bluuebunny/crossref_metadata_2025 huggingface dataset:
Docetaxel, oxaliplatin, and capecitabine (DOX) combination chemotherapy for metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Di Lauro Luigi , Sergi Domenico , Belli Franca , Fattoruso Silvia Ileana , Arena Maria Grazia , Pizzuti Laura , Vici Patrizia
Published: March 2020

e15065

Background: So far, the prognosis of advanced gastric cancer is dismal. Combination chemotherapy of docetaxel (D), cisplatin (C) and fluorouracil (F) showed activity in metastatic gastric cancer, but this regimen was complicated by a high incidence of myelotoxicity. We performed a multicenter phase II trial substituting C with oxaliplatin (O) and F with capecitabine (X) in chemotherapy-naive patients (pts) with gastric or GEJ adenocarcinoma. Methods: Pts with measurable distant metastases received D 60 mg/mq iv, O 100 mg/mq iv on day 1 and X 500 mg/mq orally twice daily continuously, with cycles repeated every 3 weeks for a maximum of 8. G-CSF was used only as secondary prophylaxis. The primary endpoint was overall response rate (RR) according to RECIST. Toxicity was reported according to NCI-CTC v 3.0. Optimal Simon's two-stage design was employed with 6/15 responses required in the first stage to allow continuation to 46 pts. Results: 46 pts were enrolled: M/F 28/18; median age 66 years (32-75); median ECOG PS 1 (0-2); primary tumor resected/ unresected 16/30; disease location was gastric in 34 and GEJ in 12 pts; sites of disease were liver in 27, nodes in 25, peritoneum in 20, lung in 8 and bone in 5 pts. At the time of analysis all pts were evaluable for response and toxicity. In 46 pts, 3 CR and 21 PR were observed, for an overall RR of 52.1% (95% CI, 37.7%-66.5%). Responses were obtained in 15/27 pts (55%) with liver metastases. Disease remained stable in 14 pts (30.5 %). Median TTP was 6.8 months and median OS was 12.6 months. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 41%, 4% and 9% of the pts, respectively. Febrile neutropenia was observed in 2 pts (4%). Other grade 3 toxicities included mucositis in 2 pts (4%), vomiting in 3 pts (6.5%) and diarrhea in 2 pt (4%). There were no severe neurotoxicity, nor treatment-related deaths. Conclusions: The DOX combination is an active and well tolerated novel chemotherapy regimen for treating metastatic gastric or GEJ adenocarcinoma and deserves further evaluation in randomized trials and, hopefully, in neoadjuvant setting.
Poorly differentiated neuroendocrine carcinoma (NEC G3): Prognostic factors and potential novel targets.
Authors: Heetfeld Maximilian , Kasajima Atsuko , Koch Arend , Milone Francesco , Steffen Ingo , Dietel Manfred , Sasano Hironobu , Wiedenmann Bertram , Pavel Marianne E.
Published: March 2020

e15071

Background: Poorly differentiated neuroendocrine carcinomas (NEC G3) represent a subgroup of neuroendocrine neoplasms with aggressive clinical behavior and poor prognosis, but showing quite variable clinical courses. In metastatic disease objective response to first-line therapy with cisplatin/ etoposide ranges between 40-67%, however median duration of response is short (4 to 9 months). There is no established second-line therapy. Methods: Clinical data of 42 patients with gastro-entero-pancreatic NEC G3 were analyzed in retrospect. In 26 cases tissue was analyzed for cell size, expression of p-mTOR and downstream effectors (p-eIF4E and p-4EBP1), somatostatin receptor (SSTR)-subtypes and growth factor receptors (EGFR and IGF-1R). Histopathological findings were analyzed using Kaplan-Meier curve, log rank test and Cox regression. Results: Patients with large cell NEC showed a more favorable survival than patients with small cell NEC. Median overall survival (mOS) was 31 versus 11 months (P=0.034). Expression of p-mTOR and p-eIF4E was seen in 64% and 24% of cases. High expression levels of p-mTOR (mOS 9 vs 25 months, P=0.026) and expression of p-eIF4E (mOS 9 vs 25 months, P=0.015) was significantly associated with shorter survival. In multivariate Cox regression p-mTOR and p-eIF4E proved to be independent prognostic factors for survival taking cell size and TNM staging into account. EGFR (cytoplasmatic and nuclear) and IGF-1R expression was found in 73.1%, 65.4% and 69.2% of the cases respectively, without significant association to survival. Expression of SSTR subtypes, Ki67 value and response to first line chemotherapy was not of prognostic value analyzed by log rank test. Conclusions: The clinical impact of cell size discrimination requires further evaluation in NEC G3. The mTOR pathway seems to play a role in tumor growth in some NEC and may represent a novel therapeutic target.
Primary tumor histology and location as predictive factors for clinical outcome in metastatic gastric cancer (GC) patients receiving first-line chemotherapy.
Authors: Bittoni Alessandro , Scartozzi Mario , Giampieri Riccardo , Faloppi Luca , Bianconi Maristella , Mandolesi Alessandra , Del Prete Michela , Pistelli Mirco , Cecchini Luca , Bearzi Italo , Cascinu Stefano
Published: March 2020

e15081

Background: Recently, a new classification for GC has been proposed, based on Lauren’s histology and on anatomic tumour location, identifying three subtypes of disease: type 1 (proximal non diffuse GC), type 2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to compare clinical outcome, in terms of response rate (RR), progression-free survival (PFS), and overall survival (OS), according to different GC subtypes (1, 2, 3) in metastatic GC patients (pts) receiving first-line chemotherapy. Methods: Advanced GC pts treated with a first-line combination chemotherapy were included in our analysis. Pts were divided in three subgroups (type 1, type 2, and type 3) as previously defined. Results: A total of 248 advanced GC pts were included: most of pts belonged to type 2 (45.15%) and type 3 (43.55%); type 1 included 28 pts (11.30%). The majority of pts (65.4%) received a fluoropyrimidine-based chemotherapy doublet while the remaining 88 pts received a three drugs regimen including a platinum derivate and a fluoropyrimidine with the addition of an anthracycline, a taxane or mytomicin C. Most of pts (55.5%) received a second-line treatment, with FOLFIRI o taxanes. The three subgroups resulted comparable for relevant clinical factors such as ECOG PS, tumour stage, number of metastatic sites, previous surgical resection, first-line combination and use of second-line treatments; as expected peritoneal carcinosis was more common in type 2 pts. RR was found to be higher in type 1 pts (RR= 46.1%) and type 3 (34,3%) compared to type 2 (20,4%), (p= 0.015). Type 2 pts presented a shorter PFS, median PFS 4.2 months, compared to type 1, mPFS= 7.5 months, and type 3, mPFS= 5.9 months (p= 0.007) and also a shorter OS with a median OS of 9,8 months vs 11.5 months for type 1 and 11.0 for type 3 (p= 0.024). Conclusions: Our analysis suggests that GC subtypes may be important predictors of benefit from chemotherapy in advanced GC patients. Future clinical trials should take in account these differences for a better stratification of patients. Biomarkers analysis on tumour samples are ongoing.
HPV in upper aerodigestive tract tumors in southern Brazil.
Authors: Antunes Luis Carlos Moreira , Lopes Antonio de Barros , Muller Leandro Bizarro , Fagundes Renato Borges
Published: March 2020

e15083

Background: The highest rates of esophageal cancer in Brazil occur in Rio Grande do Sul (18/100,000/year for men), where squamous cell carcinoma is the most common. Furthermore, the incidence of head and neck squamous cell carcinoma (HNSCC) is significant in this region (11/100,000/year for cancer of the oral cavity and 10/100,000/year for laryngeal cancer in men). Tobacco smoking and alcohol consumption are the major risk factors for esophageal squamous cell carcinoma (ESCC) and HNSCC. The role of HPV in the development of ESCC remains controversial. Otherwise, there is some evidence that HPV-related HNSCC is a distinct entity compared with HNSCC associated with smoking and alcohol consumption. Methods: Polymerase chain reaction (PCR) was used to evaluate the presence of HPV from 218 samples from three groups of patients. Group 1 comprised 51 patients with ESCC who underwent esophagectomy, in which two samples from each patient were analyzed: one tumor sample and another from normal esophageal mucosa. Group 2 comprised 37 patients with HNSCC who underwent Lugol chromoendoscopy. In this group, we took biopsies from the primary tumor and from esophageal mucosa (unstained areas and middle esophagus when the esophageal mucosa was evenly stained). Thirty-seven dyspeptic patients, non-smokers and without alcohol consumption who underwent endoscopy, comprised Group 3, in which we took one biopsy from middle esophagus. All samples were fixed in formalin and stored in paraffin blocks. Nested-PCR with MY09/11 and GP5/6 primers was used to detect HPV L1 in those samples. Results: Of a total of 224 samples fixed in formalin and stored in paraffin, only 6 samples had insufficient material for PCR analysis: one sample from normal distal epithelium in Group 1, one sample from a stained area and 2 samples from unstained areas in Group 2 and 2 samples from normal esophageal mucosa in Group 3. PCR was positive for one of conserved genes GAPDH, G3PDH or B-globin in 218 samples, showing that DNA was adequate for analysis. The PCR results were negative for HPV DNA in all esophageal samples, as well as in all biopsies from the primary tumor of HNSCC. Conclusions: There is no evidence that HPV is involved in carcinogenesis of the upper aerodigestive tract in southern Brazil.
Final analysis of efficacy and safety of dose-dense chemotherapy with modified TCF regimen (TCF-dd) in elderly patients (pts) with metastatic gastric cancer (MGC).
Authors: Tomasello Gianluca , Liguigli Wanda , Poli Rossana , Ratti Margherita , Toppo Laura , Brighenti Matteo , Maltese Mariangela , Perrucci Bruno , Panni Stefano , Negri Federica , Lazzarelli Silvia , Colombi Chiara , Curti Alessandra , Donini Maddalena , Martinotti Mario , Rovatti Massimo , Passalacqua Rodolfo
Published: March 2020

e15086

Background: Gastric cancer is more common in elderly pts with its highest incidence around the seventh decade of life. Most oncologists are reluctant to treat this population with the most active polichemotherapy combinations because of safety concerns. Subgroup analyses of elderly pts enrolled in European studies show limited and conflicting data.We previously reported on the feasibility and high activity of a dose-dense TCF regimen (Tomasello 2010). This is a retrospective analysis of efficacy and safety of this schema in the elderly pts subgroup (≥ 65 years). Methods: From Nov 2004 to Jan 2013, 119 consecutivepts with MGC, PS 0-2, not previously treated, received Docetaxel 70 mg/m2 d1, Cisplatin 60 mg/m2 d1, l-Folinic Acid 100 mg/m2 d1-2, followed by 5-FU 400 mg/m2 bolus d1-2, and then 600 mg/m222 h c.i. d1-2, every 2 weeks, plus Pegfilgrastim 6 mg on day 3. Pts aged ≥ 65 years (60) received the same schedule with doses reducted by 30%. Results: Overall pts characteristics: 76% male, 24% female; median age: 65, range 31-81. A median of 4 cycles was administered. 102 pts were evaluable for response (86%) and all for toxicity. In pts aged ≥ 65 y, we observed 5 CR (8%), 26 PR (43%), 10 SD (17%) and 7 PD (12%); in younger pts: 3 CR (5%), 32 PR (54%), 9 SD (15%) and 10 PD (17%); ORR by ITT was 56% (95% CI 45-64). Median OS was 11,2 months (95% CI 9,4-14,1); in elderly and younger pts was 11,2 (95% CI 7,3-15,1) and 11,8 (95% CI 9,2-16,2), respectively. Out of 48 evaluable pts aged ≥ 65 years, 24 (50%) were treated at full doses without any delay. In the elderly most frequent grade 3-4 toxicities were: neutropenia (13%, p<0.0001), leucopenia (7%), thrombocytopenia (18%), anemia (3%, p=0.02), febrile neutropenia (8%), asthenia (27%), diarrhea (10%), nausea/vomiting (10%) and hypokalemia (17%); in the younger: neutropenia (56%), leucopenia (31%), thrombocytopenia (22%), anemia (15%), febrile neutropenia (15%), asthenia (41%), diarrhea (15%), nausea/vomiting (22%) and hypokalemia (20%). Conclusions: This study shows that elderly pts can be safely treated with a TCF-dd regimen with a 30% dose reduction achieving similar efficacy results as younger pts with lesser toxicity.
The relationship between collapsin response mediator protein-1 (CRMP 1) expression and histopathogic parameters and survival in patient with gastric cancer.
Authors: Gumus Mahmut , Yasar Nurgul , Kayahan Sibel , Yuksel Sinemis , Balvan Ozlem , Guven Mert Aslihan , Dinc Nur , Aydin Dincer , Aydin Kubra , Odabasi Hatice , Korkmaz Taner , Aliustaoglu Mehmet
Published: March 2020

e15100

Background: Biomarkers which indicate invasion and metastasis in patients with gastric cancer are important. Collapsin response mediator protein (CRMP) family proteins are cytosolic phosphoproteins involved in semaphorin 3A-mediated neuronal cell growth cone collapse and cancer invasion. CRMP1 over expression levels were found to have negative association with invasion and metastasis in lung cancer tissue samples. The aim of the study was to investigate relationship between CRMP1 expression and histopathological parameters and prognostic value of CRMP1 expression in patients with gastric cancer. Methods: We analyzed 52 patients who were diagnosed with gastric cancer. The CRMP1 expression was examined by performing immunohistochemical staining. High CRMP1 expression in gastric tumor samples was defined as being immunoreactive to CRMP1 antibody in more than 50% of the cancer cells. The correlation between CRMP1 expression and age, gender, tumor grade, lenfovascular-perineural invasion, t stage and nodal involvement was investigated. Results: Among the 52 patients (CRMP1 positive/CRMP1 negative= 24/28), median age was 56 years (27-84). Thirty-five patients were male and 17 patients were female. The median follow-up time was 14 (2-60) months. The median disease-free survival time (DFS) was 20 (SE: 4; 95% CI: 13-27) months. In addition, the median overall survival time (OS) was not reached. The significant relationship was found between CRMP1 high expression levels and high grade tumors (p:0.03), and nodal metastasis (p:0.019). In univariate analysis, only high CRMP1 expression was associated with poor disease-free survival (p:0.004). Also, male gender (p:0.023), high grade tumors (p:0.044), nodal involvement (p:0.028) and high CRMP-1 expression were associated shorter overall survival. In multivariate analysis, no independent prognostic factor was found in this group. Conclusions: We found that high expression of CRMP1 was associated with tumor aggressiveness of tumor and poor survival. Larger studies and further clinical trials are warranted to confirm these findings.
Impact of multidisciplinary cancer care on the postoperative mortality and survival of patients with esophageal and esophagogastric junction cancer.
Authors: Galán Maica , Farran Leandre , Aliste Luisa , Hormigo Gloria , Calvo Mariona , Aranda Humberto , Boladeras Ana Maria , Botargues Josep Maria , de Lama Eugenia , Paúles Maria Jose , Robles Javier , Serra Olbia , Virgili Núria , Borràs Josep Maria
Published: March 2020

e15111

Background: Modern management of Oesophageal and oesophagogastric junction (OGJ) cancers requires a multidisciplinary approach, which was implemented at our health centre in 2005. This study aimed to assess the impact of this change on clinical outcomes. Methods: A retrospective cohort study was conducted, covering all patients treated for oesophageal and OGJ cancer at the cancer centre established by the Bellvitge University Hospital and Catalonian Institute of Oncology, over two time periods, i.e., 2000-2004 and 2005-2008. Descriptive and multivariate analyses were performed using survival at 1 and 3 years as dependent variables. Results: Between 1 January 2000 and 31 December 2008, 586 patients were included. Number of patients with unknown stage at diagnosis was significantly reduced. Neoadjuvant strategies at the oesophageal location clearly increased in the recent period. A multidisciplinary approach resulted in a significant reduction in surgical mortality (11.8% vs. 2%) in the period 2005-2008. Analysis restricted to patients undergoing surgery with curative intent indicated a significant increase in 1- and 3-year survival in the latter period (68.4% vs. 89.8% and 38.2% vs. 57.1% respectively). Multivariate analysis showed that variables associated with improved survival were: age; tumour stage; radical intent of treatment (surgery and radical combined chemoradiotherapy); and therapeutic strategy. Conclusions: Better selection of patients for therapy together with improved staging resulted in a significant improvement in 1- and 3-year survival in cases undergoing surgery with curative intent. These changes would support the adoption of a multidisciplinary approach to clinical decision-making in cases of oesophageal and OGJ cancer.
CRM1 expression in pancreatic carcinoma.
Authors: Mahipal Amit , Coppola Domenico , Gupta Shilpa , Centeno Barbara , Malafa Mokenge Peter
Published: March 2020

e15115

Background: Increased expression of chromosomal region maintenance (CRM1) protein, also known as exportin 1, has been described in several human cancers. It is an important regulator of subcellular localization of tumor suppressor proteins and growth regulatory proteins. Direct inhibition of CRM1 blocks cell proliferation and induces apoptosis leading to the current evaluation of CRM1 inhibitors as anticancer agents in early phase clinical trials. There is a paucity of data regarding the prevalence of CRM1 expression in pancreatic cancer. Methods: We analyzed the expression of CRM1 by immunohistochemistry (IHC) in pancreatic tissue microarray (TMA) samples (malignant and non-malignant) obtained from patients who underwent potentially curative resection for pancreatic ductal adenocarcinoma. CRM1 antibody (Santa Cruz Biotechnology) was used for immunostaining the formalin fixed paraffin embedded core sections in the TMA samples. The intensity of staining and percentage of cells stained were graded on a scale of 0 to 3, with 3 being highest. The final IHC score was obtained using the product of immunostain intensity and percentage of cells stained (Range: 0-9). Low and high CRM1 expression was considered if the IHC score was 0 to 4 and 6 to 9 respectively. Results: Seventy nonmalignant and 91 pancreatic carcinoma samples were evaluated in this study. The median IHC score was 6 (range: 0-9) and 3 (range: 1-9) in malignant and nonmalignant pancreatic tissue samples respectively (P<0.0001). High CRM1 expression was found in 11% (8/70) of normal tissue samples and 69% (63/91) of tumor samples (P<0.0001). There were 48 paired samples of pancreatic cancer tissue and normal tissue obtained from same patient. Among these patients, 33 (69%) patients had higher CRM1 expression, 7 (15%) patients had similar expression and 8 (17%) patients had lower expression in malignant tissue sample as compared to their adjacent normal tissues. Conclusions: Higher CRM1 expression occurs frequently in pancreatic cancer as compared to nonmalignant pancreatic tissue, reinforcing its putative tumor oncogenic activity, and raising the value of targeting it for pancreatic cancer therapy.
Prognostic significance of the recurrence pattern and risk factors for recurrence in patients with proximal gastric cancer.
Authors: Bilici Ahmet , Selcukbiricik Fatih , Oven Ustaalioglu Bala Basak , Tural Deniz , Seker Mesut , Gumus Mahmut , Serdengecti Suheyla
Published: March 2020

e15117

Background: The proximal gastric cancer (GC) is usually diagnosed at advanced stage and it had relatively high recurrence rate after curative resection due to high incidence of lymph node metastasis. This study aimed to investigate the pattern and time of recurrence and to evaluate the risk factors for relapse of proximal GC. Methods: Between 2000 and 2012,110 patients with recurrent proximal GC undergoing radical gastrectomy were retrospectively analyzed.The prognostic significance of the recurrence time and pattern at the diagnosis of relapse and the relationship between the pattern of recurrence and the other clinicopathological factors were evaluated. Results: The median time to recurrence was 34 months, 52.7% of patients had relapse within 2 years. The most recurrence patterns were hematogenous and peritoneal metastasis, respectively (47.3 and 39.1%). Hematogenous and loco-regional recurrence were significantly associated with younger age (p=0.04) and proximal resection was related with higher incidence of all recurrence patterns (p<0.001). Moreover, advanced pT stage was significantly correlated with increased hematogenous and peritoneal recurrence (p=0.002). The median disease-free survival (DFS) and overall survival (OS) times for patients with distant-lymph nodes and hematogenous recurrences were significantly worse than those of patients with loco-regional and peritoneal recurrences (DFS, 9.7 vs. 23.4 vs. 35.4 vs. 43.9 months, p=0.014; OS, 19 vs. 46.4 vs. 70.2 vs. 66.8 months, p=0.04, respectively). Multivariate analysis showed that the time of recurrence [p<0.001, HR: 0.37), pN stage, clinical stage and surgery type were independent prognostic factors for OS. The presence of lymph node metastasis was an independent risk factor for both overall and early recurrence (p=0.004, OR: 0.51). Conclusions: Our results indicate that the time of recurrence, surgery type, lymph node metastasis and clinical stage were independent prognostic indicators for OS, while only the presence of lymph node metastasis was an independent risk factor for early recurrence. Total gastrectomy and adequate lymph nodes dissection were rational curative treatment option for proximal GC.
Dose-escalated image-guided radiation and weekly cisplatin for inoperable squamous cell carcinoma of thoracic esophagus.
Authors: Chilukuri Srinivas , Pawar Yeshwanth S. , Subramanian Sai Shanmugam , Kiran Kumar K. , Yadala Nalini , Tike Pramod K. , Kathirvel M. , Gandhi Arun , Swamy Thirumalai , Ghadyalpatil Nikhil
Published: March 2020

e15120

Background: This study evaluates feasibility, toxicity and early outcomes of image guided volumetric modulated arc therapy (IG-RA) and weekly cisplatin for locally advanced inoperable squamous cell carcinoma (LAI-SCC) of thoracic esophagus. Methods: 41 patients diagnosed with LAI-SCC were included. Patients with performance status (ECOG) more than 1, involvement of cervical esophagus or gastroesophageal junction, distant metastasis were excluded from study. Radiotherapy was planned in two phases to a dose of 5940cGy. Phase I CTV was generated by expanding the GTV-primary craniocaudally(CC) by 4cm and laterally to include electively, the corresponding level mediastinal nodes. In the Phase II, GTV was expanded by 2cm CC and 1cm radially. ITV was generated by expanding the CTV by 0.5cm which was then expanded by 0.5cm to yield PTV. Chemotherapy consisted of 4-6 cycles of weekly cisplatin 40mg/m2. Results: The median age of patients was 53 yrs (43-72). The median length of involvement was 6cm with 80% of lesions in upper and middle third. 37/41(90%) patients completed planned chemotherapy with atleast 4 cycles of cisplatin and 40/41 patients completed full dose of radiotherapy. 10% of patients required tube feeding and 5% required hospital admission for supportive care. Endoscopy at 8 weeks post treatment was performed in 38/41 patients of whom 53% had CR, 42% had PR and 5% had stable disease locally. With a median follow up of 19 (6-32) months, 41% of total patients (17/41) are alive at last follow-up of which 32% (13/41) are disease free with no dysphagia, the 1 and 2 year overall survival are 70% and 40% respectively and median survival of 14 months. 16% alive patients have post radiotherapy stricture. The analysis of CBCT and KV image data sets showed a significant intra-fraction and inter-fraction motion of the target. The ITV and PTV margins of 0.5cm each were found to be adequate with current imaging protocol. Conclusions: IG-RA to a dose of 60Gy with concurrent weekly cisplatin is a feasible treatment option for LAI-SCC of thoracic esophagus with low acute and late toxicity and with promising early clinical outcomes. The ITV and PTV margins of 0.5cm were found to be adequate only with image guidance.
Phase II trial of sorafenib (S) and capecitabine (C) for hepatocellular carcinoma (HCC) in cirrhotic patients (pts).
Authors: Rojas-Hernandez Cristhiam Mauricio , Patt Yehuda Z. , Fekrazad M. Houman , Steinberg Kim A. , Roach Mary , Lee Fa-Chyi
Published: March 2020

e15136

Background: S is the currently approved treatment for HCC. C has antitumor activity in HCC and biliary tree cancers. The combination of the two, if tolerated, could possibly improve antitumor response, and patient-overall survival (OS). Methods: This phase II trial of S and C accrued unresectable HCC pts. with histologically confirmed disease or radiological characteristics of HCC in cirrhotics with an elevated AFP of > 400 ng/mL. Eligibility criteria were: ECOG Performance status of ≤ 2, Child-Pugh (CP) class A or B-7 cirrhosis, hemoglobin ≥ 8.5 g/dL, platelets ≥ 50,000/µL, ANC ≥ 1500 cells/µL, and a serum creatinine of ≤ 2.0 mg/dL (creatinine clearance > 30 mL/minute). HIV+ patients were excluded. All subjects received a combination of S and C, on a 14-day treatment schedule. S dose was started at 400 mg BID daily with dose adjustments for hand foot syndrome. Starting C dose was 850 mg/m2BID for 7 days and a 7-day break; doses were adjusted as tolerated. The primary end point was assessment of safety and tolerability. OS and disease control rate (DCR) were also estimated. Results: 15/47 assessed pts. met inclusion criteria. One patient was never treated and excluded from analysis. Response data were available on 13 and safety data on all 14. Median pts.’ age was 64 years (56-79), and 75 % were male. Etiologies included viral hepatitis (64%), or viral hepatitis and alcohol in another 29%; 50% of pts. had CP class A (5-6) and 50% B-7 cirrhosis. With a median follow up of 12 months (M), median OS (mOS) was 11.3 (95% CI, 2.7-21.3) M. DCR was 54% (CR 8%, PR 15% and SD 31%). Grade 3-4 adverse events included: thrombocytopenia 9(64%), neutropenia 1(7%), anemia 2(14%); electrolyte imbalance, hypophosphatemia 3(21%), hypomagnesemia 2(14%), hypocalcaemia 1 and hyponatremia 1 (7%) each. Liver abnormalities included; hyperbilirubinemia 3(21%), increased AST 2(14%). Skin and mucosal abnormalities included hand-foot syndrome 3(21%), mucositis 1, alopecia 1 and skin rash 1 each. DVT occurred in 3 (21%). Conclusions: At tolerable doses, S and C seem active and safe palliative treatment for HCC in CP A & B-7 cirrhotics. It was associated with a DCR of 54% and mOS of 11.3 M. The small sample size does not allow comparison with single agent S. Clinical trial information: NCT01032850.
Early therapy response assessment by apparent diffusion coefficient (ADC) quantification following glass-based yttrium-90 radioembolization for unresectable hepatocellular carcinoma (HCC).
Authors: Kokabi Nima , Camacho Juan C. , El-Rayes Bassel F. , Kauh John S. , Kim Hyun Sik
Published: March 2020

e15140

Background: Early objective imaging biomarker assessment of infiltrative HCC following Y90 radioembolization is not well understood. Early diffusion weighted imaging (DWI) of treated lesions was evaluated and correlated with anatomical treatment response using modified response evaluation criteria in solid tumors (mRECIST). Methods: In an IRB approved prospective proof of concept study, 10 consecutive patients (89% men, median age 55) with unresectable infiltrative HCC and portal vein thrombosis underwent Y90. MR imaging was obtained pre-Y90, 1 and 3 months post-Y90. DWI fat-suppressed single-shot echo-planar sequence with tri-directional diffusion gradient was performed (b=50,400,800 s/mm2). Using pixel-based ADC maps, mean values of treated lesions and surrounding tumor-free liver were measured by manually drawing a noncircular region of interest around corresponding areas on the same image slice. Treatment response was evaluated using mRECIST with complete response as non-enhancement of treated lesion. T-test was performed using SPSS Statistics v20.0 (IBM, Armonk, NY) and significance set at < 0.05. Results: On 30 day post therapy MR and based on mRECIST, 70% of patients had objective response (CR=30%, PR=40%, SD=20%, PD=10%). Mean pre and post-Y90 ADC value of cancer-free liver was 1.10 × 10−3 and 1.08 × 10−3 mm2/sec (p=0.65). Mean ADC value of all treated tumors pre and post-Y90 was 0.82 × 10−3 and 1.19 × 10−3 mm2/sec respectively (p <0.001). Correlating with mRECIST treatment response, mean post-Y90 ADC of lesions with objective and those with no objective response were 1.03 × 10−3 mm2/sec and 1.26 × 10−3 mm2/sec respectively (p=0.003). While there was a significant difference between ADC values of lesion with objective response vs. others, no significant difference was observed at baseline ADC of tumors with eventual objective response vs. others. Corresponding ADC values on 30 and 90 day followup scans were unchanged. Conclusions: Mean ADC value measured 30-days post-therapy shows promises as an objective imaging biomarker to assess treatment response following Y90 therapy for infiltrative HCC.
PERCIST criteria to predict survival at 3 months following intra-arterial resin-based yttrium-90 (Y-90) radioembolization therapy of unresectable intrahepatic cholangiocarcinoma refractory to standard chemotherapy: A proof of concept study.
Authors: Camacho Juan C. , Kokabi Nima , Schuster David M. , Kim Hyun Sik
Published: March 2020

e15141

Background: To investigate the prognostic value of PET Response Criteria in Solid Tumors (PERCIST) on predicting survival in patients with unresectable intrahepatic cholangiocarcinoma (ICC) after resin-basedYttrium-90 (Y-90) radioembolization. Methods: IRB approved prospective correlative study in ICC patients refractory to standard chemotherapy who had 18F-FDG PET-CT before and after Y-90 therapy. Measurable tumor was defined as a lesion ≥ 1 cm in diameter and maximum standardized uptake ((max) SUV) ≥ 2.5. (Max) SUV was measured in targeted and non-targeted lesions after local therapy (overall response). PERCIST criteria defined complete response (CR) as no FDG uptake within target lesion, and partial response (PR) as reduction of 30% in FDG (max) SUV peak in measurable lesions. Objective response included PR/CR. PET imaging was acquired pre-treatment, 1-3-and-6 months following Y90. Survival analyses were carried out with Kaplan–Meier and Log-Rank proportional models using SPSS software v20 (IBM, Armonk, NY) with significance set at <0.05. Results: 9 consecutive patients were enrolled (56% men, mean age 58). Median overall survival from Y90 was 21.7 months. Average max SUV pretreatment was 10.02 and after Y90, 6.03. At 1-month after Y90, target PERCIST criteria showed CR= 1 (11.1%), PR=1 (11.1%), SD=7 (33.3%) and PD=0 (0.0%). Following 3-month after Y90, target response was CR= 2 (22.2%), PR=3 (33.3%), SD=3 (33.3%) and PD=1 (11.1%). No correlation between survival and either target or overall PERCIST criteria response on 1-month follow-up scan was seen(p=0.260). Statistically significant prolonged overall survival was observed for patients with objective targeted response based on PERCIST criteria at 3-month scan (P=0.022). In addition, objective overall PERCIST response at 3-month showed significant correlation with overall survival (p= 0.011). Conclusions: In patients with unresectable ICC refractory to standard chemotherapy, PERCIST criteria at 3-months following Y-90 therapy predict overall survival.
A retrospective analysis of early CA19-9 progression in salvage-chemotherapy for refractory pancreatic cancer.
Authors: Nakai Yousuke , Isayama Hiroyuki , Sasaki Takashi , Takahara Naminatsu , Kogure Hirofumi , Yamamoto Natsuyo , Hirano Kenji , Ijichi Hideaki , Tateishi Keisuke , Tada Minoru , Koike Kazuhiko
Published: March 2020

e15146

Background: Early response assessment is important to differentiate patients (pts) who will benefit from salvage chemotherapy (sCx) for refractory pancreatic cancer (PaC), given its palliative nature. CA19-9 has been reported as a prognostic factor in the first-line treatment, but little data is available in sCx. Methods: Pts receiving sCx for refractory PaC at the University of Tokyo Hospital were retrospectively studied. Serum CA19-9 was measured prior to the initiation of each course. Cumulative progression-free (PFS) and overall survival (OS) were calculated by Kaplan-Meier analysis and compared by log-rank test. Prognostic value of CA19-9 change prior to 2nd course was evaluated using a landmark method. Finally, multivariate analyses by the Cox proportional hazard model were performed for PFS and OS. Possible prognostic factors were age, gender, PS, disease status, metastatic site, pretreatment albumin, LDH, CRP, CA19-9, CA19-9 change prior to 2nd course, prior PFS, treatment line (2ndline or beyond) and sCx agents. Results: A total of 167 pts (a median age of 65, 95 males, 21 recurrent and a median previous PFS of 5.8 Mo) received 239 regimens as sCx including S-1(n=87), CPT-11 (n=53), GEM+oxaliplatin(Ox) (n=20), S-1+Ox(n=29), GEM (n=14) and S-1+paclitaxel iv+ip (n=12). Median PFS and OS were 2.7 (95%CI, 2.4-3.1) and 6.1 (95%CI, 5.3-7.2) Mo, respectively. Early CA19-9 progression was defined as CA19-9 increase >17.8%, a median value of CA19-9 change prior to 2nd course in this study population. Median PFS and OS were 2.6 vs. 1.0 Mo and 7.5 vs. 3.6 Mo (p<0.001) after landmark CA19-9 measurement in pts with and without CA19-9 response. Multivariate analyses demonstrated early CA19-9 progression was a negative prognostic factor of both PFS and OS (HR 1.75 and 2.04, p<0.001). Pretreatment serum markers (albumin, LDH, CRP and CA19-9) were prognostic of OS, but not PFS. Conclusions: Early CA19-9 progression was a negative prognostic factor of both PFS and OS in S-Cx for refractory PaC. Early termination should be considered in these patients who would less likely benefit from sCx.
The clinical effects of hepatic artery infusion of recombinant adenoviral human p53 gene combined with local chemo- and radiotherapy in treatment of advanced hematocarcinoma.
Authors: Xiao Shaowen , Geng Jianhao , Zhang Shanwen
Published: March 2020

e15166

Background: Advanced are generally resistant to both chemo- and radio-therapy. P53 gene has multiple anti-cancer functions including sensitizing tumor cells to chemo- and radio-therapy. Methods: Twenty-two patients with an age of 51.5±19.0 years old, 15 males and 7 females, 21 in stage IV and 1 in stage III, were treated with combination of p53 gene, chemo- and radio-therapy. Recombinant adenoviral human p53 gene (rAd-p53) was given through hepatic artery pump at a dose of 2 x 1012 viral particles once per week for 4-9 times. The chemo-regimen consisting of doxorubicin 20mg/m2 and Oxaliplatin 40mg/m2were administered through the same pump once a week for 4-8 times. Intensity modulated radiation therapy were given at a total dose of 20 – 60 Gy in 4 weeks. Results: The overall response rate at 3 months after treatment was 31.7% (7/22, 1/22 in CR and 6/22 in PR). Thirteen patients (59.1%) were stable. Medium overall survival and progress free survival time were 11 and 5.5 months, respectively. The survival rates of one year, two years and three years were 31.8%, 13.6%, and 4.5%, respectively. No serious adverse events or complications observed. Conclusions: Combination of local p53 gene, chemo- and radio-therapy is effective and safe treatment regimen for advanced hepatocarcinoma.
Epidermal growth factor receptor as a prognostic predictor to chemoradiotherapy in the primary lesion of esophageal squamous cell carcinoma.
Authors: Gao Zhenhua , Meng Xue , Mu Dianbin , Sun Xindong , Yu Jinming
Published: March 2020

e15167

Background: Concurrent chemoradiotherapy (CCRT) is standard performed for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Some reports have revealed that patients who responded well to CCRT had favorable outcomes, whereas poor responders conversely showed a worse prognosis. The aim of this study was to identify molecular markers predicting prognosis to CCRT. Methods: Forty-seven patients with locally advanced ESCC who were treated with CCRT were included in the present study.The regimen comprised 5-fluorouracil and cisplatinumcombined with radiation therapy (1.8-2Gy/day). The chemotherapy was repeated every 3 weeks and the total radical radiation dose was 60-64Gy.The clinicopathologic features, patterns of treatment failure, and survival data were compared with the expressions of epidermal growth factor receptor (EGFR), which were determined by immunohistochemistry in biopsy specimens obtained before treatment. Univariate and multivariate analyses were performed to determine the prognostic factors that influence patients survival. Results: Overall the indices of the overexprssions of EGFR (the percentage of immunoreactivetumor cells≥50%) in all patients were 59.6%. EGFR expression was no significantly associated with gender,age,tumor differentiation grade,tumor location,depth of invasion, and metastasis status except for lymph node status (P=0.011). A significant difference was seen in the overall survival between patients with or without EGFR overexpression group(P=0.024). However, overexpression of EGFR was not associated with local recurrence or distant metastasis.In addition, a relationship between overall survival and sex (P=0.021),age (P=0.018),T stage(P=0.035), and tumor location (P=0.023) was detected.Local recurrence was found has a relationship with T stage(P=0.015) and metastasis status (P=0.026),and distant metastasis was found has a relationship with age (P=0.048). Conclusions: EGFR overexpression determined in pretreatment biopsy specimens maybe a clinically useful biomarker for predicting the overall survival of ESCC patients.
Comparative efficacy and safety analysis of sorafenib in patients with advanced hepatocellular cancer (HCC) with varying liver dysfunction: A south Texas institutional analysis.
Authors: Al-Rajabi Raed Moh'd Taiseer , Ketchum Norma , Dierschke Nicole A. , Lu Ting Wei , Pollock Brad H. , Mahalingam Devalingam
Published: March 2020

e15171

Background: Sorafenib (SOR) is the first systemic therapy to improve survival in patients (pts) with advanced (HCC), mainly amongst pts with Child-Pugh (CP) A cirrhosis. In the US however, HCC pts often present with ECOG status ≥ 1 and CP B cirrhosis. The GIDEON study reported variation in disease characteristics and treatment patterns for US pts compared to rest of the world. Our aim was to further assess clinical efficacy and safety of SOR at our institution’s minority rich South Texas HCC population. Methods: We reviewed medical records of HCC pts who received SOR from 2008-2011. The association between demographic, clinical and laboratory variables with overall survival (OS) and progression free survival (PFS) were assessed by comparison of Kaplan-Meier curves. Groups were statistically compared by the log rank test and the magnitude of association with outcome was summarized as the hazards ratio with 95% confidence interval (CI). Results: A total of 67 pts were included. Median age 55 (range 41-93), males 83%, Hispanic 76%, CP A 59% vs B 39%. The median OS (mOS) was 10.0 months (mo) (95% CI: 7.2-18.3) and median PFS (mPFS) was 4.9 mo (95% CI: 3.1-7.1); both comparable to reported efficacy of the SHARP trial. In subgroup analysis, mOS was 12.8 (95% CI: 7.7–18.3) vs 7.2 mo (95% CI: 2.6–24.4) for CP A and B (HR 0.72, 95% CI: 0.37–1.38, p = 0.32), respectively. CP A pts had a mPFS of 5.9 (95% CI: 1.6–10.0) vs 3.6 mo (95% CI: 4.4–7.6) with CP B pts (HR 0.77, 95% CI: 0.45–1.34, p = 0.36). Pts on SOR daily dose of 800 mg had a better mOS at 12.8 (95% CI: 6.9–24.4) vs 8.7 mo (95% CI: 2.0–15.8) compared to those on 400 mg (HR 0.58, 95% CI: 0.29–1.15, p = 0.11). Although no significant difference in efficacy was noted between ethnicities, pts ≥ 60 years had an improved mOS at 15.9 (95% CI: 6.9–24.4) vs 7.9 mo (95% CI: 2.0–15.8) amongst pts < 60 (HR 0.56, 95% CI: 0.28-1.12, p = 0.10). There was no difference in toxicity observed. Conclusions: SOR was well tolerated in both CP A and B groups. Efficacy analysis showed a trend towards improved survival among pts with CP A treated with a daily dose of 800mg. The improved efficacy of SOR among pts ≥ 60 may be related to a more indolent HCC in this age group.
A phase II study of TR105 in patients with hepatocellular carcinoma (HCC) who have progressed on sorafenib.
Authors: Duffy Austin G. , Rahma Osama E. , Ulahannan Susanna Varkey , Fioravanti Suzanne , Venkatesan Aradhana , Turkbey Ismail B. , Choyke Peter L. , Trepel Jane B. , Figg William Douglas , Greten Tim F.
Published: March 2020

e15177

Background: CD105, also known as endoglin, is an endothelial cell membrane receptor that is highly expressed on tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with HCC and compensated liver function (Childs Pugh A/B7), ECOG 0/1, were enrolled to a single arm phase II study of TRC105 15mg/kg IV every 2 weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal 2-stage design was employed with a 50% 4-month PFS target for progression to the second stage. Correlative biomarkers evaluated included: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Immunogenicity studies were also performed. Results: 8 pts have been treated so far; M:F 6:2; Median age = 58 (range 24-67); 7 pts had progressed following sorafenib (N=1 intolerant). N=1 pt had fibrolammellar HCC. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N=3) and epistaxis (G1; N=4). One patient with a history of ischemic heart disease developed acute cardiac syndrome during the first infusion and was replaced. No patient was progression free at 4 months by RECIST criteria. Median time on study was 8 weeks (range 4-16 weeks). Median no. of doses administered was 4 (range 2-7). Preliminary evidence of biologic response was seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in kTrans and kep and 3pts (of 3 evaluable) who demonstrated reduction in intra-tumoral color flow on color Doppler. Conclusions: TRC105 is well tolerated in this HCC population post-sorafenib. Although there was biological evidence of antiangiogenic activity it is unlikely that the study will proceed to the second stage. Full clinical and correlative data for the first stage of the study will be presented. Future role of TRC105 in HCC will most likely be as combination therapy with sorafenib or other anti-VEGF therapy. Clinical trial information: NCT01375569.
Laparoscopic transhiatal esophagectomy with neoadjuvant chemotherapy to treat carcinoma of the upper esophagus.
Authors: Wu Ji-xiang , Yu Lei , Li Jian-ye
Published: March 2020

e15181

Background: Esophagectomy for Carcinoma of the upper esophagus has traditionally been performed by open methods. Results from most series include mortality rates in excess of 5% and hospital stays frequently greater than 14 days. Laparoscopic transhiatal esophagectomy (LTHE) with neoadjuvant chemotherapy has the potential to improve these results and may lead to a sound outcome, but only a few articles have reported it. The objective of this study is to investigate the method of LTHE with neoadjuvant chemotherapy treating cervical esophageal cancer. Methods: From 2011 to 2012, LTHE was performed in 15 patients with carcinoma of the upper esophagus. There were 11 men and 4 women. Median age was 64 years (range, 44–79). Indications for operation included high-grade dysplasia (n = 4) and cancer (n = 11). Neoadjuvant chemotherapy was used in 15 patients. Results: There was no conversion to open procedure. LTHE was successfully completed in 15 patients. The median intensive care unit stay was 1.5 days (range, 1–8); hospital stay was 10.5 days (range, 8–23). Anastomotic leak rate was 6.7% (n=1). At a mean follow-up of 13 months (range, 1–24), quality of life scores were similar to preoperative values and population norms. Conclusions: LTHE with neoadjuvant chemotherapy is a safe and relatively advanced, complex procedure with little blood loss and less-invasion. Its long-term outcome needs to be investigated with large-volume cases.
Clinical features of long-term survivors (LTS) of advanced hepatocellular carcinoma undergoing molecular targeted therapy (MTT).
Authors: Lu Li-Chun , Shao Yu Yun , Chan Soa-Yu , Hsu Chih-Hung , Cheng Ann-Lii
Published: March 2020

e15182

Background: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is generally dismal. However, some patients enjoyed long survival under MTT. This study sought to clarify the clinical features of these patients. Methods: Patients with advanced HCC (Barcelona-Clinic Liver Cancer stage C) who were enrolled in six clinical trials of first-line MTT between May 2005 and December 2010 at National Taiwan University Hospital, Taipei, Taiwan were included. LTS (> 2 years) were identified, and their clinical variables were reviewed and analyzed. Results: Twenty-two LTS (11.6%), with a median age of 58.3 years, were identified from 189 patients. The median overall survival of LTS was 58.7 months. Among them, 17 (77.3%) patients were male, and 13 (59.1%) patients had chronic hepatitis B virus infection. Compared with patients who survived less than 2 years, LTS were less likely to have α-fetoprotein > 400 ng/mL, liver involvement, or macrovascular invasion. LTS were more likely to have Okuda stage I disease, and lower Cancer of the Liver Italian Program scores. Regarding response to the first-line therapy, LTS had significantly higher response rates (50.0%) and disease control rates (86.4%). The median progression free survival of LTS was 13.0 months. After first-line treatment failure, 13 (59.1%) LTS received 2nd-line or more systemic therapies, and 15 (68.2%) LTS underwent loco-regional therapy, such as surgery, radiofrequency ablation, or transarterial chemoembolization. Seven (31.8%) LTS who received salvage loco-regional treatments remained disease-free for a median time of 27.0 months. Conclusions: LTS of advanced HCC appear to be a group of patients who had less aggressive disease status and were able to receive further loco-regional therapy.