bluuebunny/crossref_metadata_2025 huggingface dataset:
RAMSETE: A single-arm, multicenter, single-stage phase II trial of RAD001 (everolimus) in advanced and metastatic silent neuro-endocrine tumours in Europe.
Authors: Pavel Marianne E. , Wiedenmann Bertram , Capdevila Jaume , Reed Nicholas , Valle Juan W. , Caglio Silvia , May Christoph , Comis Silvia , Castellana Ramon , de Herder W.W. , Metzner Cornelia , Salazar Ramon , Hörsch Dieter , Oberg Kjell E.
Published: March 2020

4122

Background: The mammalian target of rapamycin (mTOR) signaling pathway is involved in the pathogenesis of neuroendocrine tumors (NET). Everolimus (RAD001), an oral mTOR inhibitor, has antitumor activity in patients (pts) with advanced NET. In this open-label, multicenter, phase II study (RAMSETE), the safety and efficacy of everolimus monotherapy was evaluated in pts with advanced nonsyndromic, nonpancreatic NET. Methods: Pts with advanced (unresectable or metastatic), progressive, nonsyndromic, nonpancreatic NET received everolimus (10 mg/day) as monotherapy. The primary endpoint was objective response rate (proportion of pts with best overall complete response [CR] or partial response [PR] per RECIST v1.0) by central radiologic review. A secondary endpoint included progression-free survival (PFS). Results: By database soft lock (December 1, 2011), 73 pts from 16 European clinics received everolimus (median duration of treatment: 193 days). Fifty-five (75%) pts discontinued; reasons included disease progression (n=23), adverse events (AEs [n=23]), withdrawal of consent (n=4), death (n=3), and protocol deviation (n=2). In the per protocol population (N=60), 32 (53%) pts received prior antineoplastic therapy. The best response by central review was stable disease in 55%. By local review, 3 (5%) pts had a PR, with SD in 39 (65%) pts. Median PFS by central review was 185 days (95% CI: 158-255). Median PFS by local investigator review was 285 days (95% CI: 231-not estimable). 69 (95%) pts reported treatment-related AEs of any grade, including rash (n=28; 38%), diarrhea (n=20; 27%), mucosal inflammation (n=18; 25%), and decreased appetite (n=17; 23%). Treatment-related grades 3 and 4 AEs and serious AEs were reported by 27 (37%) and 18 (25%) pts, respectively. Conclusions: In this open-label trial of everolimus in pts with advanced, nonsyndromic, extrapancreatic NET, a high rate of disease stabilization was achieved after prior tumor progression with favorable median PFS. This study further supports efficacy of everolimus in types of NET other than those studied in RADIANT-3 (pancreatic NET) and RADIANT-2 (NET associated with carcinoid syndrome).
Well-differentiated grade 3 digestive neuroendocrine tumors: Myth or reality? The PRONET study group.
Authors: Scoazec Jean-Yves , Couvelard Anne , Monges Genevieve , Leteurtre Emmanuelle , Belleannee Genevieve , Guyetant Serge , Duvillard Pierre , Danjoux Marie , Parot Xavier , Lepage Come
Published: March 2020

4129

Background: In contrast to the 2000 World Health Organization (WHO) classification of digestive neuroendocrine tumors (NET) in which morphologic differentiation was the first criterion, the 2010 WHO classification of NET is based mostly on histologic grade. NET are now classified into three main categories: NET G1 (mitotic count <2/10 HPF and/or ≤2% Ki67 index), NET G2 (2-20/10 HPF and/or 3-20%), and neuroendocrine carcinoma (NEC) of small or large cell type. While NET G1 and G2 are well-differentiated tumors, NEC are considered poorly differentiated G3 tumors. We looked at the agreement between grade and differentiation to determine whether all NET can be readily classified according to the 2010 WHO classification. Methods: We designed a 1-year prospective, epidemiologic study to assess the characteristics of newly diagnosed NET, including diagnostic pathology. From August 2010 to July 2011, all pathology laboratories in France were invited to register all incident cases of gastroenteropancreatic (GEP) and thoracic NET, excluding small cell carcinoma. For GEP-NET, investigators were asked to indicate morphologic differentiation (according to WHO 2000) and elements of histologic grade (mitotic index, Ki67 index), according to ENETS. Results: Of 500 invited centers, 80 participated; 1417 incidental cases were included and 77 excluded (duplicates or exclusion criteria), totaling 1340 cases; 778 (58.1%) were GEP-NET; 660/778 (85%) were well differentiated, 72 (9%) poorly differentiated, and 46 (6%) adenocarcinoid, nonclassified, or not evaluable; 422 (54.2%) were G1, 220 (28%) G2, 104 (13.5%) G3, and 32 (4.1%) had missing grades. Of those deemed G3, 72 (69%) were described as poorly differentiated, 21 (20%) as well differentiated (mean Ki67 index 35%, range 25%-60%), and 11 (10.5%) as adenocarcinoid. Conclusions: In this prospective, epidemiologic study, overall agreement between grade and differentiation was good. However, a significant proportion of G3 NET were classified as well differentiated and thus unclassifiable by 2010 WHO classification. This group of tumor deserves to be included in future classifications to help the clinician decide whether they should be treated as NET G1/G2 or NEC G3.
Bilateral testicular cancer within two prospective, population-based SWENOTECA protocols in clinical stage I nonseminoma.
Authors: Tandstad Torgrim , Solberg Arne , Hakansson Ulf , Angelsen Anders , Haugnes Hege Sagstuen , Oldenburg Jan , Kjellman Anders , Dahl Olav , Cohn-Cedermark Gabriella ,   SWENOTECA
Published: March 2020

4508

Background: Contralateral tumor (CLT) occurs in 3.5-5% in men diagnosed with testicular cancer. The precursor lesion, ITGCNU, transforms into invasive germ cell cancer in 50-100%. Although radiotherapy eradicates ITGCNU effectively, mandatory biopsy of the contralateral testis to detect ITGCNU is controversial. Whether, adjuvant chemotherapy (ACT) reduces the incidence of bilateral cancer is also uncertain. Methods: 988 patients with clinical stage 1 nonseminoma were included in two prospective, population-based SWENOTECA protocols. Thirteen patients were excluded due to previous contralateral biopsy, synchronous bilateral cancer or protocol violations. Treatment was either adjuvant chemotherapy (n=490), or surveillance (n=485). Contralateral testicular biopsy was recommended, but performed only in 283 patients. In case of ITGCNU radiotherapy to 16 Gy was recommended.The estimated cumulative incidence of CLT was calculated using the Kaplan-Meier method. Results: With a median follow-up of 6.3 years, twenty-nine (3.9%) patients developed CLT including five patients with synchronous cancer. Biopsies showed ITGCNU in 3.2%. The incidence of CLT was similar following ACT, 3.7 % (11/490), and surveillance, 3.1% (12/485), p=0.99. Biopsied patients had a risk of developing CLT of 4.3% (9/283), and seven patients treated for CIS never developed CLT. Unbiopsied patients had a risk of 3.0 % (14/668). The proportion of bilateral cancers was similar in biopsy negative patients 3.6% (7/274) and unbiopsied patients 3.0 % (14/668). Young age at orchiectomy was a significant risk factor for metachronous cancer, HR 0.94 (CI: 0.89-0.99), p=0.04. All patients with ITGCNU were offered RT. One irradiated patient developed CLT cancer, and one developed CLT before RT was given. Conclusions: In this selected population ACT did not reduce the incidence of CLT. There was a high proportion of false negative biopsies, which might explain why biopsy negative patients had the same risk of CLT as patients not undergoing biopsy. Young patients had the highest risk of developing contralateral cancer, the risk of CLT decreased by 6% yearly.
Effect of denosumab on prolonging bone-metastasis free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.
Authors: Saad Fred , Smith Matthew Raymond , Shore Neal D. , Oudard Stephane , Miller Kurt , Tombal Bertrand , Sieber Paul , Fizazi Karim , Van Veldhuizen Peter , Damião Ronaldo , Marx Gavin M. , Morote Juan , Ye Zhishen , Dansey Roger D. , Goessl Carsten Dietrich
Published: March 2020

4510

Background: Denosumab, an anti-RANK-ligand monoclonal antibody, has been shown to prolong BMFS by a median 4.2 months and with a 15% risk reduction vs. placebo in men with non-metastatic CRPC and baseline PSA value ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤10.0 months. To determine the efficacy of denosumab in men at greatest risk for bone metastases, we evaluated BMFS in a subset of men with PSADT ≤6 months (previously reported in Smith MR, et al: J Clin Oncol. 23:2918-2925, 2005). Methods: 1,432 men with non-metastatic CRPC (baseline medians: PSA: 12.3 ng/mL, PSADT: 5.1 months, ADT duration: 47.1 months) were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or placebo. The first patient enrolled February 2006; primary analysis cut-off was July 2010, when >660 men had developed bone metastasis or died. The primary endpoint was BMFS (time to first bone metastasis or death from any cause). BMFS results are presented for men with baseline PSADT ≤6 months. Results: Median BMFS in the placebo group of men with PSADT ≤6 months was 6.5 months shorter than for the placebo group in the full population (18.7 months vs. 25.2 months), indicating that these men are at particularly high risk. In this group of men with PSADT ≤6 months, denosumab prolonged BMFS by a median of 7.2 months and with a 23% reduction in risk compared with placebo (Table). Conclusions: Patients with shortened PSADT are at higher risk of developing bone metastasis and denosumab is markedly effective at prolonging BMFS in this subset of patients. [Table: see text]
Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE).
Authors: Smith Matthew Raymond , Sweeney Christopher , Rathkopf Dana E. , Scher Howard I. , Logothetis Christopher , George Daniel J. , Higano Celestia S. , Yu Evan Y. , Harzstark Andrea Lynne , Small Eric Jay , Sartor A. Oliver , Gordon Michael S. , Vogelzang Nicholas J. , Smith David C. , Hussain Maha , De Bono Johann Sebastian , Haas Naomi B. , Scheffold Christian , Lee Yihua , Corn Paul G.
Published: March 2020

4513

Background: Cabozantinib (cabo) inhibits MET and VEGFR2. High rates of bone scan resolution, pain relief and overall disease control, independent of PSA changes, were previously reported in a phase II study in mCRPC patients (pts). This is a NRE cohort in docetaxel (D)-pretreated pts with a novel primary endpoint of bone scan response based on computer-aided quantitative assessment of bone scan lesion area (BSLA) and a double-reader, independent, blinded review (Nucl Med Commun, in press). Methods: D-pretreated (≥225 mg/m2) CRPC pts with bone metastasis were required to have progressed in soft-tissue or bone within 6 months of last dose of D. Pts received 100 mg cabo qd. Tumor response was assessed q6 wks. Bone scan response (BSR) was defined by a ≥30% decline in BSLA. Pain intensity (worst pain over the past 24 hrs; BPI scale 0-10) and interference with sleep and daily activity were prospectively assessed using an IVR system. Analgesic use was collected by diary. Bone turnover markers and CTCs were assessed. Results: 93 D-pretreated pts were enrolled (89 evaluable with ≥6 wks f/u). Median age was 67, 46% received cabazitaxel and/or abiraterone, 32% had visceral disease, 51% had fatigue, and 18% had anemia. 44% had worst pain ≥4 of which 95% were taking narcotics. Median CTC count was 49 and 80% had ≥5. Median f/u was 125 days (range, 23-305). Of 85 pts evaluable for BSR, 51 (60%) had a PR, 24 (28%) SD, 5 (6%) PD and 5 (6%) d/c’d prior to f/u scan. 21/30 pts (70%) had reduction of measurable disease.16/33 pts (49%) with BPI ≥4 and ≥12 wks f/u had pain reduction durable for ≥6 wks; 46% had decreased narcotic use, including 27% who discontinued use. Sleep and daily activity were improved in pts with pain relief. Among pts with elevated serum levels, 74%, 67% and 47% had declines on treatment of ≥30% in CTx, NTx and bALP, respectively. In 59 pts with CTCs ≥5, 92% had a decrease of ≥30% and 39% converted to <5 CTCs at weeks 6 or 12. 12% discontinued cabo due to AEs. Most common Gr 3/4 AEs were fatigue (19%), nausea (10%) and anemia (10%). Conclusions: Cabo treatment resulted in high rates of bone scan response, durable pain relief, and reductions in bone turnover markers and CTCs in D-pre-treated CRPC pts with bone metastases.
Prognostic model for overall survival in patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy.
Authors: Galsky Matt D. , Krege Susanne , Lin Chia-Chi , Hahn Noah M. , Ecke Thorsten , Moshier Erin L. , Sonpavde Guru , Godbold James H. , Oh William K. , Bamias Aristotelis
Published: March 2020

4524

Background: Patients with metastatic urothelial cancer (UC) treated with cisplatin-based chemotherapy have heterogeneous clinical outcomes. Pretreatment prognostic variables have previously been defined (Bajorin, JCO, 1999) but have not been extensively validated or expanded upon. Methods: Pretreatment clinical parameters from 400 international patients with metastatic UC treated on phase II and III first-line clinical trials with cisplatin-based chemotherapy from 11/1997 to 10/2011 were evaluated (cisplatin + gemcitabine +/- paclitaxel or +/- antiangiogenic agent = 235; MVAC = 83; cisplatin + 5FU +/- paclitaxel = 79). Parameters were subjected to multivariable regression analysis to determine which patient characteristics had independent prognostic significance for survival. Results: Complete data were available on 361 patients, median survival was 13.9 months (95% CI 12.4, 16.5); 247 have died. In multivariable analysis, ECOG performance status (≥1), visceral metastases (lung, liver, bone), and white blood count (WBC, continuous variable) were significantly associated with poor survival (P < .05), whereas perioperative chemotherapy, hemoglobin, platelets, creatinine clearance, site of primary tumor, and number of metastatic sites were not (Table). The cut-off for WBC was established at 10. Median survival times for patients with 0, 1, 2, or 3 risk factors were 26.9, 16.8, 12.8, 9.7 months (log rank p value < 0.0001). When subjected to internal validation, the model achieved a bootstrap-corrected c-index of 0.60. External validation is ongoing utilizing data from a phase III trial (n=186) of MVAC versus docetaxel plus cisplatin. Conclusions: A model derived from pretreatment parameters from an international cohort of patients was constructed that confirmed, and expanded upon, known prognostic factors in metastatic UC. This model may be useful for patient counseling and clinical trial design. Better predictions require the identification of additional factors that affect survival. [Table: see text]
Accelerated BEP for metastatic germ cell tumors: Combined analysis of Australian and U.K. phase I/II trials.
Authors: Grimison Peter S. , Chatfield Mark D. , Mazhar Danish , Toner Guy C. , Chester John D. , Stockler Martin R. , Stark Daniel P. , Thomson Damien B. , Shamash Jonathan , Friedlander Michael , White Jeff , Gebski Val , Wason James , Boland Amy L , Rimmer Yvonne L. , McDonald Angus , Gurney Howard , Rosenthal Mark , Singhal Nimit , Williams Michael V. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group; West Anglia Cancer Research Network
Published: March 2020

4531

Background: Standard chemotherapy for advanced germ cell tumors is 3-weekly BEP (bleomycin, etoposide, cisplatin). 5-year overall survival is > 90% in good risk disease, but only ~80% in intermediate and ~ 60% in poor risk disease. Accelerated versions of standard regimens have proven more effective in other malignancies. We aimed to determine tolerability and activity of accelerated (2-weekly) BEP by combining data from two single arm, multi-center, phase I/II trials. Methods: The UK trial (n=16) included patients with intermediate and poor risk metastatic germ cell tumours. The Australian trial (n=45) also included patients with radiologically measurable good risk disease. BEP chemotherapy was repeated every 2 weeks for 4 cycles (3 cycles for good risk). The Australian and UK regimens differed for cisplatin (20mg/m2 D1-5; 50mg/m2 D1-2), etoposide (100mg/m2 D1-5; 165mg/m2 D1-3), bleomycin (30kIU weekly x 12 or 9; 30kIU at 4-6 day intervals x 12), and pegylated G-CSF (6mg D6; 6mg D4) respectively. Primary endpoint for combined analysis was 2-year progression-free survival. Results: 61 patients were enrolled from 2004-09 (UK) and 2008-10 (Australia). 17 had poor risk, 28 intermediate risk, 16 good risk disease. Median follow-up is 27 months (range 6 to 81). Adverse events are presented in the table. 45 of 61 patients (74%) achieved a complete response to chemotherapy +/- surgery (9 of 17 poor risk (53%), 20 of 28 intermediate risk (71%), 16 of 16 good risk disease (100%)). 11 of 61 patients have relapsed. 2 patients have died of disease (both intermediate risk). 2 year overall survival is 98%. 2 year progression-free survival is 65% for poor risk, 86% for intermediate risk, and 92% for good risk disease. Conclusions: Efficacy data are promising, particularly for intermediate and poor risk disease. Adverse events appear comparable to standard BEP. These results provide the rationale for an international trial randomised trial comparing accelerated and standard versions of BEP. [Table: see text]
A retrospective analysis of patients with intermediate-risk germ cell tumor (IRGCT) treated at Indiana University from 2000 to 2010.
Authors: Albany Costantine , Satpute Shailesh R. , Brames Mary J. , Suleiman Yaman , Al Nasrallah Nawar , Perkins Susan M. , Hanna Nasser H. , Einhorn Lawrence H.
Published: March 2020

4534

Background: Based on the International Germ Cell Cancer Collaborative Group (IGCCCG), IRGCT represents 26% of non-seminomas and 10% of seminomas with 2 year PFS of 74% (63-85%). Most patients are treated with 4 cycles of Bleomycin, Etoposide and Cisplatin (BEP). However, the optimal therapy for this heterogeneous group is not well defined. Our hypothesis was that many patients with IRGCT may not require BEPx4 as they are clinically closer to good risk rather than to poor risk disease. Methods: We conducted a retrospective analysis of all patients with testicular cancer seen at Indiana University (IU) between 2000- 2010. We identified 170 pts with IRGCT of whom 84 consecutive pts received their therapy at IU. 2 chemotherapy categories were identified: BEP (or equivalent) x4 or BEPx3 (+/-EPx1). Results: 45 pts received either BEPx4 (41), VIPx4 (2) or BEPx2 followed by HDCTx2 (2). 39 pts received BEPx3 (9) or BEPx3+EPx1 (30). Treatment decisions were based on clinical characteristics and markers amplitude. There were 78 (93%) non-seminoma, 6 (7%) seminoma. 27 (32%) stage II and 57 (68%) stage III. Mean AFP 3899 (range 1000-9550; n=50), mean hCG 16354 (range 5000-49000; n=34). The overall 1 and 2 year Kaplan-Meier estimates were 93% and 87% for PFS and 98% and 92% for OS. Results are depicted below. Conclusions: Our results for patients with IRGCT treated from 2000-2010 are superior to the IGCCCG pts treated from 1975-1990. Routine administration of BEPx4 probably represents overtreatment in a substantial percent of IRGCT. [Table: see text]
Large retroperitoneal lymph nodes (RPLN) as a novel risk factor for venous thromboembolism (VTE) in germ cell tumor (GCT) patients (pts) receiving first-line chemotherapy (chemo).
Authors: Tran Ben , Beausoleil Michel S , Amir Eitan , Jewett Michael A , Sturgeon Jeremy F. G. , Anson-Cartwright Lynn , Chung Peter W. M. , Warde Padraig Richard , Winquist Eric , Moore Malcolm J. , Bedard Philippe
Published: March 2020

4535

Background: VTE causes substantial morbidity and mortality in GCT pts. The Khorana model is a validated predictive model that stratifies VTE risk in cancer pts receiving chemo; Khorana score ≥3 (K3) identifies pts at high risk. Many GCT pts have bulky RPLN that can cause venous stasis in the lower limbs. This study examines the incidence of VTE in GCT pts and assesses large RPLN as a novel predictor of VTE risk. Methods: Retrospective data from the Princess Margaret Hospital GCT database was complemented by review of medical records. GCT pts receiving 1st line chemo between 2000-2010 were included. Pts diagnosed with VTE prior to chemo and pts receiving thromboprophylaxis (TP) were excluded. Pts diagnosed with VTE during or within 3 months of completing chemo were identified. Large RPLN were defined as having maximal diameter ≥5cm. Odds ratios for VTE risk with large RPLN and K3 were calculated. Discriminatory accuracy (DA) of each predictor was calculated using area under the receiver operating characteristic curves (AUROC). An external cohort from London Regional Cancer Program, with similarly collected data, was used to validate results. Results: In the test cohort 21 (10%) of 216 pts developed VTE. Both large RPLN (OR 6.2, p<0.001) and K3 (OR 11.8, p<0.001) were significantly associated with VTE. Positive predictive value (PPV) was lower for large RPLN compared to K3 (21% v 44%, p<0.014) but sensitivity was greater (71% v 40%, p=0.001), while DA showed no difference (AUROC 0.73 v 0.67, p=0.46). In the validation cohort 10 (9%) of 111 pts developed VTE. There was a non significant trend for associations between VTE and both large RPLN (OR 2.54, p=0.16) and K3 (OR 4.5, p=0.13). When compared to K3, sensitivity was greater for large RPLN (60% v 20%, p=0.003), but there was no difference in PPV (14% v 29%, p=0.25) or DA (AUROC 0.61 v 0.57, p=0.72). Conclusions: VTE occurs in 1 in 10 GCT pts receiving curative chemotherapy. Large RPLN is a novel and clinically applicable predictor of VTE risk, although prospective validation would be beneficial. Randomized controlled trials of TP in GCT pts should be considered in pts at high risk of VTE, identified by large RPLN or K3.
Association of inherited genetic variation with clinical outcome in patients with advanced renal cell carcinoma treated with mTOR inhibition.
Authors: Pomerantz Mark M , Gray Kathryn P. , Schutz Fabio Augusto Barros , Percy Andrew , Lampron Megan , Signoretti Sabina , Hirsch Michelle S. , Rosenberg Jonathan E. , Lee Gwo-Shu Mary , McDermott David F. , Atkins Michael B. , Kantoff Philip W. , Freedman Matthew L , Choueiri Toni K.
Published: March 2020

4543

Background: Mammalian target of rapamycin (mTOR)-targeted therapy is standard in patients with metastatic renal cell carcinoma (mRCC). Predictive biomarkers for response are lacking. We sought to characterize outcome after mTOR inhibition based on germline variation in 2 critical genes in the mTOR pathway: phosphoinositide-3-kinase catalytic alpha (PIK3CA) and mTOR. Methods: 76 Americans of European ancestry treated with temsirolimus or everolimus for mRCC were included. Germline DNA was genotyped for all common genetic variation (minor allele frequency [MAF] >0.05) across PIK3CA and mTOR, tagging with single nucleotide polymorphisms (SNPs) at r2>0.8. Associations between genotype and progression-free survival (PFS) and overall survival (OS) from the start of mTOR-targeted therapy were measured using univariate Cox model. Results: Among 76 patients, 66% were poor or intermediate risk and 89% received prior systemic therapies. Median follow up was 23.7 months. Median PFS and OS were 4.3 and 12.7 months, respectively. Two intronic PI3KCA SNPs were significantly associated with PFS and OS, and a SNP in the 5’ UTR of mTOR was associated with OS. Associations were maintained when adjusted for age, gender and MSKCC RCC risk categories using Cox PH model (Table). The PI3KCA SNPs are in modest linkage disequilibrium (r2 ~0.36). Conclusions: We suggest that inherited variation at PIK3CA is associated with PFS and OS after mTOR inhibition. If results are validated, prospective studies could explore the role of genotyping in treatment selection for mRCC. Further work will be needed to identify causal alleles and define the mechanism underlying the associations. [Table: see text]
Safety and activity of the investigational agent orteronel (ortl) without prednisone in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rising prostate-specific antigen (PSA): Updated results of a phase II study.
Authors: George Daniel J. , Corn Paul G. , Michaelson M. Dror , Hammers Hans J. , Alumkal Joshi J. , Ryan Charles J. , Bruce Justine Yang , Moran Susan , Lee Shih-Yuan , Mortimer Peter , Hussain Maha
Published: March 2020

4549

Background: Ortl is an investigational, oral, non-steroidal selective 17,20-lyase inhibitor that suppresses androgen production. Ortl affects cortisol synthesis less than similar agents due to limited inhibition of 17α-hydroxylase, and may permit steroid-free dosing. Ortl 300 mg BID was examined in patients (pts) with nmCRPC and rising PSA. Methods: Eligible pts had nmCRPC with PSA ≥2 ng/mL (PSA ≥8 ng/mL if doubling time >8 mo), and surgical/medical castration, with testosterone (T) <50 ng/dL. Prior chemotherapy, ketoconazole, or concomitant corticosteroids were excluded. Starting dose of ortl was 300 mg BID and continued until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was the percentage of pts with PSA ≤0.2 ng/mL after 3 mo. Secondary endpoints included safety, PSA kinetics, time to metastases, changes in endocrine markers and circulating tumor cells (CTCs). Results: 39 pts were enrolled with baseline demographics including median age 71 y, ECOG PS ≤1, median PSA 12.1 ng/mL (range 2.6-67.8), T 7.9 ng/dL (1.4–17.3), and ACTH 19 ng/L (n=33; 0-47); 3 pts had dose reduction due to adverse events (AEs). Gr ≥3 AEs occurred in 16 pts (drug-related in 14); Gr ≥3 AEs ≥5% were dyspnea (8%), hypertension (13%), fatigue, hypokalemia, pneumonitis (5% ea). 7 pts (18%) had serious AEs; most common was pneumonitis (2=Gr 3, 1=Gr 2). 8 pts discontinued due to AEs; 2 pts required corticosteroids. At 3 mo, 6 pts (16%) achieved PSA ≤0.2 ng/mL; PSA50 and PSA90 rates were 76% and 32%, respectively; median PSA declined by 83% (n=34); median T declined by 89% to 0.78 ng/dL (n=31), and median ACTH increased by 171% to 43 ng/L; median cortisol declined by 21%. At 6 mo, PSA50 and PSA90 rates were 45% and 21%, respectively. Median time to PSA progression was 14.8 mo. 17 pts (44%) were on treatment >6 mo. Of 37 pts with baseline CTC/7.5 mL assessed, only 1 had CTC ≥5 and converted to <5; 6 had 1–4 CTCs at baseline, none converted to ≥5 during treatment. Conclusions: Ortl without steroids produces marked and durable declines in T and PSA, has manageable toxicities, and is feasible in men with nmCRPC.
Time to testosterone (T) and PSA rises during first “off treatment” interval (1OFF-2ON) of intermittent androgen deprivation (IAD) as prognostic for time to castration resistance (CRPC) and prostate cancer mortality (PCM) in men with biochemical relapse (BR).
Authors: Yu Evan Y. , Kuo Kevin F , Hunter-Merrill Rachel , Gulati Roman , Hall Suzanne P , Gambol Teresa E , Etzioni Ruth D , Higano Celestia S.
Published: March 2020

4557

Background: A recent phase III trial of intermittent vs. continuous AD supports IAD as standard of care for men treated with AD for BR. To identify potential prognostic factors during 1OFF, times to T and PSA rises from our prospective trial of IAD in men with BR were analyzed in relation to times to CRPC and PCM. Methods: 72 men with BR after definitive local therapy were treated with IAD, each cycle consisting of 9 months of leuprolide and flutamide followed by a variable “off treatment” interval. T and PSA were followed monthly; AD was resumed when PSA reached a pre-specified value. Cycles repeated until CRPC, defined as ≥2 PSA rises with T≤50 ng/dL. Markers of interest from 1OFF-2ON were time to first T>50, time from first T>50 to first PSA rise ≥0.1 ng/mL, time to first PSA rise ≥0.1, and PSA doubling time (PSAdt), calculated using the first 3 PSA measurements starting from first PSA ≥0.1. The associations of these markers with CRPC and PCM were evaluated using Cox proportional hazards models (or logistic regression if the Cox proportional hazards assumption was not met), controlling for age at study entry and Gleason score categorized to ≤7 or >7. Results: A 30-day increase in time to first T>50 was significantly associated with a 75% increase in the risk of PCM. A 30-day increase in time to PSA rise from 1OFF or after T>50 was significantly associated with a 23% or 72% reduction in the risk of CRPC, respectively. While neither of the associations of PSAdt with CRPC or PCM were significant, they were of moderate size: PSAdt displayed a moderate reduction in risk of CRPC by 35% and PCM by 38%. Conclusions: During the first “off treatment” interval of IAD, the time to first T>50 is prognostic for PCM. Time to first PSA rise after 1OFF and after first T>50 are both prognostic for CRPC. [Table: see text]
Predictive biomarkers in circulating tumor cells (CTC) from patients with castration-resistant prostate cancer (CRPC) through genomic analysis.
Authors: Danila Daniel Costin , Anand Aseem , Yao Jianchao , Gierszewska Magdalena , Kramer Melissa , Muller Stephanie , Fleisher Martin , McCombie William R. , Scher Howard I.
Published: March 2020

4562

Background: Mutations in the ligand binding domain of androgen receptor (AR) in prostate cancer cells may alter their sensitivity to treatment with specific antiandrogens. To predict for tumor sensitivity to treatment with novel AR targeted therapies, we explored the frequency of mutation detection and copy number alteration in CTC isolated from patients with CRPC enrolled on trials with these targeted therapies. Methods: We used fluorescence-activated cell sorting (FACS) methodology to enrich EpCAM+, CD45-, DAPI- cells. For mutation detection and genomic copy number alteration in CTC in low number of cancer cells found in clinical samples, we optimized next-gen deep sequencing by Illumina. Results: In patients with progressive CRPC , >10 or >50 EpCAM+ events (EPE) were isolated by FACS in 88% or 58% of patients, in whom 32% and 10% had unfavorable (>5 cells/7.5 ml) CTC counts using CellSearch. EPE, expressing prostate-specific mRNAs, provide sufficient high quality DNA for genomic sequencing and copy number analysis. Adequate coverage was obtained from as few 50 EPE, with a recovery rate of 89% from FACS sorted samples. The detection threshold of a mutation was established at 1:4 alleles. To further expand genomic profiling in CTC, we optimized Nimblegen exome mutation detection by deep sequencing on HiSeq PE101. Our initial analysis established the polymorphism frequency detection thresholds in heterogeneous cell populations, and confirmed the sequencing coverage. Somatic missense mutations in AR, APC and TP53 found in CTC but not in paired WBC were confirmed by Sanger sequencing. In parallel, copy number alterations in CTC are studied. Conclusions: Somatic mutations detected in CTC isolated from patients with CRPC can serve as predictive markers of tumor sensitivity to targeted therapies. We established standard operating procedures for specimen processing, and confirmed the sequencing coverage and polymorphism detection thresholds in heterogeneous cell population. Currently we are proceeding to clinical samples to study the associations between specific molecular alterations in CTC as predictive markers of sensitivity and clinical outcomes.
The impact of preoperative ASA score and serum albumin on early complication and survival rate of patients undergoing radical cystectomy for bladder cancer.
Authors: Djaladat Hooman , Fairey Adrian Stuart , Cai Jie , Miranda Gus , Skinner Eila C. , Daneshmand Siamak
Published: March 2020

4576

Background: American Society of Anesthesiologist Score (ASA-S) is used to evaluate patient physical status before surgery. Serum albumin (Alb) is also a marker of nutritional status. We evaluated the impact of preoperative ASA-S and Alb on early complication rate and survival of patients who underwent radical cystectomy for bladder cancer. Methods: 1964 patients with primary bladder cancer underwent radical cystectomy between 1971 and 2008 at USC. Preoperative serum Alb and ASA-S were available in 1471 and 1140 patients respectively. Post cystectomy early complication was defined as any surgery related/unrelated event leading to lengthening hospital stay or re-admission within 90 days of surgery. Recurrence free survival (RFS) and overall survival (OS) for these cohorts were reviewed using a Kaplan-Meier and Cox proportional hazards models. Results: The demographic data of patients based on their serum Alb and ASA-S is presented in the Table. The median follow up was 12.4 years (0 - 36.6 yrs). Low serum Alb (<3.4 g/dL) and high ASA-S (3 or 4) were associated with higher early complication rate (43% vs. 33%, p= 0.03 and 40% vs. 28%, p= 0.0001 respectively). In multivariable analysis, low serum Alb level was an independent predictor of RFS (HR 1.35, 95% CI 1.00-1.81) and OS (HR 1.62, 95% CI 1.29-2.04). High ASA-S was an independent predictor of OS (HR 1.45, 95% CI 1.13-1.85), but not RFS. Conclusions: Preoperative low serum Alb and high ASA-S are independently predictive of post cystectomy decreased OS. Low serum Alb is also a risk factor for recurrence after cystectomy. These parameters potentially could be used in nomograms to predict post-cystectomy prognosis. [Table: see text]
PI3KCA mutations in advanced urothelial carcinoma: A potential therapeutic target?
Authors: Molins Joaquim Bellmunt , Werner Lillian , Guix Marta , Guancial Elizabeth Ann , Schutz Fabio Augusto Barros , O'Brien Robert , Stack Edward C. , Loda Massimo F. , Berman David M. , Hirsch Michelle S. , Signoretti Sabina , Gallardo Enrique , Rojo Federico , Ross Robert W , Kantoff Philip , Choueiri Toni K. , Rosenberg Jonathan E.
Published: March 2020

4582

Background: PI3KCA is frequently mutated in human cancer; however, information is scarce regarding its relevance in urothelial carcinoma (UC). We determined the prevalence of mutation and impact on clinical outcome of PI3KCA uniformly-treated patients with metastatic UC. Impact of PI3K and dual PI3K/mTOR inhibition was tested in vitro in UC cell lines with either H1047R or E545K mutation. Methods: 141 samples from invasive UC were scanned for mutations. Of those, complete clinical data was available from 85 cases treated with platinum-based combination chemotherapy for advanced or metastatic disease. DNA was extracted from FFPE material. Mutation status was determined by iPLEX sequencing and confirmed with hME sequencing. Overall survival (OS) was measured from beginning of treatment for metastatic disease to time of death or censored on the last known alive date. Cox proportional hazard model was used to assess the associations of PI3K mutational status and OS. Growth inhibitory effects of a specific PI3K inhibitor and a dual PI3K/mTOR inhibitor (both from Selleck) on UC cell lines with or without mutations were tested using MTT assays. Results: Mutations in the PI3KCA gene were observed in 14 (10%; 95% CI 6-16%) specimens. E545K was detected in all 14 specimens, though one specimen contained mutation at both E545K and H1047R. Among patients with clinical data, there was no statistically significant association between PI3KCA mutational status and OS (HR for having PI3KCA=0.49, 95% CI [0.15, 1.57], p-value 0.22). Preliminary in vitro experiments showed that cell growth was more potently inhibited with dual PI3K/mTOR inhibitors than with PI3K inhibitors. Conclusions: Mutations in the PI3KCA gene were detected in 10% of invasive UC and did not correlate with OS in patients with metastatic UC treated with platinum-based chemotherapy. PI3K inhibition in vitro impacts UC cell growth, though dual PI3K/mTOR inhibitors may have more significant effects than PI3K inhibition alone.
Second-line treatment of advanced urothelial cancer with paclitaxel and RAD001 (everolimus) in a German phase II trial (AUO trial AB 35/09).
Authors: Niegisch Guenter , Retz Margitta , Thalgott Mark K. , Balabanov Stefan , Honecker Friedemann , Stöckle Michael , Ohlmann Carsten Henning , Boegemann Martin , vom Dorp Frank , Gschwend Juergen , Hartmann Arndt , Ohmann Christian , Albers Peter
Published: March 2020

4590

Background: Efficacy of second-line treatment after cisplatinum failure in patients (pts) with advanced urothelial cancer is limited. Based on encouraging preclinical data and results from several phase I trials in solid cancers, we evaluated the safety and efficacy of the combination of paclitaxel and RAD001 (everolimus) in these pts. Methods: In this single-arm, multicenter phase II trial, pts failing prior cisplatinum based combination treatment for advanced urothelial cancer were treated with paclitaxel (175 mg/m² i.v., three-weekly) and the mTOR-inhibitor RAD001 (10 mg p.o., once daily). Pts were treated until tumor progression by RECIST criteria or until a maximum of 6 cycles was completed. A one-stage design was used to evaluate the overall response rate (ORR) as primary endpoint. Results: 27 pts (18 men, 9 women; median age 63 (35-76) years; ECOG ≥ 1: 11/27pts, hepatic metastases: 10 pts, Hb<10 g/dl: 8 pts; upper urinary tract: 9 pts, lower urinary tract 15 pts, both: 3 pts) were enrolled between 07/09 and 12/11. As of 01/12, 19 pts are evaluable for the primary endpoint and the toxicity profile (6 pts still on treatment, 1 patient has withdrawn consent). Main toxicities (all CTCAE grades) were anemia (10/19 pts), leucopenia (8/19 pts), and neuropathy (9/19 pts). Grade III/IV toxicities were anemia (4/19 pts) and leucopenia (4/19 pts). No treatment related deaths were observed. Median number of cycles was 4 (1-6). Complete remission (CR) and partial remission (PR) was observed in 0/19 and 3/19 pts, respectively (ORR 16%). Stable disease (SD) was observed in 10/19 pts. Median time-to-progression (TTP) was 2.7 months (95% confidence interval [CI] 1.6 – 4.4), median overall survival (OS) was 6.5 (CI 4.5 – 9.2) months. Conclusions: Frequency and severity of toxicities were acceptable. Using the combination of RAD001 and paclitaxel as second-line treatment for advanced urothelial cancer after cisplatinum-failure, response rates and survival times comparable to vinflunine were observed.
Activity of intravesical CG0070 in Rb-inactive superficial bladder cancer after BCG failure: Updated results of a phase I/II trial.
Authors: Friedlander Terence W. , Weinberg Vivian K. , Yeung Alex , Burke James , Lamm Donald L. , McKiernan James M. , Nemunaitis John J. , Stephenson Joe , Small Eric Jay , Fong Lawrence , Meng Maxwell V.
Published: March 2020

4593

Background: Loss of retinoblastoma (Rb) tumor suppressor activity occurs commonly in bladder cancer and leads to upregulation of the E2F-1 transcription factor. CG0070 is a replication-competent oncolytic adenovirus genetically modified to express GMCSF under control of the human E2F-1 promoter. Updated results from a phase I study of CG0070 in patients with recurrent superficial bladder cancer (T1, Ta, Tcis) after BCG treatment are presented here. Methods: The V-0046 phase I/II study previously reported the safety and evidence of efficacy of single and multiple doses of intravesical CG0070. Efficacy was determined using quarterly cystoscopy, biopsy, and/or urine cytology. Tumor Rb status was assessed immunohistochemically in 18 tumors. Results: 35 patients were treated with either a single dose (n=13) of CG0070 ranging from 1x1012 to 3x1013 viral particles (vp) or with weekly x 6 (n=9) or every 4 week x 3-6 doses (n=13) ranging from 1x1012 to 1x1013 vp per dose. The most common adverse events regardless of schedule were flu-like illness, dysuria, hematuria, bladder spasm, and nocturia. No maximum tolerated dose was reached. Urine GMCSF and CG0070 levels were detectable in almost all patients suggesting in-vivo viral replication. The CR rate in the single dose cohort was 23% (3/13), and 64% (14/22) in the multi-dose cohorts. The CR rate for patients with either CIS or Ta tumors was 65% (15/23). Of all responders, 11 recurred with a remission duration ranging from 3.0 - 33.4 months and 6 patients, all in the multiple dose cohorts, remain in remission as of last follow-up with a remission duration ranging from 3.3 – 38.2 months. Phosphorylated (inactive) Rb was detected in 13 of the 18 (72%) patients evaluated. Nine of these 13 patients (70%) had a complete response. All patients (5/5, 100%) with known phosphorylated Rb treated in the weekly cohort experienced a CR. Conclusions: CG0070 was well tolerated with minimal toxicities. Complete responses were more frequently observed in the multiple-dose cohorts, including durable CRs in patients with inactive Rb and in patients with CIS. Further study in Rb-inactive superficial tumors is warranted.
Bone metastases in patients with relapsed/refractory germ cell tumors (GCT) undergoing first salvage chemotherapy: A retrospective analysis of a large international database.
Authors: Oechsle Karin , Oing Christoph , Honecker Friedemann , Berger Lars Arne , Bokemeyer Carsten , Beyer Joerg , Lorch Anja ,   for the International Prognostic Factor Study Group (IPFSG)
Published: March 2020

4597

Background: Bone metastases (mets) are rare events in GCT patients (pts) and data on characteristics, risk factors, treatment and outcome in these pts are largely missing. Methods: A subgroup of 104 ptswith bone metsfrom the IPFSG database was analyzed. All patients experienced unequivocal relapse/progression after > 3 cycles of cisplatin-based chemotherapy and received conventional-dose (CDCT) or high-dose salvage chemotherapy (HDCT). Results: 104 / 1594 pts presented with bone mets (6,5%) at first relapse. Histology was pure seminoma in 26%, and non-seminoma in 74%. At initial diagnosis, 54% of pts had presented with "poor risk" according to IGCCCG. Overall response rate (ORR; CR+PR) to 1st-line chemotherapy was 89%. Median PFS after primary treatment was 3 months (range 0 - 140). Bone mets at first relapse were accompanied by abdominal, lung, mediastinal, liver and brain mets in 54%, 48%, 28%, 36%, and 14%, respectively. Tumor marker profiles were heterogeneous (elevation of AFP / ß-HCG: 51% / 37%). Salvage treatment was CDCT in 34%, and HDCT in 66% of pts. ORR to salvage chemotherapy was 68% for the total cohort, and 43% vs. 81% for CDCT vs. HDCT (p<.01). For the total cohort, 2y-PFS and 5y-OS were 24% and 16%, respectively. 2y-PFS and 5y-OS were significantly higher in pts after HDCT compared to CDCT (2y-PFS 29% vs. 14%, p=.01; 5y-OS 19% vs. 9%, p=.04). Conclusions: Pts relapsing with bone mets after platinum-based CTX were characterized by "poor risk" disease at initial diagnosis, but characteristics at first relapse were heterogeneous. Treatment response and outcome was improved in pts with HDCT compared to CDCT. Further prospective evaluation of characteristics and treatment approaches in GCT pts with bone mets is warranted.
Metastatic malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): Results with PNET-based chemotherapy.
Authors: Jain Amit , Einhorn Lawrence H. , Brames Mary J.
Published: March 2020

4598

Background: Metastatic germ cell cancers are highly chemosensitive and have 80% cure rate with cisplatin based chemotherapy. Post-chemotherapy teratoma can usually be surgically resected. However, teratoma, which is pleuripotent tissue, can undergo malignant transformation along mesodermal elements to PNET. Unlike teratoma, PNET can metastasize and render a patient unresectable and incurable. We report the results of treatment of patients with PNET with cyclophosphamide + doxorubicin + vincristine (CAV) alternating with ifosfamide + etoposide (IE). Methods: We reviewed 81 patients with histologically confirmed PNET transformed from testicular teratoma at Indiana University from 1998 to 2011. We identified 13 cases who were treated with chemotherapy comprising cyclophosphamide 1000-1200 mg/m2, doxorubicin 50-75 mg/m2, and vincristine 2 mg alternating with ifosfamide 1.8 grams/m2 plus etoposide 100 mg/m2 for 5 days. Treatment was given every 3 weeks with a maximum of 6 cycles or until progression or undue toxicity. Hematopoeitic growth factors were usually incorporated. The remaining 68 patients underwent surgical resection. Results: Ten patients had unresectable disease and 3 were treated in an adjuvant setting. Median age was 31 years (range 20-53). Ten of 13 patients had received prior platinum based chemotherapy. Eight of 10 evaluable patients achieved objective response. Five of those were rendered with no evidence of disease(NED) with further surgery. Although 4 of the 5 patients subsequently relapsed, 1 patient remains alive with NED at 69 months. The 3 patients who received adjuvant treatment after retroperitoneal lymph node dissection (RPLND) are alive with NED at 1, 4 and 8 years. Conclusions: CAV and IE alternating chemotherapy has high objective response rate for PNET transformed from teratoma and results in occasional long term disease free survival when combined with subsequent resection. We recommend adjuvant CAV alternating with IE chemotherapy for patients with PNET after RPLND due to the high probability of recurrent disease and their high chemosensitivity to this regimen.
Phase I results of a phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients previously treated with VEGFR tyrosine kinase inhibitors.
Authors: Hutson Thomas E. , Dang Long H. , Lauer Richard C. , Starodub Alexander , Hauke Ralph J. , Galsky Matt D. , Bylow Kathryn A. , Logan Theodore , Cowey Charles Lance , Bibby David C. , Kremmidiotis Gabriel , Doolin Elizabeth E. , Lavranos Tina C. , Sonpavde Guru , Hahn Noah M. , Sweeney Christopher , Sarantopoulos John ,   Hoosier Oncology Group
Published: March 2020

4603

Background: BNC105P is an investigational agent that destabilizes tubulin polymers leading to selective damage of tumor vasculature, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Preclinical investigations have demonstrated that BNC105P is effective at selectively damaging the vasculature in both primary and metastatic lesions. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. It follows that the combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: The phase I component has been completed. The BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single grade 3 events of anemia and pericardial effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia and oral mucositis were also observed. Seven phase I subjects achieved at least disease stabilization with a minimum time on therapy of 18 weeks (6 cycles). Across all subjects a median of 6 cycles (range: 1-15) was administered. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.