bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical impact of first response evaluation (FRE) in metastatic colorectal cancer (mCRC) patients (pts) treated with a cetuximab-based regimen (C-R): Results of a mono-institutional experience.
Authors: Rojas Llimpe Fabiola Lorena , Di Fabio Francesca , Giaquinta Stefania , Pini Sara , Adua Daniela , Pinto Carmine
Published: March 2020

e14717

Background: Some reports suggest positive impact from early tumor shrinkage in progression-free survival (PFS) and overall survival (OS) in mCRC pts receiving C-R. The aim was to evaluate the clinical impact of FRE in mCRC pts treated with a C-R in first-line (1st-L) or after 1st-L. Methods: Between May 2004 and Dec. 2012, 73 pts referred to our institution. The FRE was assessed 8-10 wks after the start of treatment by a CT-scan according to RECIST criteria 1.0. At the time of FRE, pts who achieved CR/PR were considered as responders (resp), and SD/PD as non-responders (non-resp). Were included KRAS wild-type (KRAS-wt) and KRAS undefined tumors (KRAS-ud). PFS and OS are reported in months. Results: Pt characteristics: 51M (70%) and 22F (30%); median age 62(27-80) yrs; 59 colon (80.8%) and 14 rectum (19.2%); median number of metastatic sites 2 (1-5); synchronous mts 47 (64.4%), metachronous mts 26 (35.6%); 46 (63%) KRAS-wt, 27 (37%) KRAS-ud. Twenty-nine (39.7%) pts were treated with C-R in 1st-L (all KRAS-wt), and 44 (60.3%) after 1st-L (17 KRAS-wt, 27 KRAS-ud). C was combined with FOLFIRI in 36 (49.3%) pts, irinotecan in 36 (49.3%), and was alone 1 (1.4%). At the time of FRE 26(35.6%) pts were resp: 13 1st-L and 13 after 1st-L; 47 (64.4%) were non-resp: 16 (34%) 1st-L and 31 (66%) in after 1st-L. In pts treated as 1st-L, the PFS in resp vs non-resp was: 13 (95% CI 6-20) vs 5 (95% CI 4-5) (p=0.03); the OS was: 23 (95% CI 11-34) vs 11 (95% CI 9-13) (p=0.11). In pts treated after 1st-L the PFS in resp vs non-resp was: 13 (95% CI 8-18) vs 5 (95% CI 0.4-9) (p< 0.0001); the OS was: 17 (95% CI 12-21) vs 12 (95% CI 6-19) (p 0.67). In the KRAS-wt pts the PFS in resp vs non-resp was: 13 (95% CI 11-15) vs 5 (95% CI 4-6) (p 0.00); the OS was 23 (95% CI 16-30) vs 11 (95% CI 8-14) (p 0.02). In the KRAS-ud pts the PFS, in resp vs non-resp was: 9 (95% CI 0-20) vs 3 (95% CI 0-8) (p 0.00), the OS was: 18 (95% CI 1-36) vs 13 (95% CI 10-15) (p 0.03). A Cox regression model, including: sex, age, KRAS, line of therapy, FRE, skin rash grade, shows that the FRE was the main predictor of PFS (p<0.0001) and OS (p=0.011). Conclusions: The FRE seems to predict the clinical outcome in pts receiving C-R as 1st-L or after 1st-L.
Phase I/II trial of carbon-ion radiotherapy with concurrent gemcitabine for patients with locally advanced pancreatic cancer.
Authors: Shinoto Makoto , Yamada Shigeru , Yasuda Shigeo , Imada Hiroshi , Shioyama Yoshiyuki , Honda Hiroshi , Kamada Tadashi , Tsujii Hirohiko , Saisho Hiromitsu
Published: March 2020

e15008

Background: Carbon-ion radiotherapy (CIRT) offers the potential advantage of improved dose localization and enhanced biologic effect. The purpose of this trial was to establish the recommended dose of gemcitabine and CIRT, evaluating the tolerance and efficacy of gemcitabine combined with CIRT for the treatment of the patients with locally advanced pancreatic cancer. Methods: Patients with histopathologically proven, locally advanced pancreatic adenocarcinoma, which involved the celiac trunk or superior mesenteric artery without distant metastasis, were eligible for this trial. The radiation fractions were fixed at 12 fractions in 3 weeks, and the dose of gemcitabine and radiation were gradually increased. First, the dose was fixed at 43.2GyE/8 fractions and the gemcitabine dose was increased from 400, to 700 to 1000mg/m2. Subsequently, the gemcitabine dose was fixed at 1000mg/m2 and the radiation dose was increased from 43.2GyE to 55.2GyE by 5% increments. Gemcitabine was administered for 3 consecutive weeks, once a week. Results: Seventy-five patients were registered from April 2007 through February 2012. Of these patients, 71 were clinically eligible for the study. The most common Grade 3 acute toxicities were hematological toxicity (51%) and anorexia (8%). Dose limiting toxicity developed in three patients: Grade 3 gastric ulcer in 1 and Grade 4 leukopenia in 2. No other serious side effects were found. The two-year local control rate and two-year overall survival rate were 40% and 40% in all patients. The median survival time was 21 months. In the high dose group (n=47), in which patients were irradiated with at least 45.6 GyE, the two-year survival rate was 62%. Conclusions: CIRT was well tolerable even when concomitantly administered with the highest dose of gemcitabine (1000mg/m2).
What are NCI-designated cancer centers using for gastric and esophageal cancer HER2 testing?
Authors: Trosman Julia R. , Weldon Christine B. , Tsongalis Gregory J. , Schink Julian C. , Benson Al Bowen
Published: March 2020

e15010

Background: HER2 testing in gastric and esophageal cancers (GEC) is a new area with evolving research on which testing methods are best. Based on the ToGA trial, guidelines recommend IHC/reflex to FISH, but studies show effectiveness of other protocols as well (e.g. Yan et al, J Clin Pathol 2011). Our study provides a benchmark on practices for GEC HER2 testing at NCI Cancer Centers. Methods: We conducted an IRB approved web survey of 58 NCI cancer centers (pathologists and oncologists) providing adult GEC care. The survey included 14 questions on HER2 testing methods, reflex and retest practices and awareness of institutional lab accreditation. Results: The study achieved a response rate of 93% (54/58 sites). In this cohort, 41% (22/54) of sites conduct HER2 GEC tests using concurrent FISH and IHC methods. An IHC testing method with reflex to FISH is used at 39% (21/54) of sites, of which all 21 sites reflex IHC 2+ results, and 9 of 21 automatically reflex IHC beyond 2+ (see table, results are not mutually exclusive). FISH only testing is done at 15% (8/54); concurrent FISH and CISH testing at 2% (1/54); concurrent SISH and IHC testing at 2% (1/54), and SISH only testing at 2% (1/54) of sites. The survey separately asked about HER2 testing methods for breast cancer (BC), which were compared by site to GEC HER2 practices: 65% (35/54) of sites conduct HER2 testing in a similar manner - analogous methods in similar order (p= 0.0471); 19% (10/54) of sites use primary IHC in GEC but primary FISH in BC, and 17% (9/54) of sites conduct primary or concurrent FISH testing in GEC but primary IHC in BC. Lab CAP certification for their sites was known by 89% (56/63) of GEC pathologists vs 34% (19/56) of GEC oncologists (p < .0001). 67% (42/63) of GEC pathologists were aware of whether their lab underwent a HER2 IHC and/or FISH proficiency test, vs 4% (2/56) of GEC oncologists (p<.0001). Conclusions: For gastric and esophageal HER2 testing, concurrent FISH and IHC and expanded reflex testing, beyond IHC 2+ results, are the common practice at the NCI cancer centers. [Table: see text]
A phase I/II study of biweekly docetaxel (D) in combination with fixed-dose cisplatin plus fluorouracil (CF) in patients (pts) with advanced esophageal cancer (AEC) (JCOG0807).
Authors: Hironaka Shuichi , Tsubosa Yasuhiro , Mizusawa Junki , Kii Takayuki , Kato Ken , Tsushima Takahiro , Chin Keisho , Tomori Akihisa , Okuno Tatsuya , Taniki Toshikatsu , Ura Takashi , Matsushita Hisayuki , Kojima Takashi , Doki Yuichiro , Fujitani Kazumasa , Taira Koichi , Seki Shiko , Nakamura Tsutomu , Kitagawa Yuko ,   Japan Esophageal Oncology Group
Published: March 2020

e15016

Background: Thougha triplet chemotherapy with D plus CF (DCF) has shown promising activity, high incidence of adverse events (AEs) especially in febrile neutropenia (FN) was observed in previous studies for head and neck cancer (TAX323, 324) and gastric cancer (TAX325). To reduce its AEs with keeping activity, we conducted a multicenter open-label phase I/II study of biweekly D plus CF for AEC. Methods: Eligibility criteria included histologically proven AEC with measurable disease, age 20 to 75, non-resectable or recurrent disease, performance status (PS) 0 to 1. Pts received escalating doses of D (dose level (DL) 1: 30 mg/m2, DL 2: 40 mg/m2, on days 1, 15) in combination with fixed dose of CF (cisplatin 80 mg/m2 on day 1, fluorouracil 800 mg/m2on days 1-5) repeated every 4 weeks with 3+3 design in phase I part (P-I). The primary endpoint of P-I was dose limiting toxicity (DLT) and that of phase II part (P-II) was response rate (RR) defined by central peer review. Based on a SWOG two stage design (p0=35%, p1=50%; one-sided a=0.1, β =0.2) at least 22 responders among 50 eligible pts should be observed to satisfy the primary endpoint. Results: Between Feb 2009 and Mar 2010, 62 pts were enrolled for P-I and P-II. In P-I, 10 pts were enrolled with DLT of 0/3 in DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended dose for P-II was determined as DL1. Thus, 3 (P-I) and additional 52 pts (P-II) were analyzed: 53 for efficacy (excluded 2 ineligible pts) and 55 for safety. Pts characteristics were as follows: male/female 49/6, age median 61 (range 44 to 75), PS 0/1 39/16. The RR was 62% (95% confidence interval, 48-75%, p<0.0001) by central peer review. Median OS and PFS were 11.1 and 5.8 months. Grade 3/4 toxicity was observed in neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%) and nausea (11%). No grade 3/4 FN was observed. Treatment related death occurred in one patient due to pneumonitis. Conclusions: Biweekly D (30mg/m2) combined with CF showed promising activity and tolerability. A phase III study comparing CF with DCF is warranted. Clinical trial information: UMIN000001737.
Efficacy of platinum chemotherapy agents in the adjuvant setting for adenosquamous carcinoma of the pancreas.
Authors: Wild Aaron Tyler , Dholakia Avani Satish , Fan Katherine Y. , Kumar Rachit , Laheru Dan , Diaz Luis A. , Zheng Lei , Le Dung T. , De Jesus-Acosta Ana , Ellsworth Susannah G. , Hacker-Prietz Amy , Voong K Ranh , Weiss Matthew , Hruban Ralph H. , Tran Phuoc T. , Cameron John L. , Pawlik Timothy M. , Wolfgang Christopher Lee , Herman Joseph M.
Published: March 2020

e15028

Background: Pancreatic adenosquamous carcinoma (PASC) is a rare morphological subtype of pancreatic adenocarcinoma. PASC accounts for only 1-4% of exocrine pancreatic cancers and carries a particularly poor prognosis. Due to the rarity of PASC, studies of therapies specifically targeting this histopathologic entity are exceedingly limited. Based on efficacy exhibited by platinum agents against squamous carcinoma of other body sites, addition of these agents to adjuvant regimens may benefit patients with PASC. This retrospective study was performed among the largest series of patients with PASC identified to date in order to determine whether addition of platinum agents improves survival. Methods: Records of all patients who underwent pancreatic resection at our institution from 1986-2012 were reviewed to identify those with PASC. Demographic, surgical, pathologic, adjuvant therapy, and survival data were collected. Patients were divided into non-platinum (NPG) and platinum (PG) groups based on whether or not they received a platinum agent as part of adjuvant therapy. Results: In total, 62 patients with PASC were identified among 5,627 cases (1.1%). Fourteen patients received a platinum agent in the adjuvant setting (PG), while 48 did not (NPG). These two groups were comparable in regard to median age (65 vs. 69 yrs, p=0.34), gender (36 vs. 46% female, p=0.50), performance status (78 vs. 79% ECOG 0, p=0.98), histologic grade (86 vs. 77% grade 3, p=0.49), positive resection margins (14 vs. 29%, p=0.26), lymph node involvement (71 vs. 79%, p=0.54), median tumor diameter (4.0 vs. 4.3 cm, p=0.64), and proportion receiving radiotherapy (57 vs. 42%, p=0.31). PG patients received a median of 5.5 cycles (IQR, 3.3-6.0) of platinum chemotherapy, with 10 patients (71%) receiving cisplatin-based regimens and 4 (29%) receiving oxaliplatin-based regimens. PG patients experienced significantly longer median survival (19.1 months, 95% CI 12.8-25.4) compared to NPG patients (9.8 months, 95% CI 7.3-12.4) (p=0.024). Conclusions: Addition of a platinum agent to adjuvant regimens for resected PASC may improve survival among these high risk patients, though collaborative prospective investigation is needed.
From functional genomics to precision medicine: The therapeutic potential of targeting ROCK signaling in pancreatic cancer.
Authors: Chin Venessa T. , Nagrial Adnan , Chantrill Lorraine A. , Chang David K. , Chou Angela , Humprhis Jeremy , Cowley Mark , Wu Jiamin , DiPetro Renee , Watson Clare , Spielman Calan , Steinmann Angela , Pinese Mark , Pettitt Jessica , Johns Amber , Waddell Nicola , Grimmond Sean , Timpson Paul , Biankin Andrew Victor , Pajic Marina ,   Australian Pancreatic Cancer Genome Initiative
Published: March 2020

e15029

Background: Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options for metastatic disease. PC is a genetically highly heterogeneous disease that lends itself to a personalised approach to translational research (Biankin et al. Nature. 2012 Nov 15;491(7424):399-405.). Genomic sequence data from the Australian Pancreatic Genome Initiative (APGI) has identified a subset of patients with ROCK-1 amplification. ROCK-1 is a downstream target of Rho, a small GTPase, which is involved in cell adhesion and motility and has been shown to play a role in cancer cell growth and invasiveness (S. Boeck, P. Stieber, et al. Oncology 2006; 70:255., Lane J, Martin T et al. Int J Onc 2008; 33:585-593.). Our aim is to identify biologically and clinically relevant, targetable phenotypes for PC by examining therapeutic efficacy of two ROCK-1 inhibitors, Y-27632 and fasudil in model systems with aberrant Rho/ROCK signaling. Methods: Using extensively characterised model systems of PC, including unique primary patient derived xenografts (PDX) and patient derived cell lines (PDCL) established in the laboratory, we are examining the efficacy of individualized rationally designed combination therapies based on targeting Rho/ROCK signaling. Using innovative techniques, including organotypic assays, we are examining the effect of the targeted approach on cell proliferation, migration, invasion and metastasis in relevant models of PC. Results: Here we demonstrate significant differential sensitivity of pancreatic PDXs and PDCLs with aberrant Rho/ROCK signaling to ROCK combination therapy when compared with standard therapy, gemcitabine. Finally, these compounds impair invasiveness of human pancreatic tumour cells, suggesting that ROCK-1 is a targetable phenotype for the treatment of PC. Conclusions: By carefully defining the key cancer subtypes and expanding our knowledge about the interplay of the key regulators and activators of the Rho/ROCK pathway, the promise of ROCK inhibitors for PC therapy may be realized. As fasudil is already in clinical use for the treatment of cerebral vasospasm, this work may be quickly translated to the clinic.
Supplement use in patients with hepatocellular carcinoma.
Authors: Lee Valerie , Goyal Abhishek , Hsu Christine Cho-Shing , Rodriguez Rosa D. , Siegel Abby B.
Published: March 2020

e15037

Background: Vitamin and herbal supplement use has been steadily rising in the United States. Few data are available evaluating this use in patients with hepatocellular carcinoma (HCC). We analyzed our prospective database of patients with HCC to determine predictors of supplement use and associations with survival. Methods: We prospectively enrolled 146 patients with newly-diagnosed HCC between 10/2008 and 11/2012. Upon enrollment, patients completed an epidemiologic questionnaire and provided detailed demographic and lifestyle data including diet, exercise, smoking and use of vitamins and herbal supplements. Clinical characteristics and overall survival were collected from medical records. We assessed if socioeconomic, lifestyle, or clinical characteristics predicted vitamin and herbal supplement use in HCC patients. We also evaluated if use was predictive of overall survival. Results: The median age was 62, and 79% were men. 60% had underlying HCV and 38% had HBV; 64% were Child-Pugh A and 19% were metastatic. 71% of our cohort used vitamins and 45% used herbal supplements. Most commonly used were antioxidants (including vitamins C, E, A and selenium) (51%), multivitamins (46%), vitamin D (25%), and milk thistle (23%). Vitamin D use was higher in women and those without HCV. Use of vitamin C was associated with being HBV positive (OR = 3.01, P = 0.01) while HCV patients were more likely to use milk thistle (OR = 2.80, P = 0.03). In a univariable model, use of milk thistle at baseline was associated with a trend toward worse overall survival (HR = 1.78, P = 0.09), despite not being associated with other poor prognostic signs like higher stage or AFP, or worse Child-Pugh score. Use of other vitamin or herbal supplements did not predict survival. Conclusions: The majority of patients with newly-diagnosed HCC have used some form of vitamin or herbal supplement, with almost a quarter having used milk thistle in their lifetime. In our analyses, use of milk thistle may be associated with worse survival. Though our cohort is small, this emphasizes the prevalence of supplement use in patients with HCC and the need to further evaluate the safety and efficacy of these alternative treatments in various patient populations.
A phase I study of temsirolimus as novel therapeutic drug for patients with unresectable hepatocellular carcinoma (HCC).
Authors: Chan Stephen Lam , Mo Frankie , Hui Edwin P. , Koh Jane , Chu CM , Hui Joyce , Li Leung , Loong Herbert H. , Ho Wing Ming , Ma Brigette , To Ka Fai , Yu Simon , Chan Anthony T. C. , Yeo Winnie
Published: March 2020

e15048

Background: The oncogenic PI3K/Akt/mTOR pathway is frequently activated in hepatocellular carcinoma (HCC). Preliminary studies on mTOR inhibitors such as temsirolimus show promising results but there is limited data on the dose limiting toxicities (DLTs) in chronic liver disease, a co-morbidities commonly occurring in HCC pts. This phase I study aims to determine DLTs and maximum tolerated dose (MTD) of temsirolimus in advanced HCC. Methods: Patient (Pt) eligibilitie criteria include unresectable disease, ECOG <= 2, adequate organ functions. Temsirolimus was given i.v. in 250ml NS over 30 min on day 1, 8, and 15 every 3 weeks; dose levels were: 20 (level I), 25 (level II) and 30 mg (level III). DLTs are defined as grade 4 hematological toxicity or grade 3/4 non-haematological toxicity during cycle 1 (according to NCI CTC v3), or treatment delay >2 weeks. The MTD is defined as the dose below which > 2 of 3 or > 2 of 6 patients experiencing DLT. After determination of the MTD, additional pts to make up to 10 patients were treated at this dose to further define toxicity. The study has been registered in ClinicalTrials.gov (NCT00321594). Results: 19 pts were entered; level I (n=3), level II (n=10), and level III (n=6). 2 of the 6 pts in level 3 developed DLT; 1 developed grade 3 syncope and 1 had treatment delay for >2 weeks due to prolonged neutropenia. In cycle 1, grade 3/4/5 toxicities included: raised ALP 2/0/0, oral mucositis 2/0/0, neutropenia 1/0/0, syncope 1/0/0, dehydration 1/0/0 and dysphagia 1/0/0. A total of 77 cycles were administered; overall grade 3/4/5 toxicities: raised ALT 2/0/0, raised ALP 2/0/0, raised bilirubin 2/0/0, cough 1/0/0, dehydration 1/0/0, dysphagia 1/0/0, dyspnea 1/0/0, abdominal distension 1/0/0, anemia 1/0/0, hemorrhoids 1/0/0, hyperglycemia 1/0/0, hypokalemia 2/0/0, hyponatremia 1/0/0, infection 5/0/0 (1 dental, 2 pulmonary, upper airway 2), oral mucositis 2/0/0, neutropenia 1/0/0, thrombocytopenia 2/0/0, pleural effusion 1/0/0, pneumonitis 1/0/0, syncope 1/0/0. Clinical benefit rate (PR, CR or SD ≥12 weeks) was 36.8% (7 of 19 pts had confirmed SD). Conclusions: At the MTD of 25 mg weekly every 3 weeks, temsirolimus is well tolerated with no DLTs. Clinical trial information: NCT00321594.
KRAS, BRAF, PIK3CA, and human papilloma virus (HPV) status in squamous cell anal carcinoma (SCAC).
Authors: Casadei Gardini Andrea , Capelli Laura , Ulivi Paola , Giannini Massimo , Freier Eva , Tamberi Stefano , Passardi Alessandro , Rosetti Paola , Calistri Daniele , Saragoni Luca , Puccetti Maurizio , Valgiusti Martina , Amadori Dino , Frassineti Giovanni Luca
Published: March 2020

e15055

Background: In literature three studies have described KRAS status in SCAC: they analyzed 139 patients, only 1, 4% were mutated. In this study we analyzed BRAF and PIK3CA status. The evaluation of these two genes is important for predicting the response to anti-EGFR drugs. There is one study that values the positivity of HPV in SCAC. This study with few patients shows that the positivity of HPV16 is predictive for improvement of progression free survival (PFS). Methods: 79 patients were treated for anal cancer at the Oncology center of Forlì, Ravenna and Faenza in the last ten years. Up to now we analyzed 29 patients (9 with relapse of disease). DNA was extracted from paraffin-embedded sections and KRAS, BRAF and PIK3CA gene status were assessed by Pyrosequencing methodology, using 3 different kits: anti-EGFR MoAb response (KRAS status), anti-EGFR MoAb response (BRAF status), and anti- EGFR MoAb response (PIK3CA status) (Diatech, Jesi, Ancona, Italy). Reactions were run on a PyroMark Q96 ID (Qiagen). The presence and genotyping of Human Papilloma Virus (HPV) were assessed using the AMPLIQUALITY HPV-HS Bio and AMPLIQUALITY HPV-Type (AB ANALITICA, Padova, Italy) kit. Results: KRAS and BRAF genes were wild-type in all cases. Conversely, PIK3CA gene resulted mutated in 9 of 31 cases (28.1%). In particular, 7 mutations occurred in exon 9 (4 E454K and 3 E542K) and 2 in exon 20 (H1047R and H1047L) of the PIK3CA gene. Patients without relapse of disease were positive in 94% of cases for HPV16 and in 40% for mutation of PIK3CA. Patients with relapse of disease were positive in 70% of cases for HPV16 and 37,5% for mutation of PIK3CA. Conclusions: KRAS and BRAF genes were wild type in 100% of cases. This study demonstrates that the SCAC could potentially respond to an anti-EGFR drug.The mutation of PIK3CA does not seem to be predictive for response to treatment. Positivity for HPV16 seems predictive for PFS and overall survival. Furthermore, the study shows that PIK3CA mutation may contribute to carcinogenesis in some cases of this tumor. In addition, patients with a mutation of PI3K could have benefit from specific drugs that inhibit this kinase.
Weekly nab-paclitaxel in combination with cisplatin as neoadjuvant chemotherapy in patients (pts) with locally advanced esophageal squamous cell carcinoma (SCC): Preliminary results of a phase study.
Authors: Jiang Youhua , Yun Fan , Chen Qixun , Zhou Xinming , Huang Zhiyu , Gong Lei , Yang Haiyan , Yu Haifeng , Liu Jinshi , Chen Pengcheng , Zhao Qiang , Mao Weimin
Published: March 2020

e15062

Background: This phase II study was aimed to define the pathological response rate and safety of combining weekly nab-paclitaxel and cisplatin as neoadjuvant chemotherapy in pts with locally advanced esophageal SCC. Methods: Pts with resectable locally advanced thoracic esophageal SCC staged by EUS, CT and/or PET-CTscan. All pts received nab-paclitaxel (100 mg/m2, d1, d8, d22 and d29) and cisplatin (75 mg/m2, d1 and d22) as neoadjuvant chemotherapy, followed by esophagectomy.Postoperation: 2 cycles of adjuvant chemotherapy with same regimen was given in 4-6 weeks after the resection.The primary endpoint was pathological response rate. The second endpoints included R0 resection rate,down-staging rate, 3 years overall survival (OS) and progression-free survival (PFS). Results: From 01/2011 to 10/2012, 31 pts were enrolled . 28 male:3 females; II A/II B/III A/III B/III C in 2 (6.5%), 4 (12.9%), 9 ,(29.0%), 8 (25.8), and 8 (25.8%) pts. 26/31 pts went to surgery (83.9%). 26 had R0 resection (100%).Pathological complete response (pCR) was achieved in 3 pts (11.5%). Near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) in 1 pt (3.8 %). Down-staging was observed in 15 of 26 patiens (57.7%). 5 pts did not going to surgery: 2 for progressive disease (6.5%), 3 for refused. 20/26 pts (76.9%) received adjuvant chemotherapy,3 pts (11.5%) received adjuvant chemoradiotherapy. Grade 3/4 toxicities in 31 evaluable pts during chemotherapy were as follow: neutropenia (12.9%), anemia (6.5%), thrombocytopenia (3.2%), nausea/vomiting (12.9%), neutropenia fever (6.5%), asthenia (12.9%). Surgical complications: 1anastomotic leaks (3.8%). No treatment-related death. At a median follow up of 9 months, 26 pts were all disease-free survival. Conclusions: In pts with locally advanced esophageal SCC, weekly nab-paclitaxel and cisplatin as neoadjuvant chemotherapy achieved a high pathological response rate and R0 resection rate .The toxicity was well tolerated. Evaluation of nab-paclitaxel and cisplatin in randomized trials was warranted. Clinical trial information: NCT01258192.
Uptake and patterns of use of gemcitabine for stage IV pancreatic cancer.
Authors: Oberstein Paul Eliezer , Hershman Dawn L. , Chabot John A. , Khanna Lauren , Insel Beverly J. , Neugut Alfred I.
Published: March 2020

e15074

Background: Gemcitabine was approved by the FDA in 1996 and subsequently became the standard of care for patients with advanced pancreatic cancer. We investigated the frequency and predictors of gemcitabine use among the elderly with stage IV pancreatic cancer. Methods: We used the SEER-Medicare database to identify subjects >65 years who were diagnosed with stage IV pancreatic cancer between 1/1/98-12/31/05, and survived for >30 days following diagnosis. After excluding patients who received non-gemcitabine chemotherapy, we used multivariate logistic regression models to analyze the association between patient and tumor characteristics and receipt of gemcitabine compared to no chemotherapy. Results: Among 3,208 patients analyzed, 1,614 (50.3%) received gemcitabine chemotherapy, 1,480 (46.1%) received no chemotherapy; 114 (3.5%) received non-gemcitabine therapy and were excluded from multivariate analysis. Among patients diagnosed early in the study period (1998-2000) the rate of gemcitabine use was 44.9%. In multivariate analysis, gemcitabine use was not associated with gender, race, tumor histology, or increasing comorbidities. Unmarried patients were less likely to receive gemcitabine (OR=0.65, 95% CI 0.55-0.76), and use decreased with increasing age (for those 75-79, OR=0.72. 95% CI 0.58-0.90, for those 80-84, OR=0.38, 95% CI 0.30-0.49, for those >84, OR=0.21 95%CI 0.15-0.30) compared to those 65-69. Patients diagnosed in 2004-2005 (OR= 1.51, 95% CI 1.23-1.84) were more likely to receive gemcitabine compared to those diagnosed in 1998-2000. Higher socioeconomic status were associated with increased utilization of gemcitabine (highest quintile OR=2.14, 95% CI 1.60-2.85, second and third quintile OR=1.45, 95%CI 1.10-1.93, compared to lowest quintile.) Conclusions: Although chemotherapy for stage IV pancreatic cancer confers a small survival benefit, uptake of gemcitabine was rapid with 55% of elderly patients receiving this therapy by 2004-2005. Future studies should explore the reasons behind the increased use in patients with higher socioeconomic status.
Metformin in diabetic pancreatic cancer patients: Benefit or not—Multicenter experience.
Authors: Esbah Onur , Oksuzoglu Berna , Eren Tulay , Helvaci Kaan , Guler Tunc , Duran Ayse Ocak , Bal Oznur , Ozdemir Nurıye Yıldırım , Aksoy Sercan ,   on behalf of the Anatolian Society of Medical Oncology
Published: March 2020

e15110

Background: Risk factors for the pancreatic cancer are cigarette smoking, obesity, family history, chronic pancreatitis and type 2 diabetes mellitus. Diabetes mellitus is associated with 2-3 fold increase in the risk of pancreas cancer development. Down-regulation of mTOR pathway which begins with the insulin signaling is the possible protective effect of metformin in the oncogenesis of pancreatic cancer. In this study, we aimed to evaluate whether the use of metformin in diabetic pancreas cancer patients has an advantage or not. Methods: The data of 467 patients with the diagnosis of pancreas cancer in from 2003 to 2012 were analyzed, retrospectively. Results: Four hundred and sixty seven patients with the median age of 62 (20-85) were reviewed Median tumour size was 42 mm (14-145 mm). According to 2010 TNM staging, 23 patients had stage 1 (4.9%), 97 patients stage 2 (20.8%), 70 patients stage 3 (15%) and 277 patients had stage 4 disease (59.3%). Diabetes mellitus was detected in 173 (37%) patients. In this group 23 patients had stage 1 (4.9%), 97 patients stage 2 (20.8%), 70 patients stage 3 (15%) and 98 patients had stage 4 disease (56.6%). Thirty seven percent (64 patients) of the patients with diabetes were using metformin. Median time for metformin usage was 14±2,3 months. Median follow-up time was 7 months (1-88 months). Median overall survival (OS) of all pancreas cancer patients was 8 months. Surprisingly, median OS of diabetic pancreas cancer patients and non-diabetics was 9 and 8 months, respectively (statistically not significant). Median OS of diabetic patient subgroup who use metformin or not was 7 versus 10 months, respectively (statistically not significant). In the subgroup of stage 3 pancreatic cancer patients with diabetes mellitus, the median OS were 16 months and 10 months according to metformin usage or not, respectively (p=02). Conclusions: In this study, the median OS of diabetic pancreas cancer patients was superior from the non-diabetics. Multi-center prospective trials including large number of patients are needed to understand well enough the benefit of metformin in diabetic pancreas carcinoma patients.
A phase II clinical and translational study of MK-2206 in patients with metastatic neuroendocrine tumors (NETs).
Authors: Reidy Diane Lauren , Pietanza Maria Catherine , Segal Michal , Capanu Marinela , Saltz Leonard
Published: March 2020

e15133

Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poor prognosis in NET cell lines. In patients treated with mTOR inhibitors, up-regulation of AKT may be a key driver in development of resistance. We hypothesized that blockade of AKT in patients with refractory NETs would result in eliminating one of the key drivers of tumor growth and prolong PFS. We evaluated the safety and efficacy of MK-2206, an orally active, allosteric Akt inhibitor of human Akt1, Akt2, and Akt3 as monotherapy in metastatic well differentiated progressive neuroendocrine patients. Methods: A phase II study was performed in which patients received MK-2206 at a dose of 200 mg PO once weekly. Archived pretreatment tumor tissue was obtained for putative biomarkers. Results: The study terminated early on the basis of a business decision by the sponsor. Eight patients were treated (6 carcinoid, 2 pNET); female, 25%; median age, 58.5 years, range 66-25). There were no complete or partial responses. 1 patient (atypical thymic carcinoid with brain metastases refractory to all standard therapies including mTOR and VEGF inhibitors) experienced a 17% decrease in tumor size (SD) for over 10 months and an additional 3 patients had SD for 12 weeks or longer by RECIST 1.0 (4/8, 50%; range 4.2-10.2 months). The most common grade 3 adverse events potentially related to MK-2206 were hyperglycemia (3 pts, 37.5%), elevated liver function tests (3 pts, 37.5%), and rash (3 pts, 37.5%). There were no serious adverse events (SAEs) related to MK-2206. Tumor from the patient with greatest radiographic response was evaluated by next generation sequencing, which failed to identify mutations in the AKT pathway (i.e., PTEN, AKT, and PI3KCA). Conclusions: MK-2206 alone was well tolerated, except for hyperglycemia, transaminitis, and rash, all of which were manageable. Although the study was incomplete, evidence of antitumor response in a refractory carcinoid tumor is of interest. Further evaluation of agents targeting AKT and/or PI3K are warranted in NETS. Preclinical studies are ongoing to better define a potential targeted population. Clinical trial information: NCT01169649.
Perioperative epirubicin, oxaliplatin, and capectabine (EOX) in locally advanced resectable gastroesophageal junction and gastric adenocarcinoma.
Authors: Kalachand Roshni Deepa , Mongan Anne-Marie , Doherty Mark , King Sinead , O'Farrell Niamh , Reynolds John Vincent , O'Byrne Kenneth John
Published: March 2020

e15142

Background: Perioperative chemotherapy with epirubicin, cisplatin and fluorouracil (ECF) confers a 13% absolute 5-year survival benefit over surgery alone in resectable gastroesophageal cancer. In the metastatic setting, the EOX regimen is at least as effective as ECF, with a favourable toxicity profile. This retrospective analysis presents the experience of a high-volume tertiary referral center with perioperative EOX in patients with resectable GEJ and gastric adenocarcinoma. Methods: Patients with cTxN+/cT3N0 gastroesophageal adenocarcinoma treated between 2006-2012 with perioperative EOX (epirubicin 50mg/m2 d1 q22d, oxaliplatin 130mg/m2 d1 q22d and capecitabine 625 mg/m2 bd d1-21 q22d), given as three neoadjuvant and three adjuvant cycles, were retrospectively identified from a prospectively recorded upper gastrointestinal cancer database. Efficacy and toxicity data were assessed. Results: 52 patients, including 41 (82%) males, with a median age of 62 (range 35-79) received perioperative EOX with curative intent. GEJ tumours represented 39 (75%) of cases, and the others were gastric cancers. 47 patients (90%) completed 3 cycles of neoadjuvant EOX. One patient died of non-neutropenic sepsis after cycle 2. 44 (85%) of patients progressed to surgery, 5 of whom were deemed unresectable. 28 (71%) surgeries were D2 resections, and the R0 resection rate was 67%. There was one postoperative death, due to pancreatitis. 28 (54%) of patients commenced adjuvant EOX, and 25 (48%) completed the planned treatment. Grade 3-4 toxicities were observed in 17% of patients, with the commonest being fatigue (8%) and nausea (4%). Pathological response rate, as defined by Mandard Tumour Regression Grade 1-3, was seen in 26%, with 3 (6%) pathological complete response. The median progression-free survival was 7 months, with a median overall survival of 22 months, and a 2-year survival rate of 45%. Conclusions: In our institution, perioperative EOX in gastroesophageal cancer is associated with a reasonable safety profile, and efficacy consistent with that reported in the MAGIC trial.
HER2 expression and response to neoadjuvant chemoradiotherapy in esophagogastric adenocarcinoma.
Authors: Duckworth Lizette Vila , Chan Ellie , Alkhasawneh Ahmad , Zuluaga-Toro Tania , Lu Xiaomin , Hughes Steven J. , George Thomas J.
Published: March 2020

e15145

Background: Targeting HER2 overexpression with trastuzumab in metastatic esophagogastric adenocarcinoma (EGA) improves survival with clinical trials currently examining the impact of HER2 inhibition in early stage disease. This study analyzed the pattern of HER2 overexpression in matched-pair tumor samples of patients (pts) undergoing neoadjuvant chemoradiotherapy (chemoRT). Methods: This analysis included pts with EGA who underwent neoadjuvant chemoRT followed by esophagectomy at the University of Florida from 2001 to 2011 who did not receive anti-HER2 therapy. Demographics, risk factors, tumor features, and outcome data were analyzed. Central blinded IHC was performed on paraffin embedded tumor specimens with HER2 expression scored as negative (-) (0, 1+), indeterminate (2+) or positive (+) (3+). Descriptive statistics, Chi-square exact test, uni and multivariate analyses were used for statistical analyses. Results: 49 pts (41M/8F) were analyzed with median age 65 years (39-87). Most tumors were stage II (55%) or III (43%). 9/49 pts (18%) had pathologic complete response (pCR), another 10/49 had near pCR or not enough tumor (NET) to examine. HER2 expression was more common in lower stages (stage I, II vs III). Baseline HER2 expression did not correlate with treatment response. Univariate analysis did not show significant correlation of age, stage, smoking, pre or post treatment HER2 expression with survival. For matched-pair samples failing to achieve pCR or NET (n=30), pre and post treatment HER2 expression profiles are presented in the Table. HER2 expression appears UP regulated in response to neoadjuvant chemoRT. Conclusions: Our study demonstrated the degree of pre-treatment HER2 expression in EGA does not predict the response to chemoRT. However, HER2 overexpression is more frequent in post treatment samples without pCR. This suggests that HER2 may be upregulated by chemoRT with unreliable concordance between pre and post treatment samples. This has implications for both early and advanced stage therapeutic interventions with targeted therapies. [Table: see text]
Optimal cycles of fluoropyrimidine-based adjuvant chemotherapy for patients with resectable gastric cancer.
Authors: Liu Yunpeng , Qu Xiujuan , Qu Jinglei , Zhang Jingdong , Liu Jing
Published: March 2020

e15160

Background: Although several clinical trials have suggested that postoperative adjuvant chemotherapy could improve survival, there has no study on the optimal cycles of treatment. This retrospective analysis was carried out to evaluate the outcomes of gastric cancer patients treated with 5-6 cycles of FU-based treatment as compared to a cohort treated with 3-4 cycles or 7-8 cycles. Methods: We retrospective identified 254 patients with stage IB-IIIC gastric cancer who received 3-8 cycles of adjuvant chemotherapy after gastrectomy with D1 or D2 lymphadenectomy. The endpoint was overall survival. Factors associated with prognosis were also analyzed. Results: Of the 254 patients, 74 patients treated with 3-4 cycles, 112 patients treated with 5-6 cycles and 68 patients treated with 7-8 cycles. The 3-year OS rates for 3-4 cycles, 5-6 cycles and 7-8 cycles cohort was 56.6%, 73.9% and 67.7%, respectively. Patients who received 5-6 cycles were more likely to have better OS than those received 3-4 cycles (p=0.003), two further cycles of treatment did not improved OS (p=0.885). In the multivariate analysis, cycles of chemotherapy were associated with OS independent of clinical covariates (p=0.008). Subgroup analysis was suggested that for patients with older adult (age ≥60), FU-platinum combined chemotherapy, stage III, poorly differentiation, and gastrectomy with D2 lymph node dissection, 5-6 cycles of adjuvant chemotherapy was associated with a statistically significant benefit of OS (P<0.05). Conclusions: Our result indicated that 5-6 cycles of adjuvant chemotherapy may lead to a favorable outcome for gastric cancer patients following primary surgical treatment. In view of the limited resources of medication, reduced incidences of toxicity and better quality-of-life with shorter duration of treatment, optimal cycles of adjuvant treatment should be explored further.
A correlative analysis of biochemical and radiologic hepatic disease in metastatic pancreatic adenocarcinoma (PA).
Authors: McHugh Deaglan Joseph , Teo MinYuen , Rozumna-Martynyuk Nataliya , McDermott Raymond S.
Published: March 2020

e15163

Background: The liver is the most common site of distant metastases (mets) in patients with PA. We aimed to study radiomorphology of PA-related liver mets and its correlation with the degree of biochemical hepatic dysfunction. The impact of liver failure on patient mortality was also assessed. Methods: Using National Cancer Institute-Organ Dysfunction Working Group guidelines, patients were stratified into 4 groups A (Normal), B (Mild), C (Moderate), D (severe) based on serum bilirubin and aspartate transaminase levels. Two sets of results were recorded for each patient - at diagnosis (baseline) and the the last available prior to death. CT scan at diagnosis were used to measure both the number and diameter of two largest lesions for each patients’ liver mets. Results: 58 patients with metastatic PA were identified. 5 of these patients were excluded from this study as their imaging was not available. 34 (59%) had hepatic mets. Of 34 patients, 47.1% (n=16) had diffuse mets. 23.5% (n=8) had 6-10 liver mets. 20.6% (n=7) had 2-5 liver mets. 8.8% (n=3) had a solitary metastasis. Four of these patients were excluded as they were still alive at the time of the biochemical analysis. Of 31 patients at baseline: 25.8% (n=8), 35.5% (n=7), 22.6% (n=7), 16.1% (n=5) of patients had group A, B, C and D hepatic dysfunction respectively. The median time between last liver function testing and death was 10 days (range 0-114 days). Prior to death, 16.1% (n=5), 35.5% (n=11), 6.5% (n=2), 41.9% (n=13) of patients had group A, B, C and D dysfunction respectively. Of the 13 patients with severe hepatic dysfunction prior to death, 7 had no radiographic evidence of extrinsic obstruction. No difference in number of liver mets were seen between groups A and B when compared to C and D. However, groups C+D had higher mean size, 2.8 x 2.3 vs. 2.4 x 1.8 cm (p=0.047). No survival difference was noted (4.6 vs 2.5 months, p=0.425). Conclusions: The majority of patients had diffuse liver mets at diagnosis. There was no significant correlation between the radiological burden of hepatic disease and the degree of hepatic impairment at diagnosis. PA-related liver mets was the likeliest cause of death in up to 22.6% of patients.
Temozolamide plus capecitabine as salvage treatment for patients with advanced neuroendocrine tumors (NETs) in the community setting.
Authors: López-López Carlos , Jiménez Paula , Crespo Guillermo , Grande Enrique , Custodio Ana B. , Mangas-Izquierdo M. , Pérez Arnillas Quionia , Barrio-Alonso M. J. , Soria Rivas Ainara , Barriuso Jorge
Published: March 2020

e15169

Background: Streptozotocin and doxorubicin-based chemotherapy schemes have been widely used in the treatment of advanced NETs. Unfortunately, balance between efficacy and toxicity is clearly improvable. Novel combinations of cytotoxic agents like temozolamide and capecitabine have shown promising antitumoral activity in retrospective series.We aimed toevaluate the efficacy and safety of this combination in patients with advanced NETs derived from the daily clinical practice. Methods: We analyzed the clinical outcome of 34 patients (pts) treated with temozolamide (150 mg/m2 qo, days 10-14) plus capecitabine (1.000 mg/m2 bid, days 1-14) every 28 days, between June-2008 and December-2012 in five referenced centers in Spain. Results: 21 pts (61%), were pancreatic primary NETs (pNETs). 8 pts (24%) were treated as first-line. 26 pts (76,5%) had ECOG 0 or 1. One (2,9%), 18 (52,9%), and 11 (32,4%) pts had low (G1), intermediate (G2) or high-grade (G3) respectively. Grade was not available in 4 pts (11,8%). Median administered cycles were 8 (range 1-26). At the time of the data cut-off (Dec-2012) 5 pts (14,7%) were still on treatment after a median follow up of 6,4 months. 13 pts (38,2%) had partial response (PR) and 12 (32,4%) stable disease (SD) according to RECIST 1.1 criteria. Estimated median time to progression (TTP) was 9,4 months IC95% (4,2-14,6) in the intention to treat population. Thrombocytopenia was the most frequent toxicity found in grade 3 or more (9%). Other grade 3 toxicities according to CTCAE v4.0 were observed in less than 5% of pts. Conclusions: These encouraging results show a promising activity and a favorable safety profile of the combination of temozolamide and capecitabine in patients with advanced NETs and deserves for further clinical research in the future.
Survival analysis of treatment with S-1, alone or in combination with CDDP (SP), in elderly patients with advanced gastric cancer: A 10-year retrospective cohort study.
Authors: Makiyama Akitaka , Kajitani Tatsuhiro , Oda Hisanobu , Fujimoto Chinatsu , Esaki Taito
Published: March 2020

e15170

Background: In Japan, the elderly population is increasing, and steadily increase the number of deaths in the elderly gastric cancer patients. However, the standard treatment of elderly gastric cancer has not been established, either treatment of S-1 or SP is carried out in the clinical practice, while SP is considered as standard therapy in the young people. Now, we investigated the impact of S-1 and SP on survival time in clinical practice. Methods: Between 2003 and 2012, advanced gastric cancer patients over 70 years of age received S-1 or SP as first line therapy were retrospectively reviewed to investigate clinical outcomes. Patient characteristics analyzed included age, gender, performance status (PS), tumor histology, renal function and metastatic site. In addition, we have analyzed prognostic factors in multivariate analysis. Results: Among 93 patients (pts), 67 pts (72%) received S-1 and 26 pts (28%) received SP. Patient characteristics between the two groups showed no significant differences in gender, histology, metastatic site, or creatinine clearance level, but did show an imbalance in PS (tended with better at SP group) and age (tended with younger at SP group), significantly. Even though the background factors were favorable results in SP group, there were no significant differences in median progression-free survival (median 139 vs. 102 days; p = 0.96) and overall survival (median 330 vs. 263 days; p = 0.55) between S-1 and SP group, respectively. Grade 3-4 neutropenia (10 vs. 27%, p < 0.05) , fatigue (3 vs. 15%, p < 0.05) and Grade 1-2 creatinine increased (9 vs. 31%, p < 0.01) were more frequent in the SP group than in the S-1 group, respectively. According to the multivariate analysis, exposure to CDDP was not independently associated with a better prognosis. Conclusions: Despite the obvious limitations of this analysis, there does not appear to be a benefit for the addition of CDDP in the elderly gastric cancer patients due to the increase of toxicity. A randomized controlled trial in this age group is warranted. We will also report the results of clinically meaningful prognostic factors associated with the primary treatment at annual meeting.
Expression of immunohistochemical markers in ampullary cancer (AC) and association with behavior.
Authors: De Barros E. Silva Milton Jose , Ribeiro Adriana Regina G. , Begnami Maria D. , Costa Felipe D'Almeida , Costa Wilson Luiz , Maia Joyce Maria L. , Mello Celso Abdon , Freitas Helano C. , Diniz Alessandro Landskron , Ribeiro Heber Salvador de Castro , Coimbra Felipe José Fernandez , Fanelli Marcello Ferretti
Published: March 2020

e15184

Background: Curiously, the ampulla is formed by the union of two distinct types of mucosa: intestinal (GI) and pancreatobiliary(PB). Based on this fact, ACs could have different biologic behaviors. Methods: Between 1999 and 2012 we performed a retrospective analysis of patients with AC that underwent a pancreaticoduodenectomy (PD) with curative intent in our institution and the expressions of immunohistochemical markers related to GI origin (CK20 and CDX2) and to PB origin: (CK7 and MUC1) and its association with outcomes. Results: Twenty-seven patients underwent (PD), (M:F=15:12), median age was 62 (range33-83), 85.2% had R0 resection, 29.6% had positive lymph-nodes, 44.4% had perineural invasion, 22.2% had vascular invasion, 29.6% had lymphatic invasion, 59.2% had moderately differentiated tumors. AJCC stage pathologic grouping was: I=33.3%, II=37%, III= 29.6%; Median follow-up was 33.8 months. Relapse free survival was 43% in 3 years and overall survival was 53.7% in 5 years. The relapse rate was 59.2% and the majority of these relapses (69%) were distant metastasis without local relapse. Only positive lymph-node status (p=0,004, HR: 5.99) and R1 resection (R1: p=0.015, HR: 8.75) were independent prognostic factors for relapse on multivariate analysis. Among the patients, 21 were evaluated for the expression of immunohistochemical markers. Ten AC were classified into TGI type, 9 into PB type and 2 into unusual. An association between PB type and positive lymph node status (p=0.05) and more advanced stage (p=0.05) was found (Fisher’s exact test). There was no difference in relapse and survival between the histological subtypes, however, more PB patients had received adjuvant therapy. Conclusions: Histological subtypes of AC may have different behavior, but they are frequently neglected during decision of adjuvant therapy.