bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant chemoradiotherapy versus chemotherapy for resectable gastric cancer: A systematic review and meta-analysis.
Authors: Soon Yu Yang , Leong Cheng Nang , Tey Jeremy Chee Seong , Tham Ivan Weng Keong , Lu Jiade Jay
Published: March 2020

4066

Background: The benefits of adjuvant chemo-radiotherapy (ChRT) over chemotherapy (Ch) for resectable gastric cancer are currently unclear. We performed a systematic review and meta-analysis (direct and indirect) of published randomized controlled trials (RCT) to compare the effects of adjuvant chemo-radiotherapy with chemotherapy on overall and disease-free survival for patients with resectable gastric cancer. Methods: We searched MEDLINE and CENTRAL from the date of inception and annual meeting proceedings of ASCO and ASTRO from 1999 to November 2012 for RCTs comparing adjuvant ChRT with Ch, adjuvant ChRT with surgery alone and adjuvant Ch with surgery alone. The primary outcome was overall survival (OS); secondary outcomes included disease-free survival (DFS) and toxicity. Hazard ratios (HR), confidence intervals (CI) and p values (p) were estimated with fixed effects models using Revman 5.1. Results: We found five trials comparing adjuvant ChRT with Ch (n = 1110), three trials comparing adjuvant ChRT with surgery alone (n = 651) and 31 trials comparing adjuvant Ch with surgery alone (n = 8273). Meta-analysis of direct comparison trials showed that adjuvant ChRT significantly improved both OS (HR 0.79, 95% CI 0.64-0.98, p = 0.03) and DFS (HR 0.76, 95% CI 0.64-0.92, p = 0.004) when compared with Ch. Subgroup analyses showed that the effects on OS and DFS were similar regardless of use of D2 nodal dissection, intensity modulated radiotherapy techniques, fluorouracil or platinum-based chemotherapy. There were no significant differences in toxicity between the two groups. The results for the direct and indirect comparisons were statistically consistent. Conclusions: There was a significant survival benefit of adjuvant chemo-radiotherapy over chemotherapy, with no increase in toxicity for patients with resected gastric cancer. Future efforts should also focus on predictive markers, and toxicity or quality-of-life assessments, to individualize adjuvant therapy and optimize the therapeutic ratio.
Comparison of HER2 expression in paired biopsies and surgical specimen of gastric and esophageal adenocarcinoma: Impact of neoadjuvant chemotherapy.
Authors: Watson Sarah , Validire Pierre , Cervera Pascale , Zorkani Nabila , Lemay Frederic , Perniceni Thierry , Paye Francois , Tournigand Christophe , Louvet Christophe
Published: March 2020

4069

Background: HER2 is overexpressed in 10 to 20% of gastro-esophageal adenocarcinoma (GE-ADK), and is a target for trastuzumab in metastatic patients. We conducted a study to compare HER2 expression between diagnostic biopsies (DB) and surgical specimens (SS) of GE-ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. Methods: Pathological specimens from biopsies of 228 patients operated on with a curative aim in two French hospitals between 2004 and 2011 were collected. Two cohorts treated (n=141) or not (n=87) with a NAC were constituted. Two blind independent pathological HER2 analyses on DB and on SS were performed using IHC and CISH. HER-2 overexpression (HER2 +) was defined by a score 3+ in IHC, or 2+ with a positive CISH test, and according to the specific HER2 scoring guidelines for GE-ADK. Results: Paired HER2 status could be determined for 218 out of the 228 patients (95.6%). HER2 + rates were 13.3% on DB (29/218) and 14.7% on SS (32/218). HER2 + tumors were mainly cardial or esophageal adenocarcinomas, with a well-differentiated, intestinal histological type. HER2 status differed between DB and SS in 13 patients (6%). When DB analyses were added to SS analyses, 5 additional patients were HER2 +, the relative increase in HER2 + cases being 13.5% (17.1% for patients with NAC versus 7.1% for patients without NAC, p=0.4, NS). Differences between DB and SS HER2 expression could be explained by the intratumoral heterogeneity and also by a possible HER2 expression decrease in SS after NAC. Conclusions: The determination of HER2 status on DB provides results that complete those obtained with SS. Combining the analysis of DB and of SS enables to optimize the selection of trastuzumab-eligible patients in case of metastatic relapse, especially in patients previously treated with NAC. [Table: see text]
A validated miRNA expression profile for response to neoadjuvant therapy in esophageal cancer.
Authors: Skinner Heath D. , Xu Enping , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Suzuki Akihiro , Hofstetter Wayne Lewis , Komaki Ritsuko , Ajani Jaffer A. , Wu Xifeng
Published: March 2020

4078

Background: For patients with esophageal adenocarcinoma (EAC) preoperative chemoradiation (trimodality therapy) is the preferred approach. We examined several patient cohorts to create and validate a miRNA signature predictive for response to this therapy in esophageal carcinoma. Methods: Pre-treatment tumor specimens from 10 patients with EAC treated with trimodality therapy were examined using a TaqMan Human MicroRNA Card Set (v3.0) for expression of 754 miRNAs, of which 306 were overexpressed. miRNA expression between patients with a pathologic complete response (pCR) and those with a non-pCR was then analyzed. 44 miRNAs differentially expressed between pCR and non-pCR patients were then examined in an additional 42 EAC patientsÕ tumors (model set) using the Fluodigm 48.48 Dynamic Array and were used to generate a miRNA expression profile (MEP) predicting for response in three groups: low, intermediate and high-risk. The MEP was then validated in an additional 72 EAC patients using the Illumina miRNA Expression Array. ROC curves were generated for clinical stage, MEP and a combination of both. Results: For the model set, pCR rates in low risk patients based on the MEP were 75%, 42.9% in intermediate risk and 12.5% in high-risk patients (ptrend=0.008). In the validation set the pCR rates were 66.7%, 36.5% and 15.7% for low, intermediate and high-risk patients respectively (ptrend=0.025). The AUC for the ROC using the MEP was 0.72 (p=7.8x10-12) in the model set, 0.69 (p=1x10-4) in the validation set and 0.7 for the two cohorts combined (p=1.4x10-18). When clinical stage was added to the predictive model, the ROC for each group was 0.79 (p=2.6x10-19), 0.75 (p=8.7x10-27) and 0.77 (p=2x10-41) respectively. Conclusions: The MEP represents the first validated miRNA signature for therapeutic response in esophageal carcinoma and improves significantly on clinical staging. Its use could select patients at high-risk for therapeutic resistance for trial-based therapy, as well as low-risk patients for whom resection may possibly be safely omitted.
A phase II clinical trial of ganetespib (STA-9090) in previously treated patients with advanced esophagogastric cancers.
Authors: Kwak Eunice Lee , Goyal Lipika , Abrams Thomas Adam , Carpenter Amanda , Wolpin Brian M. , Wadlow Raymond Couric , Allen Jill N. , Heist Rebecca Suk , McCleary Nadine Jackson , Chan Jennifer A. , Goessling Wolfram , Schrag Deborah , Evans Colleen , Ng Kimmie , Enzinger Peter C. , Ryan David P.
Published: March 2020

4090

Background: Subsets of esophagogastric (EG) cancers harbor genetic abnormalities, including amplification of HER2 or MET, or mutations in PIK3CA, EGFR, or BRAF. These genes encode clients of the molecular chaperone heat-shock protein 90 (HSP90), and inhibition of HSP90 may promote the degradation of these oncogenic signaling proteins. Ganetespib is a novel triazolone heterocyclic inhibitor of HSP90 that is a biologically rational treatment strategy for advanced EG cancers. Methods: This was a multicenter, single-arm Phase 2 trial. Eligibility: Histologically confirmed advanced EG cancer; progression on ≤ 2 lines of systemic therapy; ECOG PS 0-1. Treatment: Ganetespib 200mg/m2IV on Days 1, 8, and 15 of a 28-day cycle. Primary endpoint: overall response rate (ORR). Results: 26/28 patients enrolled received ≥ 1 dose of drug. The characteristics of the 26 patients were: male 77%, median age 64 years old; ECOG PS 0/1 42/58%; median number of prior therapies 2; esophageal/GEJ/gastric 27/42/31%; prior platinum 92%, prior fluoropyrimidine 88%, prior taxane 38%, prior trastuzumab 15%. Median follow-up was 83 days. The most common drug-related adverse events were: diarrhea (77%), fatigue (65%), elevated ALKP (42%), and elevated AST (38%). The most common Grade 3/4 AEs included: leucopenia (12%), fatigue (12%), diarrhea (8%), and elevated ALKP (8%). 14/26 required ≥ 1 dose modification. 22/26 patients completed at least 2 cycles of ganetespib and were evaluable for response. One complete response was seen, and this patient continues on treatment as of cycle 31 (27.5 mos). Molecular characterization of this patient’s tumor revealed a KRAS mutation in codon 12. The ORR was 1/26 (4%). Two of six patients with HER2-positive disease achieved 12% and 19% tumor reduction from baseline, respectively. TTP was 48 days (1.6 mos) and OS was 83 days (2.8 mos). Conclusions: Ganetespib showed manageable toxicity. While the study was terminated early due to insufficient evidence of single agent activity, the durable CR and 2 minor responses suggest that there may be a subset of EG patients who could benefit from this drug. The molecular determinants of response, however, have yet to be fully characterized. Clinical trial information: CT01167114.
Natural history of malignant bone disease in gastric cancer: Final results of a multicenter bone metastasis survey.
Authors: Silvestris Nicola , Pantano Francesco , Ibrahim Toni , Gamucci Teresa , De Vita Fernando , Pedrazzoli Paolo , Barni Sandro , Maiello Evaristo , Numico Gianmauro , Catalano Vincenzo , Berardi Rossana , Di Costanzo Francesco , Cinieri Saverio , Russo Antonio , Brunetti Anna Elisabetta , Santini Daniele
Published: March 2020

4091

Background: Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC) as disease-related survival improves. In literature few data on the natural history of bone disease in this malignancy are available. Methods: A retrospective, observational multicenter study aimed to define the natural history of GC patients with bone metastasis was conducted in 22 Italian hospital centres in which these patients received diagnosis and treatment of disease from 1998 to 2011. Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. Results: Median time to bone metastasis was 8 months (CI 95%, 6.125–9.875 months) considering all included patients. Median number of SREs/patient was one; less than half of the patients (31%) experienced at least one event and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid (ZOL) before the first SRE, median time to its appearance was significantly prolonged compared to control (7 months vs 4 months for control; P:0.0005). Conclusions: To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Furthermore, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis.
The association of objective response and overall survival in patients with inoperable or metastatic gastric and esophagogastric junction (EGJ) cancer: A pooled analysis of individual patient data from first-line clinical trials.
Authors: Bolt Toki Anna , Pauligk Claudia , Werner Dominique , Mayer Frank , Hofheinz Ralf Dieter , Homann Nils , Luley Kim , Al-Batran Salah-Eddin
Published: March 2020

4095

Background: The aim of the study is to determine whether the achievement of an objective response to first-line chemotherapy is prognostic of patient’s outcome in gastric/EGJ adenocarcinoma. Methods: Individual patient (pts) data from prospective first-line trials conducted by a single study group were used. Patients received platin/5-FU based chemotherapy with or without docetaxel. Responses were evaluated according to WHO criteria in all trials. Response data, patients’ characteristics (age, sex, entity, histological type, primary location, ECOG PS, and type and number of metastatic sites), type of chemotherapy, and overall survival data were analyzed. Results: 612 pts were included. Median age was 66 yrs; 31.5% had ECOG status 0, 58.3% ECOG 1, and 9.8% ECOG 2 & 3. Gastric primaries were found in 44.4% and EGJ in 35.8% of pts (19.7% were overlapping/not evaluable). According to Lauren classification, 36.8% had intestinal, 32.4% diffuse, and 8.5% mixed types (22.4% were not classifiable). 64.5% had positive non-regional lymph nodes (LN) involvement, 14.1% LN involvement without other metastases, 33.3% had peritoneal carcinomatosis, 44.0% liver and 16.7% lung metastases. Response rates were complete (CR) in 3.1%, partial (PR) in 36.4%, stable disease (SD) in 34.5%, and progressive disease (PD) in 15.0% pts (10.9% were not evaluable). Overall response rate (OR; CR + PR) was 39.5%. Median overall survival times in pts with CR vs PR vs SD vs PD were 37.9 vs 14.7 vs 10.9 vs 5.2 months, respectively; p=1.26 x 10-33). OR (CR or PR) also strongly predicted OS (16.7 vs 8.1 months in pts with vs no OR, p=1.08 x 10-17). OR remained the strongest predictor of OS in the multivariate analysis (p=6.55 x 10-7) including all baseline criteria mentioned above followed by ECOG PS (p=0.048) and the presence of non-regional LN as the only site of metastasis (p=0.034). Conclusions: The achievement of an objective response is the strongest predictor of survival in pts with gastric and EGJ cancer and could serve as a surrogate marker if validated.
Concurrent chemoradiotherapy with cetuximab plus twice-weekly paclitaxel and cisplatin followed by esophagectomy for locally advanced esophageal squamous cell carcinoma.
Authors: Lin Chia-Chi J. , Hsu Chih-Hung , Cheng Jason C. , Yen Chueh-Chuan , Shiah Her-Shyong , Huang Ta-Chen , Chen Wei-Wu , Wang Hsiu-Po , Yeh Kun-Huei , Lee Jang-Ming , Cheng Ann-Lii
Published: March 2020

4099

Background: We investigated the efficacy and safety of adding cetuximab to twice-weekly paclitaxel/cisplatin-based concurrent chemoradiotherapy (CCRT), followed by surgery, for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients with locally advanced ESCC (T3N0-1M0 or T1-3N1M0 or M1a by AJCC 2002) were treated with paclitaxel (35 mg/m2 1 h D1, 4/wk), cisplatin (15 mg/m2 1 h D2, 5/wk), cetuximab (400 mg/m2 2 h D-5, then 250 mg/m21 h D3/wk) and radiotherapy (2 Gy D1-5/wk). The feasibility of esophagectomy was evaluated for all patients at the accumulated radiation dose of 40 Gy. If esophagectomy was not feasible, CCRT was continued to a radiation dose of 60-66 Gy. Results: 66 patients were enrolled between Oct 2008 and Jun 2010, and 61 (94%) of them had T3N1M0 or M1a tumors by endoscopic ultrasonographic staging. All patients received CCRT to 40 Gy. Forty-three patients underwent surgery, and 17 patients continued definitive CCRT to 60-66 Gy. Of the scheduled doses of paclitaxel, cisplatin, and cetuximab, 80%, 79%, and 99% were given, respectively. The most common grade 3/4 toxic effects were leukopenia (51%), neutropenia (15%), esophagitis (19%), and infection (12%). The pathological complete response rate was 24% (intent-to-treat, 16/66) (95% confidence interval: 13-35%) and 37% (who underwent resection, 16/43). At the median follow-up of 34.6 months, the median progression-free (PFS) and overall survivals were 21.6 and 33.9 months, respectively. No KRAS codon 12/13 mutations were identified in 47 tumor samples. The median PFS for patients with two, one, and no adverse tumor biomarkers (Tau+, ERCC1+, pEGFR-) (n = 40) was 12.3 months, 27.6 months, and greater than 33.6 months, respectively (p = .087). Conclusions: Adding cetuximab to twice-weekly paclitaxel/cisplatin-based CCRT prior to esophagectomy is an active and tolerable treatment for locally advanced ESCC. Clinical trial information: NCT01034189. [Table: see text]
Concordance of HER2 and its related molecules between primary and paired liver metastatic sites in gastric cancer.
Authors: Shinozaki Eiji , Yamamoto Noriko , Saiura Akio , Sano Takeshi , Chin Keisho , Ogura Mariko , Matsusaka Satoshi , Suenaga Mitsukuni , Ozaka Masato , Mizunuma Nobuyuki
Published: March 2020

4108

Background: Trastuzumab is the 1st molecular targeting drug in HER2-positive advanced gastric cancer that has been shown to confer overall survival benefit adding to chemotherapy. In breast cancer it has been already used long time, it is known that there are the discordance of its target; HER2 between primary and metastatic site. Although molecular targeting drugs as Trastuzumab are expected to control the metastatic disease, molecular status is usually evaluated in the primary site because metastatic sites are difficult to biopsy. In this study we attempted to compare HER2 and its related molecular status, which have interaction each together, between primary and paired liver metastatic sites in gastric cancer. Methods: Total 58 consecutive cases with gastric cancer who underwent surgical resection of primary site and synchronous or metachronous liver metastasis were examined. HER2, EGFR, c-MET and IGF-1R status were evaluated by immunohistochemistry(IHC) in primary and paired liver metastasis. HER2 expression by IHC using HercepTest (DAKO) were assessed according to Gastric Cancer Scoring System. On the other molecular expression by IHC, positive expression was defined as 25% or more staining with intensity 2 or 3+. We analyzed the concordance of their expression in both sites. Results: The patient cohort consists predominantly of male (78%), with Lauren’s diffuse (37%) and intestinal tumors (62%). Fifty three percent of cases were synchronous liver metastasis. The positive rate of primary and paired liver metastatic sites were 10.3%, 8.6% in HER2, 1.7%, 5.1% in EGFR, 44.8%, 31.0% in c-MET and 31.0%, 29.3% in IGF-1R. The concordance between primary and paired liver metastatic sites were 91.3%, 93.1%, 75.8%, and 70.6%, respectively. Conclusions: Our data suggested that in HER2 and EGFR the concordance between primary and metastatic site were high, other hands the concordance of c-MET and IGF-1R were relatively low. It might be necessary to rebiopsy to estimate the expression of c-MET and IGF-1R in gastric cancer.
A phase II study of perioperative S-1 combined with weekly docetaxel in patients with locally advanced gastric cancer: Clinical and pharmacogenetic results.
Authors: Park Sook Ryun , Kim Young Woo , Ryu Keun Won , Lim Hyeong-Seok , Lee Jun Ho , Kong Sun-Young , Kim Mi-Jung , Choi Mihee , Park Young Iee
Published: March 2020

4114

Background: We conducted a phase II study to evaluate the efficacy and safety of perioperative S-1 + docetaxel (DS) in locally advanced gastric cancer (LAGC), and to investigate the association between CYP2A6 genotypes and treatment outcomes. Methods: Eligibility criteria included 18-70 yrs, PS 0-1, measurable lesion(s), and LAGC (clinical stage III-IV (M0) by Japanese staging system). Pts were given each 3 cycles of pre- and post-operative chemotherapy (S-1 40 mg/m2 bid on D1-14, docetaxel 35 mg/m2iv on D1, 8 q 3 wks), and underwent surgery (≥D2). Results: From Oct 2006 to June 2008, 44 pts entered into the study, and 43 pts were eligible. Median age=53 yrs (range, 33-69); PS 0/1=2/41; M/F=29/14; and stage IIIA/IIIB/IV (M0)=20/18/5. All 43 eligible pts completed preoperative DS and 40 pts (93%) completed postoperative DS. The most common G3/4 toxicities during pre- and post-operative DS were neutropenia (28% vs. 65%), stomatitis (19% vs. 5%), and abdominal pain (5% vs. 18%). The clinical response rate was 74.4% (95% CI, 61.4-87.4%) with 1 CR (2.3%) and 31 (72.1%) PRs. R0 resection rate was 97.7%, major pathologic response rate was 48.8% with 1 CR, and pathologic stage was 0/1/2/3/4 (%) = 2.3/44.2/20.9/20.9/11.6. With a median follow-up of 66.6 months, 3-yr PFS and 5-yr OS was 62.8% and 69.6%, respectively. Survival differed according to clinical response, clinical downstaging, and CYP2A6 genotypes (Table). Pts with two CYP2A6 variant alleles (V/V) had higher Cmax (27.7±4.6 vs. 20.3±1.2; p=0.045) and AUCinf (220.4±43.1 vs. 172.5±12.5; p=0.187) of tegafur, and lower Cmax (1.4±0.2 vs. 1.8±0.1; p=0.178) and AUCinf (8.4±1.2 vs. 9.7±0.5; p=0.308) of 5-FU than those with no or one variant allele (W/W or W/V). Conclusions: DS is active with a manageable toxicity profile in the perioperative setting in pts with LAGC. CYP2A6 genotype may be predictive of efficacy (S-1 and docetaxel was provided by JEIL Pharm. Co., Ltd. and sanofi-aventis Korea Co., Ltd., respectively). Clinical trial information: NCT00587145. [Table: see text]
A multitranscript blood neuroendocrine tumor molecular signature to identify treatment efficacy and disease progress.
Authors: Modlin Irvin M. , Drozdov Ignat , Kidd Mark S.
Published: March 2020

4137

Background: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) or NETs (also called “carcinoids”) are problematic since they present with advanced disease and have limited treatment options. Imaging has proved to be insensitive in identifying treatment effect. Similarly, the currently used biomarker, a neurosectory peptide, Chromogranin A (CgA) is of limited value as a predictor of treatment efficacy. We have developed a multi-transcript (n=51 genes) molecular signature for PCR-based blood analysis which exhibits a high sensitivity (85-98%), specificity (93-97%), positive predictive value (95-96%) and negative predictive value (87-98%) for the identification of GEP-NENs. This test significantly outperforms (p<0005) plasma CgA (measured by ELISA). Methods: The candidate gene signature was examined by a 2-step PCR method in a training set of 130 blood samples (GEP-NENs: n=63, treatment-naïve (n=28)) and validated in an independent set ([n=182, GEP-NENs: n=133, including complete remission (n=4), clinically stable disease (n=82) and non-responders/clinically progressive disease (n=47). Results: The PCR score was significantly elevated (p<0.0001) in the treatment-naïve group compared to treated GEP-NENs, while levels were significantly reduced (p<0.004) in 11 matched samples (pre- and post-treatment – surgical removal (n=10), RFA (n=1)). In the independent set, the scores for complete remission were not different to controls (0.5±0.25 vs. 0.4±0.16), while scores for stable disease (0.63±0.12) were significantly lower than for non-responders (5.85±0.34, p<0.002). Stable disease could be differentiated from clinically progressive disease since the latter exhibited a high score (85% vs. 10%, p<0.0001). The performance metrics for differentiation were: sensitivity (91%), specificity (91%), PPV (86%), NPV (95%). Conclusions: This study demonstrated that the multi-transcript molecular signature is both sensitive and specific for the detection of neuroendocrine tumor disease and is capable of differentiating clinically stable from progressive disease. It therefore has potential utility as a measure for monitoring treatment efficacy for GEP-NENs.
Open-label, phase IIIb, multicenter, expanded access study of everolimus in patients with advanced neuroendocrine tumors (NET).
Authors: Bechter Oliver Edgar , Unger Nicole , Borbath Ivan , Ricci Sergio , Hwang Tsann-Long , Park Young Suk , Tomasek Jiri , Raef Hussein , Laohavinij Sudsawat , JeanLouis Lisa , Panneerselvam Ashok , Saletan Stephen , Stergiopoulos Sotirios G. , Pavel Marianne E.
Published: March 2020

4138

Background: Everolimus (EVE) antitumor efficacy in patients (pts) with advanced NET was demonstrated in 2 double-blind, placebo (P)–controlled, phase III trials (RADIANT-2 and RADIANT-3). Median PFS in pancreatic (pNET) pts was 11.0 months (EVE) vs. 4.6 months (P) (HR 0.35, 95% CI 0.27-0.45, P <0.001) in RADIANT-3. Median EVE exposure in RADIANT-3 was 38 wks. EVE was approved for advanced pNET in the US and Europe in 2011. An expanded access protocol was launched to gather additional safety data and provide access to EVE for pts with advanced NET while awaiting regulatory approval. Methods: Pts aged ≥18 years with biopsy-proven NET; WHO performance status 0-2; and adequate bone, hepatic, and renal function were enrolled. Main exclusion criteria were poorly differentiated NET and cytotoxic therapy within 4 wks of enrollment. EVE (10 mg/d) was administered until disease progression, unacceptable toxicity, discontinuation, death, commercial availability of EVE, or until May 30, 2012. Pts were enrolled from April 21, 2011 to April 20, 2012. Primary objective was grade 3/4 and serious adverse events (AEs). Secondary objectives included investigator-assessed best overall response rate and PFS. Results: The full analysis set included 246 pts (pNET, n=126; non-pNET, n=120); the safety set included 240 pts (pNET, n=123; non-pNET, n=117). Median age was 61 and 66 years; 54% and 49% were male. Main primary tumor sites in non-pNET pts included small intestine (40%) and lung (22%). Median duration of EVE exposure was 12.1 wks and 24 wks in pNET and non-pNET. At data cutoff, there were 21 and 32 PFS events; 105 and 88 pts were censored. Grade 3/4 AEs were reported in 42.3% and 69.2% of pNET and non-pNET; those reported in ≥10% of pts in pNET and non-pNET included hyperglycemia (12.2% and 5.1%), diarrhea (10.6% and 31.6%), stomatitis (9.8% and 11.1%), nausea (8.1% and 10.3%), and anemia (5.7% and 11.1%). Median investigator-assessed PFS was 7.6 (95% CI 5.52-7.62) months and 10.8 (8.77-Not Estimable) months in pNET and non-pNET. Conclusions: EVE was well tolerated in pts with advanced NET. AEs were similar to those previously reported. Protocol-specified early termination of pts limits the interpretation of PFS medians. Clinical trial information: EudraCT Number: 2010-023032-17.
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC).
Authors: Cho Daniel C. , Sosman Jeffrey Alan , Sznol Mario , Gordon Michael S. , Hollebecque Antoine , Hamid Omid , McDermott David F. , Delord Jean-Pierre , Rhee Ina Park , Mokatrin Ahmad , Kowanetz Marcin , Funke Roel Peter , Fine Gregg Daniel , Powles Thomas
Published: March 2020

4505

Background: Human RCC expresses PD-L1 and has been shown to respond to immune-based therapy. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: Pts with mRCC received MPDL3280A administered IV q3w at doses between 3-20 mg/kg in a Phase I expansion study. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1. Results: As of Jan 10, 2013, 53 RCC pts were evaluable for safety and treated at doses of 3 (n=2), 10 (n=12), 15 (n=18) and 20 mg/kg (n=21). These pts had a median age of 62 y (range 33-79 y), 100% were PS 0-1 and all had had prior surgery. 83% of pts had received prior systemic therapy; 38% received immunotherapy, 57% received TKIs and 36% received anti-angiogenic therapy. Pts received treatment with MPDL3280A for a median duration of 190 days (range 21-317). The incidence of G3/4 AEs in RCC pts was 43%, regardless of attribution, with hypophosphatemia, fatigue, dyspnea and hyperglycemia (all 4%) being the most common. 13% of G3/4 AEs were attributable to study drug. 1 case of myasthenia gravis was observed in a pt who was retrospectively found to have anti-acetylcholine receptor antibodies prior to starting therapy. No G3-5 pneumonitis or diarrhea was reported. No treatment-related deaths occurred. 39 RCC pts enrolled prior to Jul 1, 2012, were evaluable for efficacy. RECIST responses, including CR, were observed across dose levels, with all responses ongoing at the time of data cutoff. Some RCC pts experienced prolonged SD prior to experiencing RECIST response. The 24-week PFS was 50%. Analysis of biomarker data from mandatory archival tumors demonstrated a correlation between PD-L1 status and efficacy. In addition, response correlated with low IL-17 expression in tumor tissue. Updated data will be presented. Conclusions: MPDL3280A was well tolerated, with no pneumonitis-related deaths. PD-L1–positive status correlates with response to MPDL3280A. Durable responses have been observed in RCC pts treated with MPDL3280A and further study is warranted. Clinical trial information: NCT01375842.
Phase II efficacy and safety study of nintedanib versus sunitinib in previously untreated renal cell carcinoma (RCC) patients.
Authors: Eisen Tim , Shparyk Yaroslav , Jones Robert , MacLeod Nicholas James , Temple Graham , Finnigan Helen , Kaiser Rolf , Studeny Matus , Loembe Arsene Bienvenu , Bondarenko Igor
Published: March 2020

4506

Background: Sunitinib (S) is established as a standard first-line therapy for patients (pts) with advanced RCC. However, treatment can be limited by the occurrence of drug-related adverse events (AEs). This Phase II study assessed the efficacy and safety of nintedanib (N) – a potent, triple angiokinase inhibitor of VEGFR-1–3, PDGFR-α/β, and FGFR-1–3, as well as RET and Flt3 – vs S in previously untreated pts with RCC. Methods: Ninety-nine eligible pts (96 of whom were treated) with advanced, unresectable/recurrent clear cell RCC, an ECOG performance status of 0–1, and no prior systemic therapy were randomized 2:1 to receive N 200 mg twice daily (n=64; given in 4-week cycles) or S 50 mg once daily (n=32; 4 weeks on, 2 weeks off schedule). Treatment continued until disease progression or unacceptable drug-related AEs. Primary endpoints were progression-free survival at 9 months (PFS-9) and, in N-treated pts only, QTc interval change (baseline to day 15). Secondary endpoints included PFS, objective response rate (ORR; RECIST 1.1), overall survival (OS), time to progression (TTP), time to treatment failure (TTF), and AEs. Results: Baseline characteristics were balanced between the arms. PFS-9 was not statistically significantly different between N- and S-treated pts (43 vs 45%; p=0.85). There were also no statistically significant differences between N and S with regard to PFS (median: 8.44 vs 8.38 mo; hazard ratio: 1.16; 95% CI: 0.71–1.89; p=0.56), confirmed ORR (18.8 vs 31.3%; p=0.19), OS (median: 20.37 vs 21.22 mo; p=0.63), TTP (median: 8.48 vs 8.54 mo; p=0.52), and TTF (median: 8.41 vs 8.36 mo; p=0.46). Grade ≥3 AEs occurred in 47% of N-treated pts and 56% of S-treated pts. Common AEs (all grades; N vs S) included diarrhea (61 vs 50%), nausea (38 vs 34%), fatigue (both 25%), and vomiting (16 vs 22%). Dermatologic AEs (8 vs 47%) were less frequent with N than S. There was no increase from baseline in QTc >60 ms on days 1 or 15 in N-treated pts, and there was no relationship between N exposure and QT interval change. Conclusions: N demonstrated similar efficacy to S and had a manageable safety profile, including a lower incidence of dermatologic AEs vs S. In addition, N was not associated with QT prolongation. Clinical trial information: NCT01024920.
Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term patient follow-up.
Authors: Drake Charles G. , McDermott David F. , Sznol Mario , Choueiri Toni K. , Kluger Harriet M. , Powderly John D. , Smith David C. , Sankar Vindira , Gutierrez Andres A. , Wigginton Jon M. , Kollia Georgia , Gupta Ashok Kumar , Atkins Michael B.
Published: March 2020

4514

Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation. PD-L1, a PD-1 ligand, has been associated with poor prognosis in mRCC pts. In a phase I study of nivolumab, a PD-1 receptor blocking antibody, in pts with previously treated mRCC and other solid tumors, an MTD was not reached at 10 mg/kg IV Q2WK. Cohorts of mRCC pts were expanded at the 1 and 10 mg/kg dose levels. Methods: Pts received nivolumab for ≤12 cycles (4 doses/cycle) until unacceptable toxicity, progression, or complete response. We report overall survival (OS), updated response data, and long-term safety for the mRCC cohorts from a data analysis in July 2012. Results: 34 pts with mRCC were treated at 1 mg/kg (n=18) or 10 mg/kg (n=16). 44% of pts had received ≥3 prior therapies (74% prior antiangiogenic therapy; 59% prior immunotherapy). Median OS across doses has not yet been reached. Median duration of response was 12.9 months for both doses with 5 of the 10 responses lasting ≥1 year. The incidence of grade 3-4 related adverse events for the RCC cohort was 21% and included hypophosphatemia (6%) and respiratory disorders (6%), with no confirmed-drug related deaths or grade 3 pneumonitis. Treatment discontinuation due to drug-related AEs occurred in 18/304 (6%) of patients in the overall treated population. Conclusions: Nivolumab produced durable survival and responses in a subset of heavily pretreated mRCC pts, with an acceptable safety profile, even after long term continuous dosing. Overall survival appears promising for this population of pts. These findings provide the basis for an ongoing randomized phase III trial of nivolumab in mRCC (NCT01668784). Follow-up data through a February 2013 cutoff is being collected. Clinical trial information: NCT00730639. [Table: see text]
A validated 34-gene signature for assessing risk of recurrence in clear cell renal cell carcinoma.
Authors: Rathmell Kimryn , Brooks Samira A , Brannon Angela Rose , Parker Joel S , Fisher Jennifer C , Sen Oishee , Nielsen Matthew Edward
Published: March 2020

4522

Background: The objective of this study is to create a molecular tool that can be applied widely to clinical specimens using existing transcript signatures for use in clinical risk prediction of clear cell Renal Cell Carcinoma (ccRCC) to improve personalized disease management. Methods: We developed a 34-gene subtype predictor to classify clear cell tumors according to two subtypes, clear cell A (ccA) or B (ccB). The training set consisted of 72 ccRCC microarray-analyzed tumor samples that had previously been classified by unsupervised clustering and logical analysis of data (LAD). The predictor was developed from a panel of genes significantly expressed in ccA and ccB tumors and associated with prognosis. The prognostic value of the algorithm was corroborated in RNA-sequencing data from 379 ccRCC samples from The Cancer Genome Atlas (TCGA) and further validated using the NanoString platform with a cohort of 163 archival fixed samples collected at the University of North Carolina. Results: Risk associated molecular subtypes, ccA and ccB, were classified in TCGA and NanoString cohorts. Subtype classification showed significant prognostic outcomes for overall survival (p<.001), cancer-specific survival (p=.003), and recurrence-free survival (p<.05) and remained significant in multivariate analyses that included age at diagnosis, gender, ethnicity, pathologic stage, and histologic grade. A prognostic model was built for overall and recurrence-free survival for non-metastatic ccRCC patients within the context of subtype and clinical characteristics. Conclusions: The ccA and ccB subtypes significantly added prognostic information to clinical parameters, particularly for non-metastatic ccRCC patients.The subtypes can be used for future analyses involving risk for developing metastatic disease and cancer-specific outcomes. This research was supported with a grant from the American Association for Cancer Research, and the UNC Lineberger Comprehensive Cancer Center Cancer Cell Biology Training Grant.
Association of IGF1R overexpression (OE) with outcome in invasive urothelial carcinoma (UC) of urinary bladder.
Authors: Gonzalez-Ribbon Nilda , Kim Jenny J. , Chaux Alcides , Munari Enrico , Faraj Shiela F. , Ellis Carla , Sharma Rajni , Bivalacqua Trinity , Schoenberg Mark , Carducci Michael Anthony , Netto George J.
Published: March 2020

4523

Background: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation. IGF1R is overexpressed in several tumors including UC and is currently under investigation as a target of Rx. We here explore IGF1R expression in UC, its association with clinicopathologic parameters and prognostic role. Methods: Fivetissue microarrays (TMA) were constructed from 100 cystectomy specimens performed for invasive UC at our institution (1994 to 2007). Formalin-fixed paraffin-embedded paired tumor and benign samples were spotted 3-4 times each. Membranous IGF1R staining was evaluated using immunohistochemistry (G11, Ventana Medical Systems). A scoring method analogous to that of Her2 expression in breast cancer was used and the highest score was assigned to each tumor. IGF1R was considered overexpressed in cases with score 1. Endpoints of the study included overall survival (OS) and disease-specific survival (DSS). Patients were followed-up for a median of 33.5 months (range 1, 141 months). Results: IGF1R OE was found in 62% of UC. No differences were noted between normal urothelium and UC regarding IGF1R OE (74% vs. 60%; P=0.14). IGFR1 OE was more frequent in tumors from African-American patients compared to Caucasians (100% vs. 59%, P=0.04). Tumors at stage pT4 overexpressed IGF1R more frequently than tumors at stages pT1-pT3 (71% vs. 29%, P=0.005). No association with other analyzed clinicopathologic parameters such as patient's age or gender, muscularis propria invasion, or lymph node metastasis) was found. OS and disease-specific survival (DSS) rates were 58% and 69%, respectively. Patients with tumors overexpressing IGF1R had a lower OS and DSS compared to those without IGF1R OE (Mantel-Cox P=0.0007 and P=0.006, respectively). Using Cox proportional hazards regression, IGF1R OE remained a significant predictor of OS (HR=3.49, P=0.001) and DSS (HR=3.54, P=0.007) after adjusting for pathologic stage. Conclusions: OE of IGF1R was found in 62% of UC. High stage tumors overexpressed IGF1R more frequently than low stage tumors. Further, IGF1R OE was a significant independent predictor of OS and DSS in invasive UC.
Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS).
Authors: Qu Angela Q. , Jacobus Susanna J. , Signoretti Sabina , Stack Edward C. , Krajewski Katherine Maragaret , Rosenberg Jonathan E. , Choueiri Toni K.
Published: March 2020

4530

Background: Neoadjuvant (NA) ddMVAC in patients (pts) with MI-UC is associated with significant pathologic response (PaR) and radiologic response (RaR). We examined the frequency of PaR and RaR as well as the level of serum and tissue biomarkers in correlation with DFS. Methods: Pts treated on phase II prospective study of NA ddMVAC (4 cycles) in MI-UC were evaluated for RaR (at least >50% decrease in the primary tumor and nodes after chemotherapy, with delayed enhancement of residual disease) and PaR (p<T1N0M0). Elevated serum tumor markers (CA125, C19-9 and ßHCG) at baseline and Day 1 of each cycle were documented. Expression level of baseline DNA ERCC1 protein in tumor biopsy tissues was determined by immunohistochemistry based on H-score <0.1 (negative) vs. >0.1 (positive). Fisher’s Exact test was used to evaluate association with response. Post-surgery DFS was estimated by the Kaplan-Meier method and compared between response and biomarker groups using the logrank test. Results: Of 39 pts (cT2:42%, cT3:42%, cT4:16%, and cN1:45%), 49% (90% CI 35-63) experienced PaR, and 62% (90% CI 47-75) achieved RaR after ddMVAC chemotherapy. Pts who achieved PaR experienced a DFS advantage, with 18-month DFS of 78% (95% CI 47-92) vs. 48% (95% CI 18-74) in those who did not (p=0.146). Those achieving RaR had a significantly longer DFS (p=0.006), with 18-month DFS of 87% (95% CI 57-97) vs. 29% (95% CI 5-60) in those who did not. Among 10 pts with any elevated serum tumor marker at baseline, only 2 pts showed normalization, both without a PaR. ERCC1(+) tumors were not associated with PaR, pT0 or RaR. DFS by ERCC1status was inconclusive due to limited sample size. 18-month DFS was 91% (95% CI 51-99) in ERCC1(+) tumors vs. 63% (95% CI 29-85) in ERCC1(-) tumors. Conclusions: ddMVAC achieves significant PaR and RaR in MI-UC pts that translates into a post-surgery DFS advantage. ERCC1(+) was not associated with response. More effective biomarkers of platinum response are needed to select pts most likely to benefit from NA therapy. Clinical trial information: NCT00808639.
Germ cell cancer (GCC): Long-term survival after treatment with bleomycin (B), etoposide (E), and cisplatin (P) in a large cohort.
Authors: Gundgaard Maria Gry , Lauritsen Jakob , Mortensen Mette Sakso , Agerbaek Mads , Holm Niels Vilstrup , Dalton Susanne O. , Johansen Christoffer , Daugaard Gedske
Published: March 2020

4533

Background: In 1997 the International Germ Cell Cancer Collaborative Group presented a classification dividing patients into a good, intermediate, and poor prognostic group for metastatic GCC with 5-year survival information. However, only a minor part of these patients were treated with today’s standard treatment. We present the first nationwide and population based study of overall survival (OS) and disease specific survival (DSS) in a large cohort of GCC patients treated with BEP. Methods: A nationwide and population based clinical database covering GCC patients diagnosed 1984-2007 was constructed, including 4,683 GCC cases. Through merging with national administrative registers, information on vital status and cause of death for all patients until November 30, 2012, was obtained. Results: The 5-year OS for the whole database cohort was 96%. A total of 1,584 patients were treated with BEP (1,099 patients with primary metastatic disease, 485 patients relapsed from stage I). Until 2001, the standard treatment was 4 cycles of BEP, after 2001 patients with good prognosis had 3 cycles of BEP. Overall survival (OS) and disease specific survival (DSS) with 95% confidence intervals (95% CI) (Table), median observation time was 13.8 years. Conclusions: This cohort study showed improved OS for GCC patients across all prognostic groups since 1997, in particular regarding the poor prognostic group. The present result is based on a large number of cases established in a population based fashion, with long follow up time and unbiased information covering all cohort members including detailed clinical information and vital status of all patients. [Table: see text]
Does chemotherapy improve survival in muscle-invasive bladder cancer (MIBC)? A systematic review and meta-analysis (MA) of randomized controlled trials (RCT).
Authors: Tjokrowidjaja Angelina , Lee Chee , Stockler Martin R.
Published: March 2020

4544

Background: There is strong evidence that neoadjuvant chemotherapy improves survival in MIBC but its uptake in clinical practice is variable. The benefits of adjuvant chemotherapy are controversial, especially with the recent presentation of 3 RCTs not included in previous MA.We sought to summarise the effects of chemotherapy, both neoadjuvant and adjuvant, on survival in MIBC. Methods: We included published summary data from recent MA and RCTs. Eligible RCTs compared the addition of chemotherapy, neoadjuvant or adjuvant, to local treatment versus local treatment alone. We searched CENTRAL, PubMed, MEDLINE, proceedings of ASCO and clinicaltrials.gov from 2004 to August 2012.The primary outcome was overall survival (OS). Disease-free survival (DFS) and adverse events (AE) were secondary outcomes. Pooled hazard ratios (HR), confidence intervals (CI) and p-values (p) were estimated with fixed effects model. Heterogeneity and subgroup effects were assessed with p-values for interaction. Results: We included 21 RCTs (n=3986), 12 of neoadjuvant (n=3047) and 9 adjuvant chemotherapy (n=939).The addition of chemotherapy significantly improved OS (HR 0.86, 95% CI 0.79 to 0.93, p=0.0004). Separate analyses of neoadjuvant therapy and adjuvant therapy yielded significant results in both subgroups (HR 0.89, 95% CI 0.81 to 0.98, p=0.02; HR 0.75, 95% CI 0.63 to 0.90, p=0.002; respectively; p-value for interaction 0.11). There were larger benefits in DFS (HR 0.77, 95% CI 0.71 to 0.84, p<0.000001), which were also noted with the addition of neoadjuvant and adjuvant therapy (HR 0.80 95% CI 0.73 to 0.88, p<0.00001; HR 0.67 95% CI 0.55 to 0.81, p<0.0001; respectively; p-value for interaction 0.10). The most common AE of grade 3 or 4 were haematological, gastrointestinal and renal impairment with median frequencies of 33%, 15% and 2% respectively in neoadjuvant; and 15%, 21% and 27% in adjuvant trials. Conclusions: Meta-analysis of available randomized trials indicates that chemotherapy, both adjuvant and neoadjuvant, improves survival in MIBC. A direct comparison of these two strategies in a large scale randomised trial is needed to determine which is optimal.
One course of adjuvant BEP in clinical stage I, nonseminoma: Mature and expanded results from the SWENOTECA group.
Authors: Tandstad Torgrim , Cavallin-Stahl Eva , Dahl Olav , Haugnes Hege Sagstuen , Langberg Carl Wilhelm , Laurell Anna , Stierner Ulrika K. , Solberg Arne , Wall Najme , Cohn-Cedermark Gabriella ,   SWENOTECA
Published: March 2020

4553

Background: The SWENOTECA group has since 1998 offered patients with clinical stage I (CSI) nonseminoma (NSGCT) treatment based on a risk-adapted approach. Patients with lymphovascular invasion (VASC+) were recommended one course of adjuvant chemotherapy (ACT) with bleomycin, etoposide and cisplatin (BEP). Patients without lymphovascular invasion (VASC-) had the choice between one course of adjuvant BEP or active surveillance. Methods: From 1998-2010, 491 patients with CSI NSGCT received one course of adjuvant BEP. Following histopathological evaluation 247 patients were classified as VASC+, 239 as VASC- and five patients had uncertain VASC status. All patients were included into a prospective, community-based, multicenter SWENOTECA management program. Initial results from patients treated during 1998-2005 have earlier been reported. We now report the mature data, expanded with patients treated during 2005-2010. Results: The median follow-up was 8.0 years. Eleven relapses were observed. After one course of adjuvant BEP 2.3% of patients relapsed. In regard to VASC status 3.4% of VASC+ and 1.3% of VASC- patients relapsed. The latest relapse was detected 3.3 years after ACT. Ten patients have died, only one due to testicular cancer. The 5 and 10-year overall survival rates were 98.9% and 96.8%, respectively. The 5 and 10-year disease-specific survival rates were 100% and 99.6% respectively. Conclusions: One course of adjuvant BEP reduces the risk of relapse in CSI NSGCT with over 90%. These mature results confirm our earlier results on one course of adjuvant BEP. There is no evidence of late relapses, or chemotherapy-resistance in relapses following ACT. To detect relapses, a follow-up of five years is sufficient.