bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemotherapy with or without definitive radiation therapy in locally advanced pancreatic cancer.
Authors: Zhong Jim , Switchenko Jeffrey M. , Behera Madhusmita , Kooby David A. , McDonald Mark William , El-Rayes Bassel F. , Landry Jerome Carl , Patel Pretesh R
Published: September 2018

4103

Background: The recently reported LAP07 randomized trial calls into question the role of radiation therapy (RT) in the modern treatment of locally advanced pancreatic cancer (LAPC). However, advances in chemotherapy and RT limit application of the LAP07 results to current clinical practice. Here we utilize the National Cancer Database (NCDB) to evaluate the effects of RT in patients receiving chemotherapy for LAPC. Methods: Using the NCDB, patients with AJCC clinical stage T2-T4, N0-1, M0 adenocarcinoma of the pancreas from 2004-2014 were analyzed. Only those that received chemotherapy and did not undergo surgery were included. Patients were stratified into chemotherapy only (CT) and chemoradiation (CRT) cohorts. Patients undergoing definitive RT, defined as at least 20 fractions (fxs) or ≥ 5 Gy per fraction (i.e. SBRT) were included in the CRT cohort. Propensity-score matching (PSM) and landmark analysis were used to address selection bias and lead-time bias, respectively. The primary endpoint was overall survival (OS). Results: 13,004 patients met inclusion criteria, of which 7,034 (54%) received CT and 5,970 (46%) received CRT. After PSM, 5,215 patients remained in each cohort. Median follow-up was 22.6 months. The CRT group had younger median age (65 vs. 67) and less treatment at academic centers (44 vs. 51%); performance status was similar between groups. The median fractionated RT dose was 50.4 Gy in 28 fxs and SBRT dose was 24 Gy in 3 fxs. The CRT cohort demonstrated better OS compared with CT alone, with median and 1-yr OS of 12 vs. 10 months, and 50% and 41%, respectively (p < 0.001). On multivariable analysis, CRT was associated with superior OS with a hazard ratio (HR) of 0.79 (95% confidence interval (CI): 0.76-0.83, p < 0.001) compared with CT alone. The SBRT subgroup demonstrated the best survival (HR 0.71 [95% CI: 0.64-0.80], p < 0.001). OS was superior for CRT after PSM and for all patient subsets. Conclusions: In unresected LAPC, the addition of definitive radiotherapy to chemotherapy is associated with superior OS when compared with chemotherapy alone. Survival was greatest when SBRT was used. Definitive radiotherapy should remain a standard option for LAPC but optimal selection criteria remain unclear.
FOLFIRINOX (F-NOX) followed by individualized radiation for borderline-resectable pancreatic cancer (BRPC): Toxicity, R0 resection, and interim survival data from a prospective phase II study.
Authors: Murphy Janet E. , Wo Jennifer Yon-Li , Ryan David P. , Jiang Wenqing , Yeap Beow Y. , Drapek Lorraine C. , Blaszkowsky Lawrence Scott , Kwak Eunice Lee , Allen Jill N. , Clark Jeffrey W. , Faris Jason Edward , Zhu Andrew X. , Goyal Lipika , Mamon Harvey J. , Wolpin Brian M. , Lillemoe Keith D , DeLaney Thomas F. , Fernandez-del Castillo Carlos , Ferrone Cristina , Hong Theodore S.
Published: September 2018

4113

Background: F-NOX is increasingly utilized in BRPC as neoadjuvant therapy. However, prospective data remains limited; the largest series is a 22 patient (pt) cooperative group trial (Alliance A021101), in which 14 pts had R0 resection. In this study, we evaluate neoadjuvant F-NOX followed by individualized chemoradiation (CRT) for BRPC. Methods: Pts ECOG PS 0-1 with biopsy-proven BRPC defined by NCCN criteria were enrolled in a single institution, NCI-sponsored phase II study (NCT01591733). Pts received F-NOX for 8 cycles. If after chemotherapy the tumor was radiographically resectable, pts received short course CRT in 5 (protons 25 GyE) or 10 fractions (photons 30 Gy) with capecitabine 825 mg/m2 bid. If the tumor was still abutting vasculature, pts received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. Primary endpoint was R0 resection rate. Results: 50 pts were enrolled from 8/2012 to 8/2016. Two pts were ineligible (lung metastasis, negative biopsy); 48 pts were evaluable. Median age was 62y (46-74). Median tumor size was 37 mm (21-56). Thirty-six pts (75%) had pancreatic head tumors. Median follow up was 18.2 months among 31 patients still alive. Of the evaluable pts, 40 (83%) completed therapy. Reasons for not completing therapy include pt withdrawal (3), physician decision (3), unacceptable toxicity (1) and progression (1). Grade 3 or greater toxicity occurred in 48% of pts, but no individual grade 3 toxicity exceeded 15%. Twenty-seven pts (56%) had short course CRT, while 13 pts (27%) had long course CRT. Twenty-nine pts were resected; R0 resection was achieved in 28/29 (96.5%). R0 resection rate among all evaluable pts was 58.3%. Median PFS among all evaluable pts was was 14.7 months; mOS was 37.7 months, with 1y OS 79.5% and 2y OS 59.3%. Among resected patients, mOS has not been reached. 1y PFS was 78.1% and 2y PFS 55.4%; 1y OS was 92.6% and 2y OS was 80.6%. Conclusions: Preoperative F-NOX followed by individualized chemoradiation in BRPC results in high R0 resection rates as well as prolonged mPFS and mOS in this large prospective cohort. Clinical trial information: NCT01591733.
Phase II study of autophagy inhibition with hydroxychloroquine (HCQ) and preoperative (preop) short course chemoradiation (SCRT) followed by early surgery for resectable ductal adenocarcinoma of the head of pancreas (PDAC).
Authors: Hong Theodore S. , Wo Jennifer Yon-Li , Jiang Wenqing , Yeap Beow Y. , Clark Jeffrey W. , Ryan David P. , Blaszkowsky Lawrence Scott , Drapek Lorraine C. , Mamon Harvey J. , Murphy Janet E. , Faris Jason Edward , Kwak Eunice Lee , Allen Jill N. , Zhu Andrew X. , Goyal Lipika , Lillemoe Keith D , Ferrone Cristina , DeLaney Thomas F. , Fernandez-del Castillo Carlos , Kimmelman Alec
Published: September 2018

4118

Background: PDAC is highly dependent on autophagy, a metabolic process that renders cancer cells resistant to cytotoxic therapies. HCQ is an inhibitor of autophagy, and has preclinical activity in PDAC. We evaluate the efficacy of concurrent and adjuvant HCQ with preop SCRT and adjuvant chemotherapy in early, resectable PDAC. Methods: Pts with radiographically resectable, biopsy-proven PDAC of the head were enrolled from 12/2011-9/2016 on this IRB-approved, NCI-sponsored clinical trial (NCT01494155). Eligibility included no involvement of SMA or celiac artery on CT; adequate renal, hepatic and hematopoetic function; and ECOG PS 0/1. SCRT was 5 Gy x 5 with protons or 3 Gy x 10 with photons concurrent with Cape 825 mg/m2 BID wk 1 and 2 M-F. HCQ was started at 400 mg po BID 1 wk prior to radiation through SCRT until the day of surgery. Surgery was performed 1-3 wks after completion of SCRT. Pts were recommended to receive 6 mo of gemcitabine-based chemotherapy after surgery. Pts resumed HCQ after discharge from surgery and continued until progression. Follow-up was performed every 3 months with CT scanning every 6 mo. Sample size of 50 to evaluate an increase of 2-year PFS from 30% to 45%. Results: 50 pts were enrolled on study and all are evaluable for this analysis. Median age- 69 (range 54-86); pre-treatment CA19-9 median 69.5 U/mL ( < 1-10235), female- 24 pts (48%). Gr 3 toxicity was noted in 2 (4%) pts (nausea-1, hyperglycemia-1). All 50 pts completed SCRT. 46 pts underwent resection. Reasons for no resections: metastatic disease-2, toxicity-1, intercurrent illness- 1. 38 pts had R0 resection, 8 had R1 resection. 29 of 46 pts had positive nodes. 1 pt achieved pathologic complete response (CR), 2 pts had near CR . 11 pts remain on HCQ. Median follow up in 26 surviving pts is 18.3 months. mPFS is 11.7 mo, mOS 23.3 mo. OS-2 yr- 43.1%, PFS-2-yr 32.0%. Conclusions: HCQ with preop SCRT and adjuvant gemcitabine-based chemotherapy is well tolerated but did not meaningfully impact DFS. Further pathologic/correlative studies, particularly in outstanding pathologic responders and long term survivors are ongoing. Clinical trial information: NCT01494155.
A phase I/II trial of TG01/GM-CSF and gemcitabine as adjuvant therapy for treating patients with resected RAS-mutant adenocarcinoma of the pancreas.
Authors: Palmer Daniel H. , Dueland Svein , Valle Juan W. , Aksnes Anne-Kirsti
Published: September 2018

4119

Background: TG01 (a mixture of 7 RAS peptides) is an injectable antigen-specific cancer immunotherapy targeted to treat patients (Pts) with KRAS mutations, found in more than 85% of pancreatic adenocarcinomas. There is scope for improvement in adjuvant treatment of resected pancreatic cancer; with 1- and 2-year published overall survival (OS) rates ranging from 56-80% and 30-54% respectively. TG01 induces RAS mutant-specific T-cell responses which are enhanced by co-administration of GM-CSF. This study evaluates safety, immunological response and OS of TG01-immunotherapy with adjuvant gemcitabine chemotherapy. Methods: Pts were eligible after an R0 or R1 pancreatic adenocarcinoma resection. As soon as possible after surgery, TG01 (0.7 mg intradermal injection (id)) together with GM-CSF (0.03 mg id) was given on days 1, 3, 5, 8, 15, 22 and 2-weekly thereafter until the end of gemcitabine (starting within 12 weeks of surgery and given for 6 cycles). Thereafter TG01/GM-CFS were given 4-weekly up to 1 yr and 12-weekly up to 2 yrs. Immune response was assessed using antigen-specific (TG01) Delayed-Type Hypersensitivity (DTH) and T-cell proliferation. OS was assessed from surgery; ~8 weeks before first TG01 injection. Results: To date, 19 pts (68% R1) from 3 sites (Norway and UK) and have been followed for 2 yrs.Eight SARs in 5 pts have occurred; 4 related to gemcitabine (anemia, pulmonary infection and 2 fever); 3 related to TG01/GM-CSF (2 anaphylaxes and 1 hypersensitivity); and 1 possibly related to all products (dyspnea). The allergic reactions only occurred after several cycles of gemcitabine and resolved within 1-2 hrs. There was no treatment related deaths.16/19 (84%) pts had a positive DTH by week 11. Proliferation of mutant RAS specific T-cells is being analyzed. OS rate at 1 and 2 yrs were 89.5% (95% CI 75.7, 100.0) and 68.4 (95% CI 47.5, 89.3), respectively. Median OS was 33.1 months (95% CI 16.8, 40.1). Conclusions: TG01/GM-CSF generated early immune responses in 84% of patients with R0/R1 resected pancreatic cancer. The regimen was generally well tolerated although some late, manageable allergic reactions were seen. OS was encouraging in view of published reports. Clinical trial information: NCT02261714.
Characteristics and outcomes of resected pancreatic cystadenocarcinoma: 1,205 cases from the National Cancer Data Base.
Authors: Wang Jiping , Wang Xuefei , Heuthorst Lianne , Clancy Thomas E. , Pezzi Christopher
Published: September 2018

4129

Background: Cystadenocarcinoma (CAC) of the pancreas is a rare pancreatic and therefore there is limited data on the characteristics, treatment and prognosis of this disease. Methods: Patients who underwent resection for CAC (n = 1,205) between 2003 and 2012 were identified from National Cancer Data Base. The clinicopathological characteristics and treatment outcomes were compared to patients with resected ductal adenocarcinoma (DAC) (n = 15,696). Cox-proportional hazard model was used to adjust for potential prognostic factors. A nomogram was constructed and validated to predict the outcomes of patients with CAC by using multiple variable Cox-proportional model and receiver operating characteristics curve methods. Results: Compared with resected DAC, patients with resected CAC are diagnosed at a younger age (58.7 vs. 61.2, p < 0.0001); female predominant (63.7% vs. 48.8%, p < 0.0001); more often Black (15.0% vs. 9.3%, p < 0.0001);had larger tumor (0-2, 2-4 and > 4cm:17.5%, 24.3%, 53.5% vs. 16.8%, 48.3% , 32.1%, respectively, p < 0.0001); have less total number of examined lymph nodes (10.6 vs. 14.5, p < 0.0001) and fewer positive lymph nodes(0.6 vs. 2.3, respectively). CAC patients were less likely to receive chemotherapy (28.8% vs. 62.5%, p < 0.0001) and radiation therapy (16.4% vs. 36.9%, p < 0.0001). CAC patients had significantly better overall survival than those with DAC (5 year survival: 55.6% vs. 17.3%, p < 0.0001). The survival advantage was primarily seen in patients with early stage disease (5 year survival: 70.9% vs. 36.9% in stage I patients, p < 0.0001, and 32.7% vs. 14.5% in stage II patients, p < 0.0001 respectively) and persisted after adjusting the known prognostic factors including age, AJCC staging, Charlson-Deyo score, type of surgery, chemotherapy, tumor size, and lymph node ratio (adjusted hazard ratio: 0.43, 95% confidence interval: 0.39-0.48, p < 0.0001). Conclusions: Patients with CAC had significantly better survival than those with pancreatic DAC even after controlling for known prognostic factors. The proposed nomogram could accurately predict patients’ outcome and may be used as a tool for clinical decision making.
Phase II study of individualized sunitinib (SUN) as first-line therapy for metastatic renal cell cancer.
Authors: Bjarnason Georg A. , Knox Jennifer J. , Kollmannsberger Christian K. , Soulieres Denis , Ernst D. Scott , Zalewski Pawel , Canil Christina M. , Winquist Eric , Hotte Sebastien J. , North Scott A. , Heng Daniel Yick Chin , Macfarlane Robyn Jane , Venner Peter M. , Kapoor Anil , Hansen Aaron Richard , Eigl Bernhard J. , Czaykowski Piotr , Boyd Ben , Wang Lisa , Basappa Naveen S.
Published: September 2018

4514

Background: Higher SUN exposure is associated with better outcomes. Patients (pts) with minimum toxicity on the standard schedule do worse than pts needing dosing changes for toxicity. Methods: It was hypothesized that toxicity-driven dose/schedule individualization would improve the primary endpoint (PFS) from 8.5 (EFFECT trial) to 14 months (mo), with 99 pts required to detect this with 90% power and 2-sided alpha = 0.05. In a prospective phase II study (eligibility as EFFECT) pts start on 50 mg/day (d) for 28 d with treatment (Rx) breaks reduced to 7 d. If grade-2 toxicity develops before d 28, pts stay on a 50 mg on the next cycle with the number of d on Rx individualized aiming for ≤ grade-2 toxicity. Dose is reduced to 37.5 mg and then 25 mg if pts do not tolerate a 50 mg or 37.5 mg dose respectively for at least 7 d. Pts with minimum toxicity on d 28 are escalated to 62.5 mg and then 75 mg. Results: 117 pts were enrolled in 12 centers. Nine non-evaluable pts came off early due to toxicity (5), non-compliance (2) and global deterioration (2). Of 108 pts evaluable for response (IMDC favorable 31.5%, intermediate 58.3%, poor 10.2%. Bone mets 19%, Nephrect 83%), 10 are still on Rx. Dose was escalated in 20 pts (18.5%) to 62.5 mg (12 pts) and then to 75 mg (8 pts). In 49 pts (45.4%) eligible for dose reduction by standard criteria, a 50 mg dose was maintained but for 7 - 24 d, while 7 pts (6.5%) stayed on a 28 d schedule. Dose was reduced to 37.5 mg in 22 pts (20.4% vs. 36 - 63% in 4 large SUN trials) and to 25 mg in 10 pts (9.3% vs. 27 - 43% in 4 trials). Rx was stopped due to toxicity in 10/117 pts (9.3% vs. 15 - 19% in 4 trials). See table for response (ORR, 108 pts) and survival (117 pts) data vs. EFFECT (146 pts). The median followup is 15.5 mo (0.6 -37.9) for PFS and 24.5 mo (4.4 - 47.7) for OS. Conclusions: The null hypothesis of the PFS being 8.5 mo can be rejected with a p < 0.001. Individualized dosing is safe and feasible in a multicenter setting and associated with improved dose intensity and one of the best ORR, PFS and OS reported for a TKI. Clinical trial information: NCT01499121. [Table: see text]
Infusional gemcitabine + docetaxel/melphalan/carboplatin (GemDMC) ± bevacizumab (BEV) as an effective high-dose chemotherapy (HDC) regimen for refractory of poor-risk relapsed germ-cell tumors (GCT).
Authors: Nieto Yago , Tu Shi-Ming , Campbell Matthew T. , Bassett Roland , Tannir Nizar M. , Ward John Francis , Hofstetter Wayne Lewis , Jones Roy B. , Andersson Borje , Gulbis Alison M , Ledesma Celina , Timmons Melissa , Trapp Michelle , Champlin Richard E. , Pagliaro Lance C.
Published: September 2018

4519

Background: Tandem HDC with carbo/etoposide (CE) is curative for a portion of relapsed GCT pts. However, outcomes of refractory or high-risk relapsed pts remain poor. We tested a new HDC regimen of GemDMC, based on DNA damage repair inhibition. We combined BEV with HDC given their potential synergy and the high vascularity of GCT metastases. Methods: Eligibility: Intermediate (int)/high-risk (Beyer Model), creatinine ≤1.8 mg/dL and adequate organ function. HDC included BEV (5 mg/kg) preceding GemDMC (HDC #1) and ifosfamide/CE (ICE) (HDC #2). Following accrual of 42 pts, we amended the trial omitting BEV. The trial was powered to distinguish a target 50% 2-yr RFS from an expected 25% in this population. Results: We enrolled 69 male pts in cohorts 1 (BEV, N=42) and 2 (no BEV, N=27) (Table). Pts were heavily pretreated and most had refractory tumors. Main AE: mucositis and renal (4 HDC-related deaths in cohort 1, 1 in cohort 2). Tumor markers normalized in 90% pts with active tumors at HDC. After HDC, 19 pts were in CR and 28 in PRm- (of these, 22 had residual lesions resected with no viable tumor found in 20/22, 2 xRT, 4 monitored). Median f/u = 39 (2-105) mo. The 2-yr RFS rates in cohorts 1 and 2 = 52% and 78%, respectively. Their respective 2-yr OS rates = 55% and 81%. Conclusions: Sequential HDC with GemDMC–ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the anticipated results. Addition of BEV increases toxicity but not tumor control. Clinical trial information: NCT00936936. [Table: see text]
Integrated biomarker analysis for 412 renal cell cancer (RCC) patients (pts) treated on the phase 3 COMPARZ trial: Correlating common mutation events in PBRM1 and BAP1 with angiogenesis expression signatures and outcomes on tyrosine kinase inhibitor (TKI) therapy.
Authors: Voss Martin Henner , Kuo Fengshen , Chen David , Marker Mahtab , Patel Parul , Redzematovic Almedina , Riaz Nadeem , Chan Timothy A. , Choueiri Toni K. , Hsieh James , Motzer Robert J. , Hakimi A. Ari
Published: September 2018

4523

Background: In RCC biology mutations in PBRM1 and BAP1are largely non-overlapping and collectively affect >50% of pts. How and through which mechanism they influence disease kinetics is poorly understood. Sunitinib and pazopanib inhibit angiogenesis, a key driver in RCC. We analyzed mutation status and gene expression signatures in a large cohort of pts receiving first-line sunitinib or pazopanib on the COMPARZ trial. Methods: RNA and DNA were extracted from archival tissue. PBRM1 and BAP1mutation status was determined via a custom exon-targeted platform. Transcriptome analysis was done using Affymetrix GeneChip HTA 2.0. We computed a 43 gene angiogenesis expression score with previously reported dynamic response to VEGF-directed therapy in xenograft models (Masiero, Cancer Cell 2013). DNA and RNA findings were correlated with clinical outcomes using parametric and non-parametric tests. Results: 412 pts contributed tumor RNA, 377 pts DNA; 362 pts both. PBRM1 and BAP1 were mutated (MT) in 44% and 15% of pts, respectively. Presence of PBRM1mutations correlated with superior PFS (p=0.008) and OS (p=0.004) on log-rank test, and PBRM1 mutation rate was higher in pts with objective response than those with progression (Fisher’s Exact, p=0.012). In contrast, pts with MT BAP1 had inferior OS compared to those whose were wild type (WT) (log-rank, p=0.012). Across all 412 pts angiogenesis score associated favorably with outcome on uni and multivariate analyses (Cox proportional hazard regression, OS p<0.001 and PFS p<0.005); scores were higher in 123 pts with objective response than 81 pts with progression as best response (Mann-Whitney, p=0.009). Angiogenesis scores were higher in PBRM1 MT vs WT patients (Mann-Whitney, p<0.001), but lower in BAP1 MT vs WT patients (p<0.001). Conclusions: PBRM1 and BAP1 mutations appear to have opposite effects in advanced RCC. Loss of PBRM1 enhances the pro-angiogenic microenvironment of RCC with favorable effects on response to TKI; BAP1 loss associates with decreased angiogenic signaling and adverse outcome to TKI. Clinical trial information: NCT00720941.
Discovery and prevalence of cancer-susceptibility germline mutations (Mts) in patients (Pts) with advanced renal cell carcinoma (aRCC).
Authors: Carlo Maria Isabel , Mukherjee Semanti , Kemel Yelena , Zhang Liying , Mandelker Diana , Vijai Joseph , Coskey Devyn Taylor , Pradhan Nisha , Hyman David Michael , Hakimi A. Ari , Coleman Jonathan , Lee Chung-Han , Feldman Darren R. , Voss Martin Henner , Offit Kenneth , Robson Mark E. , Motzer Robert J.
Published: September 2018

4524

Background: About 5% of RCC is thought to be familial, but recent studies suggest this may be an underestimate (Int. J. Cancer;100:476). We studied the prevalence of germline cancer-susceptibility mts in pts with aRCC. Methods: Pts with aRCC (stage III or IV), unselected for suspicion of an inherited cancer syndrome, were offered germline testing for 76 cancer-associated genes between 10/2015 and 12/2016. Germline sequencing was done as part of MSK-IMPACT, a matched tumor-normal next-generation sequencing platform. Results: 203/213 pts accepted testing (median age 55, range 13-55) of whom 73% had clear cell RCC (ccRCC), 92% had metastases, 20% were early onset (≤46 yrs at diagnosis), 9% had a family history of RCC, 6% multifocal RCC at diagnosis, and 15% ≥2 primary malignancies. Pathogenic/likely pathogenic mts were found in 35 pts (17%): 12 (6%) with mts in genes associated with familial RCC; 10 (5%) mts in high/moderate penetrance genes not linked to RCC (Table).13 (6%) had mts in genes of low/uncertain penetrance or for autosomal recessive disease. Mts were present in 15% of ccRCC and 19% of non-ccRCC. Mts were not more common in pts with early onset, family history, multifocal RCC, or ≥2 malignancies (p>0.1 for each by Fisher’s exact test). Notably, 4/12 pts with mts in familial RCC genes did not meet the American College of Medical Genetics (ACMG) criteria for testing (1 each VHL, BAP1, SDHA, FH). Prevalence of CHEK2 mts was compared to population databases (ExAC); CHEK2 conferred a relative risk of 10.9 (p< 0. 002; CI=3.9-24.7) for RCC. Conclusions: 17% of aRCC pts had a germline mutation in a cancer-associated gene of which 33% of the high penetrance RCC germline mts were not identified using standard clinical criteria, providing rationale for broad testing. Once the increased risk is confirmed, CHEK2 should be included in RCC genetic testing. [Table: see text]
Phase I/II trial of cetuximab with 5-fluorouracil and mitomycin C concurrent with radiotherapy in patients with muscle invasive bladder cancer.
Authors: Hussain Syed A. , Buckley Laura , Kaur Baljit , Hendron Carey , Zarkar Anjali , Ford Daniel , Viney Richard , Syndikus Isabel , Malik Zafar , Eswar Chinnamani , Desai Amisha , Southgate Elizabeth , Mangar Stephen , Van Der Voet Johannes , Lydon Anna , James Nicholas D.
Published: September 2018

4527

Background: This phase I/II trial assessed the safety, feasibility and efficacy of cetuximab (Cet) in combination with 5-fluorouracil (5FU) and mitomycin C (MMC) with concurrent radiotherapy (RT) for the treatment of muscle invasive bladder cancer (MIBC). BC2001 trial has previously reported significant improvement in locoregional control in patients (pts) with MIBC who were randomised to synchronous chemo-RT compared to RT alone (James, Hussain, Hall et al NEJM 2012). Results for phase I have been reported previously. This abstract reports the combined results of phases I/II. Methods: From September 2012 to October 2016, 33 pts were recruited (7 pts to phase I from 2 UK centres and 26 patients to phase II from 5 UK centres). Pts received loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2 for 7 weeks, continuous infusion 5FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC 12mg/m2on day 1 in combination with radical RT 64 Gy in 32 fractions. Neoadjuvant chemotherapy was mandatory in phase I but optional in phase II. Primary outcomes in phase I were feasibility and toxicity. Primary outcome in phase II was 3 month pathological complete response (CR) rate, secondary outcomes included toxicity, progression free survival (PFS) and overall survival (OS). Results: Median age of pts was 70 (range 46.9-85.6). Treatment completion rates in phase I were RT 100%, 5FU 100 %, MMC 100%, Cet 96%. Of the 28 analysable pts, phase II primary outcome data was available for 25 pts at the time of analysis with a 3 month pathological CR rate of 88%. 5 local progressions and 4 deaths were reported. 12 pts suffered at least one SAE. Grade 4 toxicities observed were dyspnoea, atrial fibrillation, interstitial pneumonitis, sepsis, thromboembolism, neutropenia and palpitations. The commonest grade 3 toxicities were skin rash, diarrhoea, low platelet count, low white blood cell count, fever and haematuria. The most common grade 1 and 2 toxicities were diarrhoea and skin rash. Data on PFS and OS will be presented. Conclusions: It was feasible and safe to add cetuximab to full dose chemo-RT with 5FU/MMC. The CR rate is encouraging and further randomised studies with this combination are warranted. Clinical trial information: ISRCTN80733590.
Atezolizumab (atezo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Safety analysis from an expanded access study.
Authors: Bellmunt Joaquim , Pal Sumanta K. , Zheng Hanzhe , Tayama Darren , Chang Dannis , Hoffman-Censits Jean H.
Published: September 2018

4532

Background: A majority of mUC pts progress on standard platinum-based chemo regimens. Atezo (anti–PD-L1) was approved in the US for mUC in the post-platinum setting. Here we report the preliminary safety results from an expanded access program conducted to grant access to atezo, prior to commercial availability, to a broader range of mUC pts than are typically eligible for Phase I-III studies. Methods: From Nov 2015-Aug 2016, this study (NCT02589717) enrolled mUC pts who progressed during or following platinum. Atezo was given 1200 mg IV q3w, and pts could be treated post RECIST v1.1 PD until lack of clinical benefit (per investigator). Safety and clinical activity were key endpoints. PD-L1 expression on immune cells (IC) was assessed with the VENTANA SP142 IHC assay on the first 73 pts prior to protocol amendment omitting this requirement. This study was ended early following FDA approval of atezo. Results: 218 pts were enrolled at 36 sites in the US, with 214 treated pts comprising the safety/efficacy population (Table). Median treatment duration was 9 wks (range 3-26), corresponding to a median of 3 doses of atezo (range 1-8). Overall, 89% of pts had an AE. Treatment-related AEs (TRAEs) occurred in 46% (any Gr) and 7% (Gr3-4) of pts; 2 treatment-related Gr 5 AEs were seen (ileus; acute respiratory failure). TRAEs ≥ 5% were fatigue, decreased appetite and anemia. TRAEs leading to dose interruption or discontinuation occurred in 11% and 6% of pts, respectively. Investigator-assessed RECIST v1.1 ORR was 15% (95% CI: 9, 23), and disease control rate (ORR + SD) was 49% (95% CI: 40, 59). Additional clinical data will be reported. Conclusions: In this expanded access study, atezo was administered to > 200 mUC pts. Overall, atezo was safe and tolerable, supporting its use in a wider platinum-based population. Clinical trial information: NCT02589717. [Table: see text]
Spectrum of tumor mutational load (TML) in genitourinary cancers (GU CA).
Authors: Hussain Muhammad Azam , Heath Elisabeth I. , Somer Bradley G. , Arguello David , Johnston Curtis , Drabick Joseph J. , Joshi Monika
Published: September 2018

4535

Background: Immunotherapy (IO) is now standard of care for bladder and kidney cancer (CA) and is investigational in other GU CA such as prostate and germ cell CA. Tumor mutational load (TML) has correlated with response to IO in several tumor types. Herein, we explore TML across different histological subtypes in GU CA. In addition, we also assess the correlation between TML and PD-L1 status. Methods: 544 GU specimens were identified: bladder, 145; kidney, 164; prostate, 221; penile, 2; testicular, 12. TML was calculated using somatic non-synonymous missense mutations from a 592-gene panel (Illumina NextSeq). A high TML was > 17 mutations/MB. PD-L1 (SP142) was done depending tumor availability. Results: High TML was more prevalent in bladder CA (14.5%, 21/145) compared to other GU CA. Urothelial carcinomas had a noticeably high TML while squamous histology had a pronounced PD-L1 expression (Figure 1). A comparison of TML-high (n=15) versus TML-low (n=76) urothelial bladder CA showed the following differences (Figure 2). TML was rare in kidney CA (1.8%, 1/57); PD-L1 was high in sarcomatoid (33.3%, 5/15), CDC/RMC (28.6%, 2/7). Prostate adenocarcinoma had few TML-high (2.3%, 5/219) or PD-L1 expressing tumors (1.4%, 3/208). Tumors of penile or testicular origin lacked high TML and PD-L1 expression. No correlation was found between a high TML and PD-L1 expression. Conclusions: TML varied considerably amongst GU CA. As in other CA, TML-high scores did not predict PD-L1 expression and vice versa. Comprehension of the underlying biology may assist in determining which CA may respond better to IO. [Table: see text]

[Table: see text]
Randomized study of intravesical chemotherapy using pirarubicin in patients with non-muscle-invasive bladder cancer in Japan: Comparing one immediate postoperative intravesical chemotherapy with short-term adjuvant intravesical chemotherapy after TURBT: Subanalysis in patients with intermediate risk.
Authors: Naya Yoshio , Mikami Kazuya , Takaha Natsuki , Okihara Koji , Miki Tsuneharu , Ukimura Osamu
Published: September 2018

4536

Background: The objective is to evaluate the efficacy defining of 2-year tumor recurrence free rate of intravesical chemotherapy using pirarubicin (THP) for patients with intermediate risk. Methods: Between October 2010 and January 2015, 206 patients were enrolled in this study and finally 113 were randomized to one immediate postoperative intravesical instillation of THP 30mg (Group A), or additional intravesical instillation of THP 30mg weekly for 8 weeks after single postoperative instillation (Group B). The recurrent risk was stratified using EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2009 update. Of 113, 100 with intermediate risk were analyzed in this study. The patients were examined by cystoscopy and urine cytology every 3 months after trans urethral resection to determine bladder tumor recurrence. The primary endpoint was 2 year-recurrence-free survival rates. A statistical analysis was performed by SAS (SAS Institute Inc., Cary, USA). Results: The 2-year recurrence free survival rates were 66.2% in Group A and 86.1% in Group B, respectively (log rank test, p = 0.0043). In patients with recurrence score between 5 and 9, the 2-year recurrence free survival was 92.3% in Group B and 22.2% in Group A (log rank test, p = 0.0013). Cox regression analysis revealed that only additional instillation of THP was significant independent factor for recurrence free rate in patients with intermediate risk. There was no patient with progression during this period. Frequent adverse effects were frequent urination and micturition pain without severe adverse effect (Grade 3 or more). Limitation of this study is a failure to enroll sufficient number for statistical analysis. Conclusions: Additional instillation of THP 30mg weekly for 8 weeks reduced the risk of tumor recurrence without severe toxicity in NMIBC patients with intermediate recurrent risk.
Intra-patient heterogeneity in urothelial cancer (UC) circulating tumor cells (CTC) and PDL1 expression to identify biomarkers of response and new therapeutic targets: A pilot study.
Authors: Arafat Waddah , Stahlfeld Charlotte , Sperger Jamie M , Heninger Erika , Gopalakrishnan Dharmesh , Barata Pedro C. , Lamenza Marcelo , Devonshire Sarah , Hoxha Nita , Profusek Pam , Rini Brian I. , Ornstein Moshe Chaim , Garcia Jorge A. , Kyriakopoulos Christos , Lang Joshua Michael , Grivas Petros
Published: September 2018

4537

Background: Recent use of immune checkpoint inhibitors (CI) has improved overall survival (OS) in a subset of patients (pts) with metastatic UC. Intra-patient tumoral heterogeneity and epithelial-to-mesenchymal transition has been hypothesized as a driver of treatment resistance to both chemotherapy and CI in UC. There is a critical need to evaluate heterogeneity in UC for biomarkers of treatment response and new therapeutic targets. Trop2 is hypothesized to play a role in UC progression and is the target of a new antibody-drug conjugate, IMMU-132 that is being tested in UC trials. We report the phenotypic comparison of PDL1 expression among CTC subpopulations in UC pts. Methods: Peripheral blood samples were collected from pts with UC treated at Cleveland Clinic and U. of Wisconsin. Immunomagnetic capture and CTC enumeration using both EpCAM and Trop2 from matched blood samples was performed in the VERSA platform. Protein expression for PDL1 in these CTC populations was quantified. Longitudinal analysis of UC pts treated with chemotherapy or CI is ongoing. Results: CTC were captured using EpCAM and Trop2 in all 10 pts in our initial cohort. The frequency of Trop2 CTC was higher than EpCAM CTC with a mean of 248 Trop2 CTC (range 2-1885) compared to 76 EpCAM CTC (range 1-632). PDL1 expression was more frequent in Trop2 CTC than EpCAM CTC. In two pts progressing on Atezolizumab, Trop2 CTC had a higher frequency of PDL1 expression compared to EpCAM CTC (85% vs 2% in pt 1 and 2% vs 0% in pt 2). In pts followed longitudinally, Trop2 CTC dropped from 1885 to 1 in a pt with response to Atezolizumab and PDL1+ CTC declined from 4 to 0. After 1 cycle of Carbo/Gem in another pt, EpCAM CTC declined from 46 to 3 while Trop2 CTC from 116 to 47. Conclusions: This is the first report of CTC heterogeneity in pts with UC identifying high frequency of Trop2 CTCs with variable expression of PDL1 across different pts. Early results from longitudinal analysis suggest CTC as potential predictive / pharmacodynamic biomarkers of treatment response. Prospective data validation in larger cohort is ongoing, while IMMU-132 clinical trials in UC may provide context for future validation.
Effectiveness of the Moreau strain of Bacillus Calmette-Guerin (BCG) for nonmuscle invasive bladder cancer.
Authors: Chade Daher Cezar , Machado Andre , Waksman Ricardo , Garcia Guilherme , Esteves Paulo , Adonias Sanarelly , Botelho Luis , Cordeiro Mauricio , Murta Claudio , Ribeiro-Filho Leopoldo , Sarkis Alvaro , Bastos Diogo Assed , Dzik Carlos , Srougi Miguel , Nahas William Carlos
Published: September 2018

4539

Background: Intravesical instillation therapy of Bacillus Calmette-Guerin (BCG) for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) after complete transurethral resection has been widely shown to be more effective than any other adjuvant treatment. However, there are several different BCG strains not appropriately evaluated in clinical setting, but in current use. BCG Moreau is by far the most utilized strain in Brazil and has been recently introduced to the European market to cover the issue of BCG shortage, but there is insufficient data regarding its oncologic efficacy. Methods: We retrospectively analyzed 336 consecutive patients, who received adjuvant intravesical instillation therapy with BCG Moreau for intermediate- and high-risk NMIBC between January 2005 and February 2015 at a single institution. The end points of this study were time to first recurrence and progression to muscle-invasive disease. Results: Median age was 62 years (interquartile range 54-76, mean 64.3 years). In addition to induction BCG therapy, 228 (67.9%) patients received maintenance BCG. However, 35 (15.4%) patients interrupted maintenance BCG due to toxicity. Overall, after at least a complete induction BCG therapy, 87 (25.9%) patients presented with disease recurrence and 33 (9.8%) patients had disease progression. When analyzing on patients who received BCG maintenance in addition to induction therapy, 31 (13.6%) patients had disease recurrence and 10 (4.4%) had disease progression. The 5-year recurrence-free survival and progression-free survival rate was 69.8% (95% CI 52.8-77.2) and 86.2% (95% CI 69.9-93.2), respectively. Conclusions: BCG Moreau has shown to be safe and effective as adjuvant intravesical treatment in intermediate and high-risk NMIBC patients. Since results are comparable to other strains, wider use of BCG Moreau may be encouraged and prospective clinical trials stimulated for higher level of evidence.
Activity of RX-3117, an oral antimetabolite nucleoside, in subjects with metastatic bladder cancer resistant to gemcitabine: Preliminary results of a phase Ia/IIb study.
Authors: Gong Jun , Chung Vincent M. , Picus Joel , Tagawa Scott T. , Gupta Sumati , Poore Julie , Peterson Christine , Benaim Ely , Pal Sumanta K.
Published: September 2018

4544

Background: RX-3117 is an oral small molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Preliminary data from an analysis of a phase 1b/2a clinical study of RX3117 in metastatic bladder cancer is described. Methods: This phase 1b/2a study (NCT02030067) was designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle in a 2-stage design. Eligible subjects (aged ≥ 18 years) were those with relapsed/refractory metastatic bladder cancer with any number of prior therapies. Prior therapy with platinum-based chemotherapy was required. The primary endpoint was to assess the efficacy and safety of RX-3117 in metastatic bladder cancer, with secondary aims of evaluating PFS and CBR. Results: With 9 subjects enrolled, median age was 66 years, ECOG PS was 0-1. All subjects had received gemcitabine/cisplatin in the perioperative or metastatic setting, and 4 subjects had received 3 or more prior therapies. The most frequent related adverse events were anemia, mild-moderate fatigue, vomiting and diarrhea. No dose limiting toxicities were observed. PFS and CBR will be presented at the meeting, as 5 subjects continue to receive therapy at the time of this submission. One subject continues on treatment at 139 days with persistent stable disease. Molecular profiling of his bladder tumor showed alterations in ARID1A, FBXW7, FGFR3, NF1, and TERT. The patient previously responded to an FGFR3 inhibitor but progressed after 9 months, with ctDNA assessments showing incurrence of TP53 alteration. Clinical benefit with RX-3117 was achieved in spite of incurrence of this alteration. Conclusions: RX-3117 demonstrated an excellent safety profile, and prolonged stable disease was seen in 1 subject who failed prior cisplatin/gemcitabine and FGFR3 inhibition. Activity persisted despite development a putative resistance alteration detected by ctDNA. Clinical trial information: NCT02030067.
Life expectancy 20 years after cisplatin-based treatment for testicular cancer (TC).
Authors: Lubberts Sjoukje , Kruyt Lara M. , Steggink Lars Christiaan , Steursma Gerrie , Nuver Janine , Oosting Sjoukje , van Ginkel Robert J. , de Jong Igle J. , Eulenburg Christine , Lefrandt Joop D. , Meijer Coby , Sluiter Wim J. , Gietema Jourik A.
Published: September 2018

4550

Background: Four decades have passed since the introduction of cisplatin-based chemotherapy for metastatic TC, providing the opportunity to evaluate very long-term survival. Although 80-90% of the patients are cured, the effect of treatment on residual life span is unknown. Aim of the study was to investigate life expectancy after TC treatment: from prolonging survival after cancer diagnosis, focus shifts to regaining a normal residual life span. Methods: Patients with metastatic TC treated with cisplatin-based chemotherapy > 20 years ago (1977 - 1996) at the University Medical Center Groningen were included. Survival status and cause of death were obtained from medical records, Netherlands Cancer Registry and general practitioners. Events were defined as death due to any cause (overall mortality) and death due to TC or TC treatment complications (TC specific mortality). Standardized mortality ratios (SMR) were calculated as ratio between observed and expected deaths, derived from the age-matched nationwide male population (Dutch Central Office of Statistics). SMRs were calculated for overall mortality, non TC specific mortality (censoring death from TC or treatment-related complications), mortality from cardiovascular disease (censoring death from other causes than cardiovascular disease (ICD-10 I0-I99)) and mortality from secondary malignancies (censoring death from other causes than secondary malignancies (ICD-10 C0-C99 excluding C62: TC)). Results: We included 321 metastatic TC patients with a median age of 28 years (range 16 - 64) at start of chemotherapy. After a median follow-up of 25 years (range 0 - 38) 106 patients died (33%). SMR for overall mortality was 4.0 (95% CI 3.6 - 4.4) and for non TC specific mortality 1.5 (95% CI 1.1 - 1.9). SMR for secondary malignancies was 1.7 (95% CI 1.0 - 2.2) and for cardiovascular diseases 1.5 (95% CI 0.7 - 2.2). Median age at death was 5-10 years lower in TC patients than expected. Conclusions: Twenty years after cisplatin-based chemotherapy, TC patients have a 50% increased risk of dying from non TC causes compared to the general population. These findings suggest that cisplatin-based treatment for TC comes at the expense of about 7.5 life years and induces early aging.
Phase II-study of sequential high-dose-chemotherapy with paclitaxel, ifosfamide, carboplatin, etoposide( P-ICE) in patients with relapsed or refractory germ cell tumors (GCT).
Authors: Kegel Thomas , Cygon Franziska , Meinert Fabian Maximilian , Hammad Khaled , Steinbach Frank , Seseke Florian , Schmoll Hans-Joachim
Published: September 2018

4552

Background: High-dose chemotherapy (HD-CTx) is an active option for salvage chemotherapy in patients (pts) with refractory or relapsed GCT. All previous trials with HD-CTx used one or two cycles of high dose chemotherapy (CTx) including 2 or a maximum of 3 drugs. Another potentially more active option is the application of four sequential HD-CTx cycles (Schmoll et al, JCO 2003). Methods: We conducted a phase II trial of 1(-2) cycle(s) induction CTx with standard dose P-ICE (Paclitaxel 135mg/m² d1, Ifosfamide 1500mg/m² d1-3, Carboplatin 150mg/m² d1-3, Etoposide 150mg/m² d1-3), followed by 4 sequential cycles of HD-P-ICE (Paclitaxel 200mg/m² d1, Ifosfamide 3300mg/m² d1-3, Carboplatin 330mg/m² d1-3, Etoposide 330mg/m² d1-3). Eligibility criteria: relapse or progression under one or more induction CTx, ECOG PS (0-1), Creatinine-clearance > 30ml/min, adaequate liver function, measurable tumor or at least marker-elevation. Results: 37 pts entered the trial and 33 are evaluable (4 pts never received HD-CTx due to lack of stem cells (3) or medical reasons (1)). Prior CTx:1 (N = 26), 2 (N = 4), 3 (N = 3); primary extragonadal: 6; seminoma/ non-seminoma 5/28; ECOG-PS: 0 (19), 1 (14). Response rate: CR/NED 17 (51.5%), CR/NED/PR-/SD- with marker normalization 21 (63.6%), PD 12 (36.4%). DFS of CR/NED: median 59 (8-105) months; RFS of all favourable responders 60 (8-105) months, PFS total 46 (2-105) months. OS for all pts. 51 (6-105) months, OS Favourable Responders: 65 (23 – 105), Nonfavourable Responders: 11 (6-27) months,. Toxicity was tolerable without treatment related death, with mainly grade 4 bone-marrow toxicity and grade 2 mucositis and/or diarrhea. Conclusions: Sequential HD-CTx with one cycle of SD-P-ICE and four cycles HD-CTx is feasible with acceptable toxicity and favourable efficacy. Sequential HD-CTx using the four most active drugs might be a potentially option for this pts-population due to good tolerability, applicability and interesting long-term outcome. Comparison of the standard approach with 1 to 3 sequential high dose cycles of Carboplatin/Etoposide is ongoing (TIGER-Trial). Clinical trial information: EUDRA-CT: 2006-006004-11.
Long-term causes of relative excess mortality after diagnosis of testicular germ cell tumor.
Authors: Kvammen Oivind , Tor Myklebust Åge , Solberg Arne , Møller Bjørn , Klepp Olbjørn Harald , Fosså Sophie , Tandstad Torgrim
Published: September 2018

4553

Background: Despite today’s excellent cure rates among testicular germ cell tumor (TGCT) patients, reduced long-term relative survival (RS) is an increasing concern. We recently reported a continuing decline in RS among TGCT patients diagnosed in Norway, even beyond 30 years of follow-up. Late effects of treatment is the main culprit. Although several reports describe increased mortality from second cancer (SC), cardiovascular disease (CVD), and other causes (OC) among TGCT survivors, data beyond 20 years of follow-up are scarce. The study aim was to analyze long-term relative risks (RR) and causes of death (CD) among TGCT patients diagnosed in Norway, 1953-2014. Methods: Data sources were the Cancer Registry of Norway and the Norwegian Cause of Death Registry. All men diagnosed with TGCT in Norway during 1953-2014 were included, except spermatocytic seminomas. End of follow-up was December 31st, 2014. Patients were classified by CD, histology, disease extent and age at diagnosis, as well as by decade of diagnosis and follow-up time. Standardized mortality ratios (SMR), compared with the general Norwegian male population, were computed. Results: At end of follow-up, 2359 of 9390 patients were deceased. CD was obtained for 2320 patients; 37.6 % TGCT, 24.5 % SC, 19.1 % CVD and 18.8 % OC. SMR for all SC were significant particularly after 20 years of follow-up (1.8 – 3.1), with similar findings in localized disease at diagnosis. SMR were most consistently elevated beyond 20-30 years for SC of the pancreas, large intestine and bladder. By contrast, SMR for CVD were significant among patients diagnosed 2000-14, both before and after one year of follow-up (2.6). There were no significant SMR for CVD beyond 20 years of follow-up. Several OC SMR were elevated, such as for digestive and genitourinary diseases beyond 20-30 years (2.2 – 5.1). Conclusions: TGCT patients have increased RR of SC and OC death even beyond 20-30 years of follow-up, while the increased RR of CVD death is mostly confined to the first decade. CVD deaths in patients diagnosed 2000-14 are a particular concern. Continuing optimization of TGCT treatment and follow-up schemes is required, including further research on toxicity mechanisms.