxicity. Methods: A multicenter phase II trial was conducted by the Gynecologic Oncology Group (GOG). Patients must have had advanced or recurrent measurable carcinoma of the endometrium and failed one prior chemotherapy regimen. Pemetrexed at a dose of 900 mg/m2 was to be administered as an IV infusion over 10 minutes every 21 days. Results: From May 1, 2006 to July 31, 2007, 27 patients were entered by ten member institutions of the GOG. A total of 101 cycles were administered with 27% of patients receiving five or more cycles. The treatment was well tolerated overall. More serious toxicities (grade 3 and 4) included anemia in 19%, leukopenia in 38%, neutropenia in 46%, and constitutional in 19%. No treatment related deaths were reported. One patient (4%) had a partial response. Twelve patients (46%) had stable disease and eleven (46%) patients had increasing disease. Median progression-free survival (PFS) was 2.7 months and overall survival (OS) was 9.4 months. Conclusions: Pemetrexed has minimal activity in the treatment of recurrent or persistent endometrial carcinoma at the dose and schedule tested.

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Does repeat usage of bevacizumab in patients with progressive recurrent ovarian cancer offer a survival advantage?
Authors: Richardson D. L. , Backes F. J. , Seamon L. G. , Seamon L. G. , Hurt J. D. , Cohn D. E. , Fowler J. M. , Copeland L. J. , O'Malley D. M.
Published: August 2020

e16510

Background: Many studies show bevacizumab (BEV) has activity in the treatment of recurrent ovarian cancer, especially when combined with cytotoxic chemotherapy. However, it is uncertain whether BEV should be continued if a patient progressives on treatment which includes BEV. Therefore, our objective is to compare response rates (RR), progression-free survival (PFS), and overall survival (OS) between patients who continued on BEV after progression on BEV (BPB) versus patients who were treated with cytotoxic chemotherapy without BEV (no BPB). Methods: All patients who received treatment with BEV (with or without cytotoxic chemotherapy) for recurrent ovarian cancer at a single institution were identified. Patients who received additional therapy after progression on BEV were included. Patients who were treated on GOG 218 or received first-line BEV or had their first BEV therapy discontinued due to side effects from BEV were excluded. RR were assessed using RECIST criteria, CA125 levels, or progressive disease symptoms. PFS was defined as the period from initiation of the treatment regimen until progression or date of last contact. OS was defined as the period from initiation of the second treatment regimen until death or date of last contact. Results: 35 patients met inclusion criteria. The median number of previous chemotherapy regimens was 4 (range 1–8). About 50% of the patients had a CR or PR prior to progressing on BEV. There were 27 patients in the BPB group, and 8 patients in the no BPB group. 13% (1/7) of patients responded to cytotoxic chemo after BEV, and 15% (4/27) of patients responded to repeat treatment with BEV, p = 1. The median PFS for patients in the no BPB group was 4.6 months (95% CI 1.6–5 mo), compared to 4.8 months (2.7–7.5 mo) for patients in the BPB group, p = 0.11. There was no difference in OS, 9.8 months (95% CI 2.73- ∞) versus 8.4 months (95% CI 5.8–15.6 months) p = 0.43 for patients in the no BPB group versus the BPB group. One patient in the BPB group died of a bowel perforation. Conclusions: We offer the first comparison of PFS and OS in patients treated with cytotoxic chemotherapy ± BEV after progression on BEV. After progressing on a BEV regimen, there was no difference in the PFS, OS or RR in those pts treated with or without BEV with an overall OS < 1 year.

[Table: see text]
Gene therapy for pretreated ovarian cancer via a novel fiber modified mdr1 targeting conditionally replicating adenovirus
Authors: Beyer I. , Bauerschmitz G. J. , Breidenbach M. , Dragoi A. , Niederacher D. , Janni W. , Rein D. T.
Published: August 2020

e16513

Background: Ovarian cancer (OC) is a leading cause of death from gynecologic malignancies. Oncolytic adenoviruses (CRAd) are a new approach for cancer treatment. In this study, we constructed a fiber-modified CRAd containing the multi drug resistance gene (mdr) 1 promoter to control viral replication (Ad5/3MDR1). Antineoplastic agents induce mdr1-gene expression triggering chemoresistance. Methods: RT-PCR was performed for expression of mdr1 in cell lines and primary patient samples. We constructed Ad5/3MDR1luc1 to determine relative activity in a variety of cell lines, patient samples, and normal control cells. Replication and oncolysis of Ad5/3MDR1 were assessed in naïve and pretreated OC cell lines. The specificity of viral replication was analyzed in co-culture of pretreated OC cell lines and human fibroid cells. A mouse model of peritoneal carcinomatosis was used to evaluate the efficacy of a combined chemo- and gene therapy for OC. Results: RT-PCR reveals a significantly (p < 0.05) increased expression of the mdr1 gene in OC cell lines and patient samples. Compared to the ubiquitous cmv promoter, mdr1 showed a high level of activity in chemoresistant OC cell lines (7.3%-11.5 %) and OC patient samples (8.8%-12.4%), whereas activity in normal fibroblasts (<1%) was low. Ad5/3MDR1 shows highly selective replication in chemoresistant OC cells in a co-culture with fibroblast cells. Cell killing of Ad5/3MDR1 was comparable to Ad5/3Δ24, a CRAD that replicates in cancer cells inactive in the Rb/p16 pathway, in chemotherapy naïve OC cells but displayed significantly (1.5 log; p < 0.05) higher oncolytic potency in pretreated OC cell lines and primary cells from pretreated OC patients. Moreover, in a therapeutic orthotopic mouse model of peritoneal carcinomatosis, dramatically enhanced survival was noted with Ad5/3MDR1. Conclusions: Ad5/3MDR1 is a promising candidate for gene therapy of metastatic chemoresistant OC with great potential for clinical testing.

No significant financial relationships to disclose.
The effects of body mass index on curative radiation therapy in cervical carcinoma: An analysis of complications and survival
Authors: Thaker P. H. , Gao F. , Zighelboim I. , Powell M. A. , Rader J. S. , Mutch D. G. , Kizer N.
Published: August 2020

e16520

Background: Recently, the rates of obese and overweight patients have increased dramatically. However, the effect of body mass index (BMI) have not been evaluated in treatment outcomes for patients with advanced stage cervical cancer receiving definitive chemotherapy and radiation therapy, and is the purpose of this study. Methods: After obtaining approval from the Washington University Human Studies Protection Office, a retrospective cohort study (n = 321) was performed on all cervical cancer patients with stage IB1 with positive lymph nodes or ≥ stage IB2 from January 1998 to January 2008. The median duration of follow up was 60 months. BMI was calculated using the National Institute of Health online BMI calculator. Main outcomes were overall survival, disease free survival, and radiation complications such as radiation enteritis/cystitis, bowel obstruction, and fistula formation. Univariate and multivariate analyses were performed, and Kaplan-Meier curves were generated. Results: Underweight patients (BMI<18.5 kg/m2) compared to normal weight (BMI = 18.5–25 kg/m2) and overweight/obese (>25 kg/m2) have a higher actuarial complication rate (p = 0.0137). Regardless of weight there is no difference in disease free survival. However, underweight patients have a significantly poorer overall survival than those patients with a higher BMI (>18.5 kg/m2) (p < 0.001). Conclusions: Underweight patients have a diminished overall survival compared to normal or obese cervical cancer patients. This is of clinical relevance when counseling underweight cervical cancer patients who will be cured of the disease with chemotherapy and radiation therapy, but have a significant risk of suffering potentially fatal complications from treatment. Further study needs to be done to elucidate this relationship further.

No significant financial relationships to disclose.
Correlation between preoperative serum CA 125 and surgicopathologic prognostic factors in endometrial cancer
Authors: Espino-Strebel E. , Luna J. T.
Published: August 2020

e16524

Background: Poor prognostic factors dictating the need for extended surgical staging among endometrial cancer patients can be accurately determined only after laparotomy. An adequate preoperative work-up is thus necessary to tailor surgical treatment individually. This prospective study was conducted to determine the correlation between preoperative serum CA125 and surgicopathologic prognostic factors in endometrial cancer. It also aimed to determine the CA125 cutoff value which best predicted the prognostic factors to which it was correlated. Methods: Endometrial cancer patients diagnosed from October 2006 to July 2008 who were eligible for primary surgical treatment were included. Serum CA125 determination was done by a chemiluminescent enzyme immunoassay prior to surgery. All patients underwent laparotomy, peritoneal fluid cytology, extrafascial/radical hysterectomy, bilateral salpingooophorectomy, bilateral pelvic lymph node dissection, and para-aortic lymph node sampling. Specimens were examined for tumor differentiation, lymphovascular space invasion, depth of myometrial invasion, cervical, adnexal, and vaginal involvement, pelvic and para-aortic lymph node metastases, and peritoneal fluid cytology. Pearson r correlation test was used to evaluate the correlation of serum CA125 with the prognostic factors. A receiver operating characteristic curve was used to determine the optimal cutoff value of preoperative CA125. Results: Ninety patients with endometrioid endometrial adenocarcinoma were included. Preoperative serum CA125 was significantly correlated with deep myometrial invasion (p = 0.02), adnexal metastasis (p = 0.01), pelvic (p < 0.01), and para-aortic node involvement (p<0.01). It was also significantly correlated with extrauterine disease (p = 0.01). A cutoff value of 55U/mL can predict extrauterine spread with 53.85% sensitivity, 84.38% specificity and 75.56% accuracy. Conclusions: Preoperative serum CA125 has a significant correlation with deep myometrial invasion, adnexal metastasis, pelvic and para-aortic lymph node involvement, and extrauterine disease at a cutoff value of 55U/mL. It is recommended that serum CA125 determination be part of the preoperative work-up of endometrial cancer patients.

No significant financial relationships to disclose.