bluuebunny/crossref_metadata_2025 huggingface dataset:
Concurrent cisplatin and radiotherapy: Decision making, tolerability, and outcomes for patients treated in a multidisciplinary bladder clinic.
Authors: Lalani Nafisha , Richter Sue , Chung Peter W. M. , Fleshner Neil Eric , Jewett Michael A. , Zlotta Alexandre , Bristow Robert Glen , Milosevic Michael , Sridhar Srikala S.
Published: February 2017

320

Background: For select muscle invasive bladder cancer (MIBC) patients, a multimodal approach using transurethral resection of the bladder tumor (TURBT) followed by concurrent cisplatin and external beam radiotherapy (EBRT) provides a curative bladder-sparing alternative to cystectomy. Our aim was to review decision making, tolerability and outcomes for patients treated in a multidisciplinary bladder clinic. Methods: Between June 1998-June 2011, MIBC patients treated with TURBT and concurrent cisplatin (40mg/m2 weekly) with EBRT (60-66Gy in 30-33 fractions to the bladder and pelvis) were identified. Post-treatment cystoscopy was performed every 3 months with regular imaging. Results: A total of 64 patients were assessed; mean age 73 (43-89), 83% were male. The decision to attempt bladder-sparing was based on patient preference (58%), nonsurgical candidate (25%), or unknown (17%). Patients received a mean 5/6 weeks of cisplatin with the most common toxicity being a 14% overall risk of grade 0-1 renal toxicity by NCIC CTC criteria. All patients completed the prescribed EBRT. No patients experienced acute toxicity requiring cystectomy or causing death. At a median follow-up of 3.5 years, 50/64 (78%) patients were alive and had their own bladders, 7/64 (11%) were alive after cystectomy for recurrence, 7/64 (11%) died. Of the 24/64 (38%) recurrences: 3/64 (5%) had positive cytology/carcinoma in-situ and received intravesicle therapy; 1/64 (2%) had local superficial recurrence and underwent TURBT; 7/64 (11%) had local invasive recurrence requiring cystectomy; 13/64 (20%) had distant recurrence, 6 received chemotherapy and 7 were observed. Estimated disease free survival was 51%, and overall survival was 90% at 3.5 years. Conclusions: Bladder-sparing therapy with concurrent cisplatin and EBRT is a well-tolerated and effective approach with outcomes comparable to cystectomy in carefully selected patients. Prospective trials are required to delineate clinical and molecular factors to further triage patients into sub-groups who may benefit from bladder sparing with neoadjuvant/adjuvant chemotherapy or molecularly-targeted agents to improve survival.
Phase Ib/II trial of gemcitabine, cisplatin, plus lenalidomide as first-line therapy for patients with metastatic urothelial carcinoma.
Authors: Tsao Che-Kai , Agarwal Neeraj , Apolo Andrea Borghese , Lee Karen M , Godbold James H. , Oh William K. , Galsky Matt D.
Published: February 2017

321

Background: Cisplatin-based chemotherapy is standard in patients (pts) with metastatic urothelial carcinoma (MUC), though outcomes remain poor and novel approaches are needed. Lenalidomide, a potent thalidomide analog with antiangiogenic and immunomodulatory properties, has been shown to enhance the antiproliferative properties of standard chemotherapy in nonclinical studies of urothelial cancer (Apolo, ASCO 2011). In this phase Ib/II clinical trial we aimed to determine the safety and efficacy of gemcitabine, cisplatin, plus lenalidomide (GCL) in pts with MUC. Methods: Pts with chemotherapy-naïve MUC received gemcitabine 1000mg/m2 days 1 and 8 and cisplatin 70mg/m2 day 1, of a 21-day cycle. In the phase Ib portion, the dose of lenalidomide was to be dose escalated in successive cohorts starting at 10 mg PO daily, on days 1-14, using standard “3+3” dose escalation rules. The primary objective of the phase II portion was to determine the progression-free survival at one year. Results: A total of 7 pts received GCL (lenalidomide 10 mg dose level) in the phase 1b portion. A single pt experienced a dose limiting toxicity (DLT), grade 4 neutropenia. A decision was made to not dose escalate lenalidomide further due to the frequent need for dose delays and reductions of GC due to cytopenias. An additional 2 pts were enrolled in the phase II portion but the study was terminated due to frequent dose delays/reductions and slow accrual. Among the 9 pts enrolled, 5 required dose reductions of G (4 requiring >1), 4 required dose reductions of C (1 requiring >1), and 6 required at least one dose delay. The most frequent grade ≥ 3 adverse events were: neutropenia (n=7), anemia (n=3), thrombocytopenia (n=3), and diarrhea (n=2). Tumor responses included: partial response (n=3), stable disease (n=3), progressive disease (n=2), and unevaluable (n=1). Conclusions: Chronic administration of the combination of GCL was compromised by overlapping myelosuppression and the need for frequent dose reductions/delays of GC due to cytopenias. Despite promising nonclinical data, combining cytotoxic chemotherapy with “targeted” small molecules faces practical challenges. Clinical trial information: NCT01342172.
Efficacy of single-agent pemetrexed in platinum refractory metastatic urothelial cancer (mUC).
Authors: Benjamin David J. , Bambury Richard M. , Chaim Joshua , Zabor Emily C. , Ostrovnaya Irina , Garcia-Grossman Ilana Rebecca , Iyer Gopa , Bajorin Dean F. , Rosenberg Jonathan E.
Published: February 2017

322

Background: No standard therapy exists for platinum refractory mUC. Single agent pemetrexed (Pmt) had objective response rates (ORR) of 8% and 28% in two phase II studies (enrolling 13 and 47 patients) and is commonly used in this setting. To address the difference in reported ORRs, we performed a retrospective analysis of Pmt use at MSKCC to evaluate objective response in a larger cohort of patients. A secondary aim was to explore whether neutrophil-lymphocyte ratio (NLR) added prognostic value beyond known factors (time from prior chemotherapy (TFPC), ECOG performance status (PS), liver metastases, and hemoglobin) in the UC salvage setting. Methods: Patients who received Pmt for platinum refractory mUC between 2008 and 2013 were identified. Baseline demographics, clinical characteristics, prior therapies, Pmt dose, and number of cycles were recorded. ORR was determined according to RECIST 1.1. Kaplan-Meier method and Cox regression were used to analyze associations with overall survival (OS). Results: 135 patients were identified with median age 66 (range 45-88), male 76%, ECOG 0 in 14% / 1 in 54% / ≥2 in 32%. Pmt was administered as 2nd-line chemotherapy in 56% / 3rd line in 30% / ≥4th line in 14%. ORR was 7% with median duration of response 10.2 months. There was no significant difference in ORR by line of therapy or PS. Median progression free survival was 2.4 months and median OS was 6.6 months. In this dataset, TFPC was not prognostic, while liver metastases, PS, and hemoglobin were prognostic. Higher NLR was significantly associated with worse OS independent of other known factors. Conclusions: In the largest reported series to date, Pmt had an ORR of 7% in metastatic UC regardless of line of therapy or ECOG performance status. This limited activity highlights the urgent need to develop novel therapeutic strategies. NLR was identified as an independent prognostic factor in this setting. [Table: see text]
Neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) in patients with high-grade upper-tract urothelial carcinoma.
Authors: Hoffman-Censits Jean H. , Trabulsi Edouard John , Chen David Y. T. , Kutikov Alexander , Lin Jianqing , Viterbo Rosalia , Hudes Gary R. , Healy Kelly A. , Hubosky Scott , Wong Yu-Ning , Kilpatrick Deborah , Adair Beth , Cione Charlotte , Plimack Elizabeth R.
Published: February 2017

326

Background: Improved safety and response rates of AMVAC over standard MVAC in patients (pts) with metastatic bladder cancer support study of neoadjuvant AMVAC for pts with muscle invasive bladder cancer (MIBC) and prenephroureterectomy (NU) for pts with high-grade upper-tract urothelial cancer (UTUC). We performed a phase II study of neoadjuvant AMVAC in MIBC and UTUC, and herein report the results of the UTUC exploratory subgroup. Methods: Pts with UTUC (ureter or renal pelvis) with high-grade UC on biopsy, or positive urine cytology and mass on cross sectional imaging, N0-N1, CrCl >=50, adequate hepatic and marrow function were eligible. Pts received 3 cycles of AMVAC (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70mg/m2) day 1, pegfilgrastim 6 mg day 2 or 3, every 2 weeks. NU, with lymph node dissection at surgeon discretion, was performed 4-8 weeks after last cycle. Exploratory endpoint was pathologic complete response (pCR) rate. Results: Accrual is complete with 10 evaluable UTUC pts enrolled at 2 institutions (FCCC, TJU) over 46.5 months. Median age 67 (range 49-83). Of 10 pts, 6 completed all 3 cycles of AMVAC. Four pts received < 3 cycles due to grade 3 acute kidney injury (1), pyelonephritis and grade 3 diverticulitis (1), flare of underlying hepatitis (1), grade 3 fatigue (1). Additional related grade 3 adverse events (AE) were anemia (1) and nausea/vomiting (1), no grade 4 or 5 AE. All pts underwent NU within 8 weeks of last chemotherapy, median 5.5 weeks. Median time from day 1 AMVAC to NU was 9 wks. 1/10 pts had a pCR, 4/10 patients were staged pT3 or N+. An additional 21.5 months of enrollment were needed in this expansion cohort to accrue 10 pts with UTUC, compared to 44 MIBC pts in 25 mos. All pts completed study treatment as of July 2013. Conclusions: In this small sample, neoadjuvant AMVAC prior to NU was clinically active with manageable toxicity. With short duration from start of chemotherapy to NU, 3 neoadjuvant AMVAC cycles should be considered for further study for high-grade UTUC prior to NU in the cooperative group setting. Clinical trial information: NCT01031420.
Development of novel metastatic prostate cancer cell lines by “organoid” in vitro culture technology.
Authors: Vela Ian , Gao Dong , Gopalan Anuradha , Sboner Andrea , Undvall Eva , Wanjala Jackline , Iaquinta Phillip , Wongvipat John , Karthaus Wouter , Clevers Hans , Solomon Stephen Barnett , Beltran Himisha , Kossai Myriam , Mosquera Juan Miguel , Rubin Mark A. , Carver Brett Stewart , Scher Howard I. , Sawyers Charles L. , Chen Yu
Published: February 2017

33

Background: The inability to propagate patient-derived prostate cancer cells in vitro is a major impediment in the mechanistic understanding of tumorigenesis and therapeutic response. In order to generate accurate in vitro models that represent the diversity of in situ prostate cancer, we have developed a three-dimensional “organoid” system to culture metastasis samples and integrated it into our precision medicine workflow of attaining and characterizing pre-treatment biopsies. Methods: Biopsy samples of prostate cancer metastases, both soft tissue and bone, acquired at the time of therapeutic or diagnostic interventions following informed consent and institutional review board approval were obtained from two institutions. Samples were digested in Type II Collagenase (Gibco) and re-suspended in growth factor reduced Matrigel (BD), plated on plastic, and overlaid with prostate culture media (PCM). PCM consists of serum free Advanced DMEM/F12 (Gibco) with multiple growth factors optimized to propagate benign primary prostate cells. Cultures were maintained at 37°C in 5% CO2. Results: In the initial 51 samples, 15 continuous organoid cultures (29%) were established from distinct sites (9 of 32 bone, 6 of 19 soft). Tumor content of the biopsy represents a major determinant of organoid growth. Once established, organoids propagate indefinitely with different kinetics (approximately 48 hours to 1 week doubling time), and can be cryopreserved. Histological analysis shows that the organoids recapitulate the structure of the in situ cancer and genomic analysis using array CGH and whole-exome sequencing (WES) shows the presence of typical copy number alterations including TMPRSS2-ERG interstitial deletion, PTEN loss, CHD1 loss, and AR amplification. WES of two organoid/metastasis pairs shows that the growth conditions do not generate additional mutations. Conclusions: This novel tissue culture technique enables the development of new cell lines derived from metastatic deposits. This advance will facilitate research by availing new and varied cell lines, which will hopefully be more closely aligned to the spectrum of behavior of the clinical disease in comparison to the limited and problematic cell line models currently available.
Safety and effectiveness of vinflunine in patients with metastatic transitional cell carcinoma of the urothelial tract (TCCU) after failure to one cisplatin-based systemic therapy in clinical practice.
Authors: Gonzalez-Grajera Belen , Puente Javier , Garcia Carbonero Iciar , Mohedano Nicolas , Lopez Criado M. Pilar , Arranz Arija Jose Angel , Gonzalez del Alba Aranzazu , Fernandez Calvo Ovidio , Villalobos Maria L. , Chirivella Isabel , Grande Enrique , Castellano Daniel E.
Published: February 2017

332

Background: Vinflunine (VFL) is the first agent to show a survival improvement for platinum-refractory patients (pts) with metastatic TCCU in a phase III clinical trial. After EMA approval in September 2009, ESMO (Bellmunt, 2011) and SOGUG (Castellano, 2012) guidelines recommend VFL as second-line therapy. Methods: This is a multicenter and retrospective study to describe the experience with VFL in Spain. Pts with histologically confirmed metastatic TCCU were treated with VFL (280-320mg/m2 every 3 weeks) until progression or unacceptable toxicity. Pts were evaluated according to institutional local follow-up program. Results: From April 2010 to June 2013, we registered 102 pts in fifteen Spanish centers. All patients are evaluable for safety and 98 for efficacy. Median age: 67years (range 45-83), ECOG 0/1/2 previous to VFL (pts%): 31/61/8. Bladder carcinoma was the primary disease site in 84 pts and 46 % of them received cisplatinum-based chemotherapy. Metastatic involvement was: lymph nodes 67.7%, lung 36.4%, bone 28.1%, and liver 21.6%. The median number of cycles of VFL was 4 (1-18). The objective response rate was 25.5% (CR in 2 pts and PR in 23 pts), stable disease in 42.9% and progressive disease in 31.6%. The median follow-up was 6.6 months (0.4 to 43): median progression-free survival 3.9 months (95% CI, 2.3 to 5.5), median time to progression 4.3 months (95% CI, 2.6 to 5.9) and median overall survival 10 months (95% CI, 7.3 to 12.8). At the time of the analysis, 79.4%pts had progressive disease after VFL and 64.7% died. Grade 3/4 adverse events included: nausea/vomiting 13.8% of pts, neutropenia 12.8%, constipation 5.9%, and abdominal pain 4.9%. No toxic death were reported. Conclusions: This retrospective analysis confirms the benefit of VFL in patients with TCCU after failure in a platinum-containing chemotherapy regimen. Results of the randomized trial are reproducible in Spanish Oncology Centers on a daily clinical practice and its toxicity profile results are acceptable and manageable.
Sources of variation in follow-up expenditure after radical cystectomy.
Authors: Vemana Goutham , Vetter Joel , Chen Ling , Sandhu Gurdarshan Singh , Strope Seth A.
Published: February 2017

335

Background: Follow-up care after radical cystectomy is poorly defined with extensive variation in practice patterns. We sought to determine sources of these variations in care as well as examine the economic impact of standardization of care to guideline recommended care. Methods: Using linked SEER-Medicare data from 1992 to 2007, we determined follow-up care expenditures (time and geography standardized) for 24 months after surgery. Accounted costs included office visits, imaging studies, urine tests and blood work. A multilevel model was implemented to determine the impact of region, surgeon, and patient factors on care delivery. We then compared the actual expenditures on care in the Medicare system (interquartile range) to the expenditures if patients received care recommended by current clinical guidelines. Results: Expenditures over 24 months of follow-up were calculated per month and per patient. The mean and median monthly expenditures were $33 and $21 respectively (minimum $0, maximum $429, 25th to 75th percentile $9 to $43). The total variance of expenditure situated at the surgeon-level and SEER region-level was 9.9% and 4.0% respectively. After accounting for the region, the total variance of expenditure situated at the patient-level and surgeon-level was 14.95% and 7.81% respectively. The assessed cost of guideline follow-up recommendations varied from 0.78-9.05 times the calculated Medicare costs. The guideline recommended cost of follow-up was higher than actual Medicare expenditures in all but one category. Conclusions: While some regional and surgeon-level variations in care were found, most variation in expenditure on follow-up care was at the patient-level, largely based on comorbidity, node positivity, chemotherapy status, readmission rates, and final cancer stage. Standardization of care to current established guidelines would create larger expenditures for the Medicare system than current practice patterns.
Pilot investigation of variants in DNA repair pathways and association with response to platinum-based chemotherapy in bladder cancer.
Authors: Kopp Ryan P. , Stratton Kelly Lynn , Garcia-Grossman Ilana Rebecca , Zabor Emily C. , Ostrovnaya Irina , Thomas Tinu , Gerber Gloria , Alanee Shaheen Riaoh , Schrader Kasmintan A. , O'Donnell Peter H. , Bajorin Dean F. , Joseph Vijai , Offit Kenneth
Published: February 2017

343

Background: Germline single-nucleotide variations (SNVs) in DNA repair genes may have a role in response to platinum-based chemotherapy in bladder cancer (BC). As a pilot project we created a discovery cohort using an extreme phenotype model of BC response to neoadjuvant chemotherapy; we identified candidate SNVs in DNA repair genes via whole exome sequencing, and sought to replicate these findings in a validation cohort. Methods: We sequenced exomes of a discovery cohort with ≥ cT2 BC and neoadjuvant chemotherapy [6 complete responders (CR, pT0N0 and 1 year disease free interval) vs. 9 non-responders]. We identified SNVs within 377 DNA repair pathway genes. We filtered for SNVs with high impact effects, and moderate impact missense variants. The discovery phase resulted in 16 candidate SNVs which we genotyped (matrix-assisted laser desorption/ionization-time of flight) within a validation cohort of 303 BC patients treated with platinum-based neoadjuvant or first-line chemotherapy. Primary outcome was pathologic (neoadjuvant) or radiographic (first-line) CR, with secondary outcome CR+partial response (PR; RECIST criteria or pathologic downstaging). We used additive genetic model and logistic regression to analyze association between individual SNVs and both CR and CR+PR. Multivariate models included MSK risk score for CR or chemotherapy (cis- vs carboplatin) for CR+PR. Results: We included 303 patients (186 neoadjuvant, 117 first-line; 272 cisplatin, 31 carboplatin), median age 64, including 67 (22%) CR and 153 (50%) CR+PR. Genotyping was adequate for analysis in 14 of 16 SNVs—none were associated with CR. SNVs associated with CR+PR were rs2072454 (EGFR, p=0.031 unadjusted, p=0.035 adjusted for chemotherapy) and rs1805321 (PMS2, p=0.014 unadjusted, p=0.019 adjusted for chemotherapy). Findings were not significant after adjusting for multiple comparisons. Conclusions: Using an extreme phenotype model we identified SNVs in genes of the DNA repair pathway that may have an association with platinum-based chemotherapy response in BC. A larger validation study is required to increase power and reduce the impact of multiple testing prior to confirming significance.
Impact of perivesical lymph nodes on survival after radical cystectomy.
Authors: Hu Brian Robin , Satkunasivam Raj , Cai Jie , Miranda Gus , Daneshmand Siamak
Published: February 2017

350

Background: Lymph node staging for bladder cancer is dependent upon both location and number. This study characterizes perivesical (PV) lymph nodes (LN) found at radical cystectomy and evaluates their prognostic impact. Methods: We reviewed our Institutional Review Board-approved database from 1971-2009 including all patients who underwent radical cystectomy with pelvic lymphadenectomy for curative intent for urothelial carcinoma. Clinical and pathologic data were obtained. Patients were analyzed in three groups: PV LN+/other LN-, PV LN+/other LN+, and PV LN-/other LN+. Kaplan-Meier curves were used to estimate recurrence free survival (RFS) and overall survival (OS). Multivariable Cox regression (including pathologic T stage, number of positive LN, highest level of positive LN, chemotherapy, and margin status) was performed to evaluate associations between PV LN status and survival. Results: A total of 2,045 patients underwent radical cystectomy for urothelial carcinoma of which 2011 met inclusion criteria. PV LN were identified in 936 (47%) patients, positive in 197 (10%) patients, and represented isolated LN positive disease in 101 (5%) patients. On univariate analysis, positive PV LN were associated with a higher likelihood of extravesical disease (>pT2) when compared with other positive LN (p=0.023). There was no significant difference in RFS or OS when comparing patients with negative PV LN to those with PV LN not identified. On multivariable analysis, patients with PV LN+/other LN+ had a significantly worse RFS (HR 1.75, 95% CI 1.29-2.38, p<0.001) and OS (HR 1.66, 95% CI 1.27-2.19, p<0.001) when compared with PV LN-/other LN+. There was no significant difference in RFS or OS when comparing patients with PV LN+/other LN- to PV LN-/other LN+. Conclusions: PV LN are identified in a significant portion of patients after radical cystectomy with pelvic lymphadenectomy. Positive PV LN, when in combination with other positive LN, portends worse survival even when correcting for the number of positive LN. No significant difference in survival was seen comparing patients with isolated positive PV LN to those with other positive LN. This study highlights the importance of PV LN in pathologic analysis and bladder cancer staging.
Somatic copy number abnormalities (SCNAs) and mutations in PI3K/AKT pathway and prognostic significance for overall survival (OS) in platinum-treated locally advanced or metastatic urothelial cancer (UC).
Authors: Bellmunt Joaquim , Werner Lillian , Riester Markus , Van Hummelen Paul , Rosenberg Jonathan E.
Published: February 2017

358

Background: An integrative analysis was conducted to identify genomic alterations and mutational status on the gene pathway level that could predict OS in patients (pt) with UC treated with platinum chemotherapy. Methods: DNA was extracted from 94 FFPE samples from invasive UC and screened for mutations and CNAs. Of those, complete clinical data was available from 85 cases. Mutations in the cancer genome were analyzed by a mass-spectrometry based genotyping platform (Oncomap version 3) and genomic imbalances were detected by comparative genomic hybridization (CGH) analysis. Regions with threshold of log2 ratio ≥0.4, or ≤ -0.6 were defined as either having copy number gain or loss and significantly recurrent CNAs across the set of samples was determined using a GISTIC analysis. To better define the co-occurrence pattern of mutations and CNAs, we grouped genes into 3 core signal transduction pathways: (1) TP53 pathway; (2) Abnormalities of in the RTK-RAS-RAF pathway including either ERBB2, FGFR3, MET, FGFR1, KRAS BRAF, RAF1 and NF1; (3) abnormalities on PI3K/AKT pathway including PTEN, PIK3CA, AKT1, TSC1, and MTOR. OS was measured from treatment to time of death or censored. Cox regression was used to assess pathways abnormalities and mutations with outcome. Results: Thirty five samples (41%) harbored mutations on at least one gene, mainly TP53 (16%), PIK3CA (9%), FGFR3 (2%), HRAS/KRAS (5%), and CTNNB1 (1%). Sixty-six per cent of patients had some sort of copy number variation. PI3K/AKT was the most affected pathway and was associated with shorter overall survival (hazard ratio (HR) =2.3 with 95% CI: 1.3 to 4.2). There was no significant association between mutational status and OS. Combined analysis of SNCA and mutations in the same pathway will be presented. Conclusions: Patients with advanced urothelial cancer receiving platinum chemotherapy have a significantly poor survival which correlated with copy number abnormalities in the PI3K/AKT pathway. This can help to identify patients that can benefit from targeted pathway specific agents.
Using radiologic response to predict prognosis in patients with muscle-invasive bladder cancer undergoing carboplatin-based neoadjuvant chemotherapy.
Authors: Hatakeyama Shingo , Yamamoto Hayato , Okamoto Akiko , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2017

361

Background: Prognosis and tumor responses of carboplatin-based neoadjuvant chemotherapy for muscle invasive bladder cancer (MIBC) are not well documented. To assess the usefulness of carboplatin-based neoadjuvant chemotherapy, we examined the correlation between radiological responses and pathologic down staging on radical cystectomy (RCx) specimens, disease free survival (DFS), and overall survival (OS). Methods: Between March 2005 and June 2013, we performed carboplatin-based neoadjuvant chemotherapy followed by radical cystectomy in 115 patients with T2-4NxM0 MIBC. After diagnostic TUR biopsy, all participants received two courses of Gemcitabine plus Carboplatin therapy. Baseline and post chemotherapy tumor size from contrast enhanced CT were reviewed. The patients were divided in two groups between responders (CR+PR), and non-responders (SD+PD). RCx and bilateral pelvic lymphadenectomy were performed approximately within a month after cessation of chemotherapy. DFS and OS distributions within radiologic response subgroups were estimated with the Kaplan-Meier method and compared using the log-rank test. To evaluate independent predictor for DFS and OS, age, gender, performance status, pathological T and N stage, down-staging, tumor grade, renal function, and radiological responses were applied by Cox-regression multivariate analysis. Results: No significant differences were observed in patient backgrounds between the groups. Radiologic responses were observed in 75 (65%) patients with 69±24% decrease in responder group, whereas tumor response was 2.8±14% in non-responders. The rate of pathological down staging to <pT2 was 37 (49%) in responders, 5 (13%) in non-responders group. Radiologic response was a strong predictor of DFS and OS. A 5-year advantages of DFS and OS in responders vs. non-responders were 88% and 86% vs. 64% and 69%, respectively (P=0.021 and P=0.013). Multivariate analysis showed radiologic response was the independent factor for DFS and OS. Conclusions: Radiological response post carboplatin-based neoadjuvant chemotherapy is associated with OS in patients with MIBC.
Multicenter sequential phase II study of flavopiridol plus oxaliplatin (Alvocidib) with or without 5-FU and leucovorin (LV) for patients (pts) with refractory germ cell tumors (GCT) including late relapse (LR).
Authors: Feldman Darren Richard , Stadler Walter Michael , Appleman Leonard Joseph , Quinn David I. , Costello Brian Addis , Schwartz Gary K. , Reuter Victor E. , Woo Kaitlyn , Patil Sujata , Fusco Anne , Smith Sloane C. , Carlson Jeremie , Bosl George J. , Motzer Robert John
Published: February 2017

364

Background: Flavopiridol + FOLFOX showed activity in refractory GCT pts in a phase I trial (Rathkopf, Clin Cancer Res, 2009). This phase II study assessed the efficacy of this regimen in refractory GCT and the necessity of including 5-FU/LV. Methods: Previously treated pts with progressive GCT were eligible if they had received or were not candidates for high-dose chemotherapy (HDCT). Pts on Arm A received flavopiridol 70mg/m2 plus oxaliplatin 85mg/m2. Arm B (flavopiridol + FOLFOX) tested identical doses of flavopiridol and oxaliplatin plus 5-FU (400mg/m2 bolus, then 1800mg/m2 over 48 hours) and LV 400mg/m2. Treatment was every 2 weeks in 6-week cycles. The primary endpoint was response rate (RR) by RECIST. An identical Simon 2-stage design was used for each arm to differentiate between a RR ≥40% vs. ≤20%, with arm B opening only if arm A was ineffective. With ≥3 responses among the first 12 pts, another 13 pts would be enrolled with responses in ≥8/25 pts needed to show efficacy. Tumor biopsies pre-, during, and post-treatment were assessed by IHC for p53, p21, and cleaved caspase-3. Results: Of 36 pts (7 arm A, 29 arm B), 33 had nonseminoma. Primary site was testis in 27 and mediastinum in 7; 22 pts had received prior HDCT and 13 had LR (>2 years), including 2 on arm A and 11 on arm B. Arm A closed early after 0/7 pts responded (2 SD). Of 25 evaluable pts on arm B, 6 achieved a PR, 9 had SD, and 10 had PD. Notably, 5/10 evaluable LR pts on Arm B had a PR, including 1 pathologic CR, 1 PR-negative markers who received radiation (RT) to a residual bone metastasis, and 1 PR-positive markers who received RT to a residual nodal mass. These 3 pts remain disease-free ≥19 months (m) post-chemotherapy and ≥17m post-RT or surgery. Median PFS and OS were 2.3m and 7.3m for all pts and 3.2m and 11.2m for arm B pts. There was 1 treatment-related death due to sepsis. Conclusions: Although neither arm met the prespecified endpoint, flavopiridol plus FOLFOX (arm B) was particularly active in LR pts, with a 50% overall RR, including several durable responses. Further study of FOLFOX with or without flavopiridol is warranted in LR pts. Correlative data will be presented. Clinical trial information: NCT00957905.
An audit of adjuvant carboplatin in patients with stage I testicular seminoma (Anglian Germ Cell Cancer Group, UK).
Authors: Kwan Amy , Shamash Jonathan , Powles Thomas , Ansell Wendy , Chowdhury Simon , Harland Stephen John , Lamont Alan , Wade Robert , Sarwar Naveed , Mazhar Danish , Wilson Peter
Published: February 2017

366

Background: Patients with stage I testicular seminoma can be managed by surveillance or treated with adjuvant radiotherapy or chemotherapy. Concerns of second malignancies induced by radiotherapy have led to a preference for adjuvant chemotherapy. The TE19 trial demonstrated the non-inferiority of a single cycle of carboplatin, given within 8 weeks of orchidectomy, to adjuvant para-aortic radiotherapy in terms of reduction in recurrence rate. This study also suggested a lower relapse rate if GFR estimation was radionuclide based. Methods: A review of case records of germ cell tumor patients within the Anglian Germ Cell Cancer Group between 10/01/2005 and 31/12/2012 was conducted to identify patients with stage I testicular seminoma who received a single cycle of adjuvant carboplatin. Tumor characteristics, clinical management, and patient outcomes were assessed. Results: A total of 336 patients with stage I seminoma who received adjuvant carboplatin were identified. The median age of diagnosis was 38 (range 21 to 78). Median tumor size was 40mm. The rete testis was involved in 131 cases (39%). A radionuclide based estimation of GFR was used in 318 patients (94.6%), the remaining patients GFR was estimated by the Cockcroft-Gault equation. The median time from orchidectomy to receiving chemotherapy was 46 days. Of the 336 patients, 22 relapsed (6.5%), with nine relapsing after 2 years (seven between 24 and 36 months, and wo after 36 months). The median time to relapse was 18 months. There was a trend towards lower progression free survival in patients whose chemotherapy was dosed based on GFR estimation by the Cockcroft-Gault equation. All relapsed patients were successfully treated with combination chemotherapy. Conclusions: These results demonstrate a higher rate of relapse for stage I seminoma patients treated with adjuvant carboplatin compared with the published data from the TE19 study. In addition they confirm that adjuvant carboplatin for treatment of stage I testicular seminoma leads to excellent outcomes in terms of long-term cure. The use of radionuclide based estimation of GFR is advised. Relapses beyond 2 years are not rare and routine cross-sectional imaging beyond this point should be considered.
Complications during cisplatin-based primary chemotherapy in patients with testicular cancer: Is there a need for thromboembolic prophylaxis?
Authors: Pfister David J. K. P. , Porres Daniel , Wolsky Ingrid , Thissen Andrea K. , Heidenreich Axel
Published: February 2017

371

Background: Cisplatin-based chemotherapy is an integral part of the multimodal therapy of patients with testicular cancer. The purpose of this analysis is to evaluate the chemotherapy associated side effects of primary treatment in a modern patient cohort and to correlate them to clinical stage and IGCCCG risk profile. Methods: We retrospectively analyzed charts of patients with testicular cancer in our institution from January 2003 until today. A total of 88 patients received systemic treatment, among those 74 as a primary treatment with 2 to 4 cycles of PEB. Side effects had been categorized according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4. Results: 46 of 74 patients receiving PEB had at least one side effect. The most common side effects were haematotoxic with leucopenia in 34 (45.9%), febrile neutropenia in 10 (13.5%), gastrointestinal in 22 (29.7%), and thromboembolic events in 10 (14.8%) of the patients including three therapy associated deaths. Adverse events in clinical stage I are low. Nevertheless there is one therapy associated death due to neutropenic fever. Although there are no differences in haematotoxic AEs in clinical stage II and III there is a significant trend of developing pulmonary embolism. Patients with clinical higher than stage IIb and intermediate/poor prognosis have the highest risk of pulmonary embolism (20% ). Conclusions: In patients with curative treatment with PEB there are significant AE´s. To reduce therapy associated morbidity and mortality, supportive treatment with granulocyte stimulating factor and therapeutic anticoagulation should be discussed at least in high-risk patients.
The impact of clinical trial evidence and sociodemographic factors on institutional practice patterns for stage I testicular cancer.
Authors: Agarwal Gautum , Valderamma Oscar , Nguyen Sabine , Luchey Adam , Pow-Sang Julio , Spiess Philippe E. , Poch Michael Adam , Sexton Wade Jeffers
Published: February 2017

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Background: Contemporary management for patients with stage I testicular cancer (TC) continues to evolve. Survival is dependent upon staging, surveillance, and the treatment(s) rendered. We sought to determine whether treatment recommendations have been impacted by evidence gained from recent clinical trials and how sociodemographic factors might affect therapeutic decisions for patients with stage I pure seminoma (PS) and nonseminoma (NSGCT). Methods: We performed a single institution, institutional review board approved, retrospective review of patients evaluated for TC from 1999 to 2013. Chi-square and logistic regression analyses were performed between multiple variables including: type of treatment, specialty of the provider, year of treatment, insurance status, distance traveled to our hospital, and education level. Results: Four hundred forty patients were evaluated; of this group 121 patients had stage I TC. For NSGCT patients, living further than 50 miles from our center was associated with treatment (p=0.013). NSGCT patients who had completed an undergraduate education were more likely to undergo surveillance compared to those with a high school education (p<0.01). If intervention was recommended, NSGCT patients evaluated prior to 2010 were more likely to undergo primary retroperitoneal lymph node dissection (RPLND) (p<0.01). After 2010 these patients were more likely to have primary chemotherapy (PC) (p<0.01). NSGCT patients evaluated by urologic oncologists had higher RPLND rates while patients evaluated by medical oncologists more often received PC (p<0.01). The percentage of PS patients receiving external beam radiation decreased from 40% to 5% after 2010, while the rate of surveillance increased from 47% to 79% (p=0.016). For all stage I patients the presence of lymphovascular invasion was associated with treatment compared to surveillance (p<0.001). Conclusions: The management of patients with stage I TC has changed significantly over the past decade. In our study, management recommendations have been shown to be dependent upon the specialty of the provider and other social factors such as distance from the hospital as well as education level, which suggests the possibility of bias during patient counseling.
Do seminoma germ cell elements affect perioperative outcomes following post-chemotherapy retroperitoneal lymph node dissection for metastatic testis cancer?
Authors: Agarwal Gautum , Buethe David D. , Russell Christopher , Espiritu Patrick , Luchey Adam , Spiess Philippe E. , Pow-Sang Julio , Poch Michael Adam , Sexton Wade Jeffers
Published: February 2017

378

Background: Post-chemotherapy retroperitoneal lymph node dissections (PC-RPLND) performed at high-volume centers are safe and comparable in risk to primary RPLNDs. The desmoplastic reaction encountered during PC-RPLND in patients with seminoma components increases the complexity of surgical dissection. We examined whether the presence of seminoma at diagnosis was associated with more adverse events in the perioperative setting. Methods: A single institution review board approved retrospective review identified 108 patients undergoing PC−RPLND from 1992 to 2012. All patients had received at least first-line cisplatin-based induction chemotherapy. Of these, 11 patients undergoing redo PC-RPLNDs were excluded from analysis. Patients were divided into two groups; those with any seminoma element in their orchiectomy or retroperitoneal specimens and those without seminoma elements. We performed independent t-tests and Chi-squared analysis of the data. Results: Of 97 patients undergoing PC-RPLND, 33 had seminoma components in their diagnostic specimens. Using the Clavien classification system to stratify post-operative complications, the percentage of seminomatous elements (less than 50% compared to more than 50%) within the primary tumor did not correlate with a higher incidence of complications; even when examining only major complications (p=0.673). There was a trend towards higher nephrectomy rate for tumors with seminoma elements compared to those without (27% vs. 8.5%, p = .058). The nephrectomy rate did show a dependence on the pathologic size of the residual mass regardless of histology (31% for more than 10 cm, 6.8% for 5 to 10 cm, 0% for 0 to 5 cm p = 0.021). There was also a trend towards blood loss greater than one liter for patients with seminoma elements compared to those without (63% vs. 43%, p = 0.078), while the transfusion rate was similar between the two groups (p=0.785). Post−operative length of stay was independent of a patient’s histology (p=0.94). Conclusions: PC-RPLND remains a safe and necessary therapeutic procedure. The presence of seminoma germ cell elements in our patient cohort did not result in a more complicated perioperative course surrounding PC-RPLND.
Predicting progression in patients followed with active surveillance for low-risk prostate cancer.
Authors: Sternberg Itay Aharon , Yu Changhong , Keren Paz Gal Elimelech , Kim Philip H. , Bernstein Melanie , Lakin Paul , Kattan Michael W. , Ehdaie Behdar , Laudone Vincent Paul , Scardino Peter T. , Eastham James Andrew , Touijer Karim A.
Published: February 2017

38

Background: Due to the inability to predict progression and need for treatment, patients with low-risk prostate cancer (LRPC) managed by active surveillance (AS) are subjected to repeated biopsies and their possible complications. We developed a nomogram predicting the risk of progression in patients on AS for LRPC. Methods: A retrospective review of all patients enrolled in an AS program at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1993 and 2012 was conducted. Demographic, clinical, and pathologic data for patients who met the inclusion criteria for AS (cT1 or cT2a, prostate-specific antigen [PSA] less than 10, Gleason 6 or less, no more than three positive biopsy cores and no greater than 50% involvement of any single core) on the diagnostic and the confirmatory biopsies were collected and used to develop a nomogram for predicting progression-free probability. Multivariable logistic regression analysis was used to model the association between each risk variable (age, PSA levels, clinical stage, biopsy features) and disease progression. Progression was defined as failure to meet the inclusion criteria during follow up. Results: A total of 1,095 patients were enrolled in an AS program at MSKCC during the study period, of which 680 met the inclusion criteria for AS on both the diagnostic and the confirmatory biopsies and had available follow-up. At a median follow-up of 3 years 101 patients progressed. A nomogram predicting the progression-free probability was designed based on characteristics at diagnosis, result of a confirmatory biopsy and the number of negative and positive surveillance biopsies to date. A concordance index of 0.596 was calculated. Conclusions: Conditioned upon external validation, this nomogram can be used to counsel patients on their risk of progression and their surveillance protocol can be adjusted appropriately, possibly avoiding unnecessary biopsies and preventing biopsy-related complications.
Vascular anomalies in patients undergoing retroperitoneal lymph node dissection.
Authors: Thissen Andrea K. , Porres Daniel , Pfister David J. K. P. , Piper Charlotte , Heidenreich Axel
Published: February 2017

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Background: Anomalies of the renal vessels usually are clinically silent and might depicted during CT scanning of the abdomen for staging purposes of urological malignancies. Awareness of these rare anomalies is crucial especially in patients undergoing staging for germ cell tumors in order to avoid overstaging and unnecessary therapy. We report on the incidence of renal vessel anomalies in an unselected group of patients undergoing retroperitoneal lymph node dissection (RPLND) for testis cancer. Methods: 245 patients with testicular germ cell tumors underwent primary or secondary RPLND following inductive chemotherapy. Prior to RPLND, all patients underwent abdominal staging by CT scans or by MRI in selected cases. CT scans were reviewed with regard to the detection of vascular anomalies of the vena cava inf., renal veins, renal arteries, and iliac vessels. CT findings were correlated with intraoperative findings. Results: Overall, vascular anomalies were encountered in 39 patients (15.9%): retroaortic left renal vein in 10 (4.1%), circumaortic left renal vein in two (0.8%), reduplication of the common iliac vein in one (0.4%), accessory renal arteries in 14 (5.7%), thrombosis of the inferior vena cava in 12 (4.9%) patients with IIC disease. Anomalies of the renal vein were detected in 10 out of 12 (83%), in two cases venous anomalies were falsely diagnosed as lymph node disease in stage I NSGCT. All arterial anomalies were identified preoperatively. CT scan identified caval thrombosis in only eight cases (68%), four cases were identified by an additional MRI of the abdomen. Conclusions: Vascular anomalies are frequently encountered in patients with RPLND for testis cancer and have to be acknowledged during surgery even with negative imaging studies. Retroaortic renal veins represent a potential pitfall of CT imaging resulting in unnecessary therapy; it should be considered in pts with CT suspicious lymph nodes caudal to the renal hilus. IVC thrombosis is associated with advanced disease and is best diagnosed by MRI of the abdomen.
Management of growing teratoma syndrome: Aachen University experience.
Authors: Pfister David J. K. P. , Porres Daniel , Thissen Andrea K. , Piper Charlotte , Heidenreich Axel
Published: February 2017

385

Background: Growing teratoma syndrome (GTS) is an infrequent clinical phenomenon. GTS is defined as an enlarging metastatic mass during systemic chemotherapy for advanced nonseminomatous germ cell tumors (NSGCT) despite decreasing serum tumor markers. Complete surgical resection of the mass is mandatory to achieve a favourable outcome. We report on our single center experience in the management of GTS. Methods: Between January 2000 and August 2009 postchemotherapeutic retroperitoneal lymph node dissection (PCRPLND) was performed in 162 patients (pts) with advanced NSGCT. Fourteen pts (4.9%) fulfilled the criteria of a GTS: enlarging metastatic mass in the retroperitoneum or visceral organs during systemic chemotherapy with normalized or regredient tumor markers. In all cases of GTS a complete radical bilateral PCRPLND including the resection of adjacent visceral and vascular structures was performed. Results: Median patient age was 24.5 (18 to 52) years. All patients exhibited NSGCT with a good or intermediate prognosis according to IGCCCG; in all cases the primary tumor contained predominantly (greater than 50%) mature teratoma; 10 and 4 patients presented with clinical stage IIC and III, resp. Median tumor diameter at time of surgery was 6,5 (3,0-35)cm. Tumor markers were normalized in 12 out of 14 patients and markers plateauted in 2 out of 14 patients. Tumor masses were localized in the retroperitoneum in 12 pts.; two patients had additional pulmonary metastases which were resected in a second approach. Median time from start of chemotherapy to surgery was 4.8 (1.5 to 26.5) months Median surgical time was 265 (165 to 585) minutes, and median blood loss 650 (450 to 2,000) ml. Four pts required resection of the inferior vena cava or abdominal aorta with implantation of a prosthetic graft; adjunctive nephrectomy was performed in three pts. After a median follow-up of 4.2 years two pts developed recurrent disease; the remainder are alive without evidence of disease. Conclusions: GTS is a rare phenomenom among pts with advanced NSGCT and necessitates complete surgical resection of all masses with curative intention. Surgery should be considered at time of progression to facilitate complete removal of the mass. Due to the complex surgery, treatment should be performed at specialized centers.