bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytokine levels in patients (pts) with localized colorectal cancer (CRC) after surgery and their relationship to fatigue and cognitive function
Authors: Vardy J. , Rourke S. , Galica J. , Pond G. R. , Park A. , Zhang H. , Clarke S. J. , Dhillon H. , Wagner L. , Tannock I. F.
Published: March 2020

3623

Background: Cytokines have been associated with fatigue and cognitive dysfunction. Here we evaluate cytokine levels in pts with CRC as part of a longitudinal study evaluating these symptoms. Methods: Serum levels of 12 cytokines were measured using a LiquiChip assay on pts with localized CRC at baseline (mean 7 weeks post-surgery or before neoadjuvant therapy), 6 and 12 months. Group A (Stage III/high risk II) received chemotherapy (CT) and group B (Stage I/II) received no CT. Pts completed concurrent questionnaires for fatigue & QOL (FACT-F), anxiety/depression (GHQ), and perception of cognitive function (FACT-COG); they had neuropsychological (NP) assessment with traditional tests and CANTAB, a computerized NP battery. Associations between cytokine levels, test results, demographic and disease-related factors were sought. Results: Baseline data are available for 82 pts: 65 group A and 17 group B, with follow-up at 6 and 12 months for 32 and 15 pts. Mean age was 58 years and 68% were male. Cytokine levels were elevated in all groups with larger ranges after surgery (selected data in table ); in healthy people they are generally undetectable. There was cognitive impairment at baseline in 28% on traditional NP tests. At 6 months CT pts had more fatigue (median FACT-F 43 vs 47), perceived more cognitive impairment (median FACT-COG 127 vs 138), and had more cognitive impairment on CANTAB (42% vs 17%), but not on traditional NP tests (32% vs 33%). At 6 months, elevated cytokines (IL-1,-6,-8,-12, TNF, IFN) were associated with greater deficit on CANTAB (p<0.06); there was no association of cytokines with time from surgery, traditional NP test score, FACT-COG, fatigue, QOL or anxiety & depression. Conclusions: Cytokine levels were elevated in most pts. Cognitive impairment is present in some pts prior to chemotherapy and CT pts have worse impairment on computerized NP tests than non-CT pts. Elevated cytokines may be associated with worse cognitive function.

[Table: see text]

No significant financial relationships to disclose.
Variation in the cost of treatment for colorectal cancer
Authors: Ferro S. A. , Cosler L. E. , Wolff D. A. , Poniewierski M. S. , Culakova E. , Khorana A. A. , Lyman G. H.
Published: March 2020

3625

Background: Recent publications have drawn attention to the escalating costs of drugs utilized for the treatment and supportive care of colorectal cancer (CRC) patients. As more advanced chemotherapeutic and supportive agents are approved, the cost of treatment will likely continue to increase. The goal of this analysis was to estimate costs of frequently used CRC chemotherapeutics and other commonly prescribed agents. Methods: Costs of drugs in CRC regimens for patients participating in a prospective, observational study from 115 community oncology practices between March 2002 and March 2005 were calculated. Standard dosages and schedules were determined through literature review and an expert CRC oncologist. Trimmed mean (90%) costs were computed using average wholesale prices (AWP) retrieved from the Lexicon Database Drug Product (January 2005). All prices noted are 95% AWP. All chemotherapeutic drugs were combined to arrive at regimen specific prices. Other regimens were defined as regimens with less than four patients. Price per cycle was estimated based on a standard patient BSA of 2.0 m2 and standard regimen schedules. Growth factor costs were derived from expected per cycle utilization, while prices for other supportive drugs were calculated using dosages for single events. Results: Patients were categorized into the following regimens ( table below). The price of a commonly used monoclonal antibody is: Bevacizumab ($2613), based on every 2 week dosing. Growth factor prices (per cycle) were estimated: Filgrastim ($2499), Pegfilgrastim ($2928), Epoetin ($552), and Darbepoetin Alfa ($1002). Prices per event for other commonly used agents were: Atropine ($245), Loperamide ($3), Ondansetron ($931), and Granisetron ($232). Conclusions: Prices of CRC regimens vary considerably, with newer agents and supportive drugs adding substantially to costs, particularly in late stage disease. Research on improved outcomes or treatment benefits associated with high cost treatment is warranted.

[Table: see text]

[Table: see text]
Amplification of HER-2/neu (erbB2) gene expression in gallbladder (GBC) and in bile duct cancer (BDC) (biliary tract cancer, BTC)
Authors: Kawamoto T. , Thomas M. , Tarco E. , Trivedi S. , Wistuba I. , Krishnamurthy S.
Published: March 2020

4011

Background: GBC and BDC (BTC) are uncommon in the United States, but are endemic in parts of South America and Asia. BTC are aggressive tumors with poor survival rates. Chemotherapy RR is <30%, and no survival benefit has been demonstrated. Improved understanding of the molecular carcinogenic mechanisms of BTC may lead to improved therapeutic regimens. Activation of HER-2/neu play a prominent role in the development of breast cancer. In this study, BTC patient (pt) specimens from the U.S., Chile, and Japan were examined the HER-2/neu immunohistochemical (IHC) expression and its gene amplification by fluorescence in situ hybridization (FISH). Methods: Specimens from 26 GBC patients (Chile, US), 12 BDC (USA), 6 cholecystitis (Chole.) (Japan) and 7 normal GB (Chile) were examined. pStage (AJCC) of the pt was: IA: 2, IB: 9, IIA: 7, IIB: 9, III: 3, IV: 4, unknown: 4. Histologic grade was G1 and G2 adenocarcinoma (adca): 22, G3 adca: 13, squamous cell carcinoma: 1, unknown: 2. All cases were screened for HER-2/neu by IHC (0–3+). HER-2/neu gene amplification (FISH (+)) (defined as a HER-2/CEP17 ratio of 2.0 or greater) was performed by double color Her-2/neu gene/chromosome 17 centromere (CEP17) FISH assays using PathVysion HER-2/neu DNA probe kit. Results: In BTC, HER-2/neu IHC 0, 1+, 2+ and 3+ scores were found in 0 (0%), 20 (53%), 11 (29%) and 7 (18%), respectively. In Chole., 3 of 6 (50%) showed 1+ while the remaining and normal GB were all negative for IHC. FISH on paraffin sections was considered successful on 36 (95%) of the 38 cases. HER-2/neu FISH (+) was detected in 7 of 36 (19%) (6 from 3+ cases and 1 from 2+ case) and none in Chole. and normal GB. There was a significant correlation between overexpression by IHC (2+ and 3+) and FISH (+) (Fisher’s exact test; P=0.0123), but no significant correlation between pStage, histologic grade and FISH (+). Conclusions: The HER-2/neu amplification was identified in 19% of BTC in comparison with the other organ cancer (breast cancer:20–25%, lung cancer: 4.5%, colorectal cancer; 2.4%, prostate cancer: 9.3%). There was a strong correlation between IHC overexpression and FISH (+). These data support therapeutic approaches using HER-2/neu targeted agents in BTC pt. HER-2/neu IHC may be a useful surrogate for its gene amplification.

No significant financial relationships to disclose.
A randomized phase II study of bevacizumab (B) and gemcitabine (G) plus cetuximab (C) or erlotinib (E) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis
Authors: Kindler H. L. , Bylow K. A. , Hochster H. S. , Friberg G. , Micetich K. , Locker G. , Kozloff M. , Moore M. , Sun W. , Vokes E. E.
Published: March 2020

4040

Background: In a phase II trial of G + anti-VEGF antibody B in 52 PC pts, we reported a 21% response rate and median survival of 8.8 months (mo) (Kindler, JCO 2005). EGFR inhibitors C and E also have activity in PC. VEGF and EGFR pathways are interdependent; dual inhibition may be synergistic. Methods: We are conducting a multi-center, randomized phase II trial of GBC vs. GBE in advanced PC pts who have: no prior therapy for metastatic disease, PS 0–2, measurable disease, no tumor invasion of duodenum, no bleeding risk. Primary endpoint: response. Trial design: 2 parallel, Simon 2-stage designs; requires 6 responses in 27 evaluable pts for 2nd stage; 63 pts/arm. All pts receive G 1000 mg/m2 over 30 minutes days (D) 1, 8, 15 Q28D; B 10 mg/kg D 1, 15 Q28D. Pts are randomized to C 400 mg/m2 D1, then 250 mg/m2 Q7D, or E 150 mg D1–5, 8–12, 15–26 Q28D. CT scans: Q2 cycles. 58 pts enrolled at 13 sites 9/04–12/05. Pt characteristics: male 66%; median age 61 (range 36–82); PS: 0/1/2: 52%/40%/8%; stage IV 95%; liver metastases 76%. Results: 49 pts (GBC/GBE 24/25) are evaluable for toxicity; 51 pts (27/24) for response. 232 cycles were administered (median 4, range 1–11). Grade ¾ toxicity (%pts GBC/GBE): neutropenia 29%/28%; anemia 4%/16%, thrombocytopenia 8%/24%, DVT-PE 17%/8%, CVA 4%/4%, GI bleed 4%/12%, hypertension 4%/4%, rash 13%/4%, pneumonitis 0%/8%, diarrhea 4%/4%; grade 5: bowel perforation 0%/4%, MI- CVA 0%/4%, other cardiac 4%/0%. Response: GBC 19% (1 complete, 4 partial), GBE 21% (5 partial). Stable disease 59%/67%. Median progression-free survival 3.6/3.6 mo (95%CI: 2.7, 4.7/2.7, 5.9), 6-month survival 41%/38% (95% CI: 11%, 71%/2%, 75%). Conclusion: GBC and GBE are active in advanced PC. Toxicity, principally related to B, is moderate. The trial proceeds to a 2nd stage if 1 more response is observed in each arm. Supported by NCI grant N01-CM-17102.

[Table: see text]
18FDG-PET in targeted therapy with cetuximab in gastric or gastroesophageal junction (GEJ) adenocarcinoma: First results of the Italian FOLCETUX Study
Authors: Di Fabio F. , Pinto C. , Fanti S. , Rojas Llimpe F. L. , Longobardi C. , Nanni C. , Funaioli C. , Ambrosini V. , Sperandi F. , Martoni A. A.
Published: March 2020

4061

Background: The aim of the study was to evaluate 18FDG-PET impact in gastric or GEJ cancer patients (pts) treated with cetuximab plus chemotherapy. Methods: Pts with stomach or GEJ unresectable/metastatic adenocarcinoma, not yet treated, EGFR+, were enrolled in the FOLCETUX study. Pts received cetuximab weekly at 400 mg/m2 iv loading dose, and then at 250 mg/m2 iv maintenance dose, weekly at 400 mg/m2 iv loading dose, and then at 250 mg/m2 iv maintenance dose, CPT11 180 mg/m2 iv d1, LFA 100 mg/m2 iv followed by 5FU 400 mg/m2 iv bolus and 600 mg/m2 iv continuous infusion 22h d1–2 (FOLFIRI) every 2 weeks, for a maximum of 24 weeks, then cetuximab alone was allowed in pts with CR/PR/SD. Anti-tumor activity was assessed by CT and PET scan at baseline and then every 6 weeks. A decrease in tumor FDG-uptake (metabolic response) was evaluated according to EORTC recommendations; objective response (OR) was evaluated with CT scan according to the RECIST criteria. Results: From November 2004 to December 2005, 22 pts (16M, 6F) performed at least 2 consecutive PET scans (at baseline and after 6 weeks), with a total of 91 PET scans (median per pts 4; range 2–8). PET was positive in 20 pts (90.9%); no FDG uptake was seen in 2 pts (9.1%) with signet ring cell carcinoma. A metabolic response correctly predicted: CR/PR in 10/12 pts (83%) after 6 weeks of therapy and in 11/12 (91.7%) after 12 weeks; SD in 4/8 pts (50%) after both 6 and 12 weeks. On the whole, response to therapy was predicted by PET after 6 weeks in 14/20 pts (70%). No correlation was demonstrated between median Standardized Uptake Value (SUV) at baseline PET and OR: 10.9 (3–29) in CR/PR pts and 9.6 (6.4–29.8) in SD pts. In the PET scan after 6, 12 and 18 weeks, the median SUV value respectively decreased to 4.4, 2.6 and <2.0 in CR/PR pts and to 7.5, 7.4 and 3.6 in SD pts. The percentage of SUV reduction after 6 weeks was 54.2 in CR/PR pts vs 30.3 in SD pts (p = 0.36); no difference was observed between intestina (55%) and non-intestinal (45%) subtypes. No significant correlation was observed between the Ki-67 and SUV value. Conclusions: These preliminary results suggest that PET can make an early prediction of the response to cetuximab plus FOLFIRI therapy.

No significant financial relationships to disclose.
Phase II multicenter trial of docetaxel+oxaliplatin in stage IV gastroesophageal and/or stomach cancer
Authors: Richards D. A. , Wilfong L. , Reznick D. , McCollum D. , Boehm K. A. , Zhan F. , Asmar L.
Published: March 2020

4071

Background: The treatment of adenocarcinoma of the gastroesophageal junction /stomach (AGEJ/S) remains a therapeutic challenge. This study was conducted to explore the efficacy and safety profile of the combination of docetaxel+oxaliplatin in patients with previously untreated advanced AGEJ/S. Docetaxel has shown significant single-agent activity and has recently been shown to increase response rates and overall survival when combined with cisplatin plus 5-FU. Oxaliplatin is associated with a more favorable safety profile compared to other platinum-based drugs (ie, cisplatin). Methods: Patients with metastatic (Stage IV) AGEJ/S were eligible. Treatment consisted of docetaxel 60 mg/m2 over 1 hour IV followed by oxaliplatin 130 mg/m2 over 2 hours on Day 1 of each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity; primary endpoints are response rate, toxicity, and progression free and overall survival. Results: We have enrolled all planned eligible patients (N = 71). Baseline characteristics include a median age of 59.5 years, 72% male patients, 76% white, and ECOG PS scores 0/1/2 of 45%/49%/6%, respectively. 32.8% of patients had distal gastric cancer (fundus or pylorus). The median number of cycles delivered to date is 6 (range, 1–14). Twenty patients (31%) have required dose reductions primarily due to neutropenia. Grade 3–4 toxicities include neutropenia (69%); vomiting (17%); nausea (16%); dehydration, fatigue, and diarrhea (13%, each), and thrombocytopenia and febrile neutropenia (7%, each). Sixty-six patients have completed ≥2 cycles. The best overall confirmed response rate, by RECIST, was 24 PR (35.6%) for an overall response rate of 35.6%. Median time to response was 2.4 months and median duration of response was 4.1 months. Median survival was 9.2 months and median PFS was 4.4 months. Conclusions: The combination of docetaxel and oxaliplatin is associated with manageable toxicity in this group of patients with AGEJ/S. The best overall response rate of 35% and median survival of 9.2 months is encouraging and comparable to other standard front-line regimens. This research was supported, in part, from a research grant from sanofi-aventis.

[Table: see text]
Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: Results of a phase II study
Authors: Kvols L. , Wiedenmann B. , Oberg K. , Glusman J. E. , O’dorisio T. M. , De Herder W. , Gao B. , Arnold R. , Anthony L.
Published: March 2020

4082

Background: Pasireotide is a novel multiligand somatostatin analogue that exhibits high binding affinity to 4 of 5 somatostatin receptor subtypes: sst1,2,3 and sst5. Compared with octreotide, pasireotide has 30, 5 and 40 times greater affinity for sst1,3 and sst5 receptors respectively and a comparable affinity for sst2. Methods: This was a Phase II, open-label, multicenter study in patients with metastatic carcinoid tumors whose symptoms (diarrhea and flushing) were inadequately controlled by octreotide LAR. Patients had histopathologically confirmed disease, elevated 5-HIAA and/or CgA levels and at least one measurable lesion (excluding bone). Patients initially received pasireotide 300 μg sc bid and escalated to a maximum dose of 1200 μg sc bid every 3 days until clinical response was achieved. Partial response (PR) was defined as a mean of <4 bowel movements (BM)/day with no more than 6 BM on any given day, and a mean of <2 flushing episodes/day for 15 consecutive days on a fixed dose of pasireotide. Complete response (CR) was defined as a mean of ≤3 BM/day, with no more than 3 BM on any given day, and no flushing episodes. Results: Safety data are reported from 45 patients as of September 2005; 44 patients (mean age 61 years) qualified for efficacy assessment. Carcinoid tumors were predominantly of midgut origin. Preliminary efficacy data in controlling symptoms of carcinoid syndrome showed PR in 9 patients (20%) at 600–1200 μg sc bid doses and CR in 2 patients (5%) at the 600 and 900 μg sc bid doses. Objective tumor response in 11 patients showed 9 with stable disease and 2 with progressive disease at 6 months. Adverse events (AEs) were primarily gastrointestinal (GI): abdominal pain (31%) and nausea (27%). Weight loss (22%) and fatigue (22%) were also reported. Most AEs were mild or moderate. Glucose-related AEs (predominantly CTC grade 1–2) were observed in 24% of patients. Most discontinuations were due to GI AEs (n = 6) or lack of therapeutic response. Conclusions: Pasireotide 600–1200 μg sc bid was effective in controlling symptoms of diarrhea and flushing in 25% of patients with metastatic carcinoid tumors inadequately controlled by octreotide LAR. The safety profile of pasireotide is similar to octreotide LAR.

[Table: see text]
A retrospective analysis of epidemiology and treatment patterns for gastric cancer at a tertiary health care center in India
Authors: Digumarti R. , Rajappa S. J. , Uppalapati S. , Surath A.
Published: March 2020

4086

Background: Gastric cancer is the second most common gastrointestinal cancer in our hospital based cancer registry. This retrospective analysis aims at studying the epidemiology and treatment patterns for gastric cancer at our hospital, which is a tertiary care cancer center for the state of Andhra Pradesh in south India. Methods: A retrospective analysis of the case records of 125 consecutive patients with gastric cancer who presented to our department between Jan 2004 and Dec 2005 were analysed. Data regarding epidemiology, stages at diagnosis and treatment plans were collected. Patients with early gastric cancer received 5FU based chemoradiation or chemotherapy only. Palliative chemotherapy included 5FU/cisplatin based regimens. Results: A total of 125 patients were analysed. The median age was 61years (range 18–82 years). 71% were males and 29% females. Being a tertiary care center, 92% were referred with a confirmed diagnosis on endoscopic biopsy. 30% were smokers, 11% consumed alcohol, 40% had both habits while 29% had neither. The most common part of the stomach involved was the antro-pyloric region (44%) followed by the body (30%), GE junction/cardia (20%) while 6% had diffuse involvement including linitis plastica. At diagnosis, 35% were early stage, 56% metastatic and 8% locally advanced tumors. 90% patients who had surgery for early stage disease had T2,3 tumors. One third had inadequate nodal staging.70% of patients who had curative resections underwent adjuvant chemoradiation and 30% had chemotherapy only. Of all patients with metastatic disease, 65% palliative chemotherapy while 45% opted for best supportive care. Conclusions: The distribution of tumors within the stomach is similar to Japanese data, which may reflect the common etiological factors like high salt diet. The fact that one third of patients had inadequate nodal dissection stresses the relevance of adjuvant chamoradiotherapy protocols. The high incidence of smoking as a contributory factor in the etiology reflects the need for aggressive anti tobacco legislation. The study reiterates the need for inexpensive and novel therapies for palliation of symptoms in patients with advanced disease and widens the scope for collaborative clinical trials.

No significant financial relationships to disclose.
Epithelial-mesenchymal transition (EMT) in resected pancreatic cancer
Authors: Yosuico V. D. , Khoury T. , Yu J. , Pande A. , Javle M.
Published: March 2020

4094

Background: EMT plays an important role in tumor invasion and metastases; its detection may have prognostic significance. We examined expression of EMT related proteins in resected pancreatic cancers and correlated results with clinical outcome. Methods: Clinical data/surgical specimens from 34 consecutive pancreatic cancer patients (pts) who underwent pancreatectomy from 1996–2002 were included. Immunohistochemical staining for vimentin (Vim 3B4), E-cadherin (36B5), MIB1 and cytokeratin (CK-AE1/AE3) was performed on formalin fixed paraffin embedded tissues. Percentages of stained cells (cytoplasmic for vimentin and CK, nuclear for MIB1 and membranous for E-cadherin) were recorded. The results were correlated with clinicopathological parameters and survival. Survival analysis (log-rank test, Cox-proportional hazard model), categorical data analysis (Pearson’s chi-square, logistic regression) and Kendall’s tau were performed at the significance level of 0.05. Results: Clinical data/specimens from 34 pts were included: 13 males, median age 66 (range 38–84); SEER stage 1 (2 pts), 2 (27 pts), 3 (5 pts); histological grade 1 (4), 2 (13), 3 (16), 4 (1). Median survival was 15 months (95% CI: 11–24 months). Sixteen pts had adjuvant chemoradiotherapy, 4 pts had chemotherapy, 1 pt had radiation. IHC Results: vimentin (11.8%), MIB1 (100%), E-cadherin (91%) and CK (100%). There was a significant negative association between vimentin and E-cadherin expression (Kendall’s tau = −0.47, p = 0.0024). Vimentin expression correlated with histological grade (exact chi-square p = 0.0247). No associations were found between these proteins and SEER stage, age, treatment or smoking. Univariate analysis revealed histological grade 50% (p = 0.0039) and MIB1 expression >10% (p = 0.0224) were related to better survival. Multivariate analysis using Cox-proportional hazard model revealed the following significant variables: histological grade (hazard ratio (HR) = 11.8, p = 0.0001), age (HR = 1.1, p = 0.0053), MIB1 (HR = 0.9, p = 0.0003) and adjuvant chemotherapy (HR = 0.2, p = 0.0288). Conclusion: Decreased E-cadherin expression (<50% expression) was associated with poorer survival; E-cadherin expression had an inverse correlation with vimentin. Acknowledgement: Supported by OSI Pharmaceuticals.

[Table: see text]
Preoperative radiotherapy and docetaxel in resectable pancreatic adenocarcinoma: A phase II trial
Authors: Viret F. , Ychou M. , Moutardier V. , Magnin V. , Rouanet P. , Monges G. , Azria D. , Turrini O. , Gonçalves A. , Giovannini M. , Delpero J. R.
Published: March 2020

4099

Background: We previously reported results a phase I trial of weekly docetaxel concurrently with radiation therapy in patients (pts) with locally advanced pancreatic adenocarcinoma (Pancreas, Vol 27, N°3, 2003). We prospectively explored this regimen in 34 pts with biopsy proven potentially resectable pancreatic adenocarcinoma. Methods: Treatment consisted of concomitant radiotherapy (45 Gy within 5 weeks directed at the pancreatic tumor and regional lymphatics) with 5 weekly doses of docetaxel (30 mg/m2/week) by 1-hour infusion, followed by a complete staging evaluation 3–4 weeks after chemo-radiation. Pts without disease progression underwent surgery. Results: From May, 2003 to July, 2005, this study enrolled 34 pts (59% men) with median age 62 years (range 45–72). Median tumor size was 3 cm. Pretreatment Endoscopic Ultrasound (EUS) staging was uT1 (7 pts), uT2 (25 pts), uT3 (2pts), uN0 (26 pts) and uN1 (8 pts). Median pretreatment CA 19.9 levels was 114 (range 1–9432). All pts (97%) but one completed radiation and 91% (31 pts) received the 5 weekly doses of docetaxel. Adverse events included grade 3/4 asthenia (28%), grade 3/4 nausea/vomiting (10%), grade 3/4 anemia (7%) and grade 3/4 neutropenia (7%). Median time between diagnosis and surgery was 3.7 months (range 2.8–8.7). Ten pts (29%) presented progressive disease after chemo-radiation and one additional patient (pt) voluntary stopped treatment procedure. Twenty three pts (68%) underwent surgical procedure, which was with curative intent in 17 pts (50%). One pt died within the 30-day post operative period. Pathological response was observed in 7 pts (30%), including 2 complete response. The median Disease Free Survival (DFS) was 11 months and the 2-year DFS was 21%. The median overall survival (OS) was 14 months. The 2-year DFS for the 17 pts resected with a curative intent was 50.4%. In this subgroup, median overall survival was not reached. Conclusions: Pre-operative combination of radiotherapy and docetaxel is feasible with tolerable toxicity and with promising pathological response. A randomized phase III study comparing this regimen (radiotherapy and docetaxel) and surgery versus surgery alone is starting. Supported in part by Sanofi Aventis, France.

No significant financial relationships to disclose.
Prediction of gemcitabine resistance in patients with pancreatic cancer
Authors: Nakahira S. , Nakamori S. , Tsujie M. , Okami J. , Takemasa I. , Takeda Y. , Nagano H. , Dono K. , Sakon M. , Monden M.
Published: March 2020

4125

Background: Pancreatic cancer is the most lethal of all solid tumors partially because of its chemoresistance. Although a deoxycytidine analogue, gemcitabine, is widely used as a first selected and a single agent for the treatment of this disease despite low response rate, molecular mechanisms of gemcitabine resistance in pancreatic cancer still remain obscure. The purpose of this study is to identify the molecular marker for gemcitabine resistance in human pancreatic cancer. Methods: Gemcitabine resistant variants were established from human pancreatic cancer cell lines, MiaPaCa2. Gene expression changes between parental cells and resistant cells were assessed by an oligonucleotide microarray covering 30,000 human oligonucleotides, and candidate genes were validated by RT-PCR and Western blotting. The association to resistance was validated by RNAi assay. Clinical effects on 18 recurrent pancreatic cancer patients treated by gemcitabine were evaluated using mRNA of specimens resected at the primary operation. Results: The 81-fold gemcitabine resistant variant MiaPaCa2-RG was selected from pancreatic cancer cell line MiaPaCa2. By microarray analysis between parental and resistant MiaPaCa2 cells, 99.6% genes were altered expression of less than 2-fold. Among 43 genes with altered expression of more than 2-fold, the most up-regulated gene in MiaPaCa2-RG cells is ribonucleotide reductase M1 subunit (RRM1) with 4.5-fold up-regulation compared with MiaPaCa2 cells. Transfection with RRM1-specific RNAi suppressed more than 90% of RRM1 mRNA and protein expression both in MiaPaCa2 and MiaPaCa2-RG cells. After RRM1-specific RNAi transfection, gemcitabine chemoresistance of MiaPaCa2-RG was significantly reduced to the same level of MiaPaCa2. The 18 recurrent pancreatic cancer patients were divided into two groups by RRM1 mRNA expression levels. There was a significant association between gemcitabine response and RRM1 expression (p = 0.018). Furthermore, patients with high RRM1 levels had a poor survival times after gemcitabine treatment than those with low RRM1 levels (p = 0.016). Conclusions: RRM1 should be a key molecule in gemcitabine resistance in pancreatic cancer through both in vitro and clinical models. RRM1 should be considered as the predictor of gemcitabine resistance.

No significant financial relationships to disclose.
Long term survival following cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for disseminated appendiceal tumors
Authors: Baraki Y. , Kostuik P. N. , Merriman B. , Nieroda C. , Sardi A.
Published: March 2020

4128

Background: Appendiceal tumors represent 2.8% of gastrointestinal tumors and less than 0.5% of gastrointestinal malignancies, but frequently involve intraperitoneal spread. Controversial treatment of disseminated tumor has consisted of extensive debulking surgery, peritonectomy, and intraperitoneal chemotherapy. We evaluated the disease free and overall survival, morbidity and mortality of patients with disseminated appendiceal tumors treated by cytoreductive surgery (CRS) and intraperitoneal hyperthermic chemotherapy (IPHC). Methods: A retrospective review of a prospective database was performed between 1999 and 2005. Thirty-one patients underwent CRS followed by IPHC using mitomycin 40 mg infused over 90 minutes at 40–42°C. Patients were given a Peritoneal Carcinomatosis Index (PCI) score pre and post operatively. Postoperatively, patients were assigned cytoreductive scores, indicating completeness of resection: CC-0 = no residual disease, CC-1 ≤ 0.25 cm, CC-2 = 0.25–2.5 cm, CC-3 ≥ 2.5 cm. Cox proportional-hazards models were used to test the influence of different variables on survival. The models were adjusted for age, grade of differentiation, histology and cytoreductive score. Results: There were 14 females and 17 males with a mean age 50 years (range 33–80). Two-thirds of all patients had a preoperative PCI score of >20. The overall survival at 1 year was 96% (95% CI, 74% to 99%) and at 3 years was 69% (95% CI, 38% to 86%). Disease free survival at 3 years was 30% ( 95% CI, 8% to 56%). There was no mortality from the procedure. Overall morbidity, including Grades 1–5 as described by the CTCAE guidelines, was 48%. A multivariate analysis was performed for grade of differentiation and was not found to be statistically significant. However, log rank test for equality of survivor functions in patients with CC scores of 0 or 1 experience recurrence of disease at a slower rate than patients with scores of 2 or 3 (p < 0.001). Conclusions: Although further study is necessary, Cytoreductive surgery followed by IPHC, where a low PCI score and a CC score of ≤1 is achieved, can lead to increased survival for selected patients having advanced appendiceal cancer with peritoneal dissemination.

No significant financial relationships to disclose.
Gemcitabine, oxaliplatin and weekly high-dose 5-FU as a 24-hr-infusion in chemonaive patients with advanced or metastatic carcinoma of the gallbladder: Preliminary results of a multicenter phase II-study
Authors: Wagner A. D. , Buechner-Steudel P. , Schmalenberg H. , Moehler M. , Kuss O. , Behrens R. , Hahnfeld S. , Kleber G. , Wein A. , Fleig W. E.
Published: March 2020

4129

Background: Combinations of gemcitabine (GEM)/5-FU, GEM/oxaliplatin (LOHP) or 5-FU/LOHP work synergistically in pancreatic and/or colorectal malignancies, and have non-overlapping safety profiles. This phase II-study was designed to evaluate the efficacy and safety of the triple combination GEM/LOHP/5-FU in patients (pts) with advanced or metastatic carcinoma of the gallbladder. Methods: One-stage, multicentre phase II study. Eligibility criteria: chemonaive pts with histologically proven advanced, recurrent or metastatic gallbladder carcinoma (ECOG 0–1; expected survival >3 months; measurable disease; adequate renal, hepatic and bone marrow function). According to the results of our previous phase I-study (Proc ASCO 2003, # 1298), pts were treated with GEM 900mg/m2 as a 30-min infusion, followed by LOHP 65 mg/m2 (2-hr infusion) after a 30 min rest and 5-FU 1500 mg/m2 (24-hr-infusion) on d 1, 8, every 3 weeks. Planned sample size: 35 response evaluable patients. The primary endpoint was tumor response, secondary endpoints were toxicity, median survival, the one-year-survival rate, clinical benefit and quality of life. Results: At time of abstract submission, median follow-up of 35 enrolled pts is 9.8 months. Pt. characteristics: m/f: 11/24, median age 61 (range 42–81), ECOG 0/1: 24/11 (69/31%) pts, locally advanced/metastatic disease 1/32 (3/91%) pts. Analysis of tumor response is still pending. Grade III/IV (NCI-CTC) toxicities occurred in 36/3% of 191 cycles and were: leucopenia 3/1%, neutropenia 4/1%, thrombocytopenia 4/1%, anemia 2/0%, nausea 1/0%, sensory neuropathy 4/0%, asthenia 1/0%, elevated bilirubin 2/0%, AP 4/0%, or elevated SGOT/SGPT 1/0%, edema 1/0%, infection 1/0%, dyspnoe 1/1%. Median survival of all pts is 9.9 months (95% CI: 7.5–11.5), the one-year-survival-rate is 30 % (95% CI: 16–47). Conclusions: GEM/LOHP/5-FU combination therapy is tolerated well in patients with gallbladder cancer. The promising survival data has to be confirmed in a phase III study. (Supported by grants from Eli Lilly and Company, Indianapolis, IN, USA and Sanofi-Synthelabo, Paris, France).

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EXIBIT: An international multicenter phase II trial of gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer
Authors: André T. , Reyes-Vidal J. M. , Fartoux L. , Ross P. , Leslie M. , Rosmorduc O. , Clemens M. R. , Louvet C. , Perez N. , Scheithauer W.
Published: March 2020

4135

Background: Biliary tract carcinomas (BTC) are often diagnosed at an advanced/metastatic stage and have a poor prognosis. The combination of gemcitabine and oxaliplatin (GEMOX) showed promising activity in a French Phase II study (4 centers) in advanced BTC (André. Ann Oncol 2004;15:1339–1343). The objective of this study is to further evaluate the efficacy and safety of GEMOX as first-line therapy in patients (pts) with advanced BTC. Methods: Eligible pts were >18 years of age with histologically proven and measurable, locally advanced or metastatic BTC, had an ECOG PS ≤ 2, adequate renal and hematologic functions, bilirubin < 2.5 × upper limit of normal, and no prior malignancy or brain metastases. Gemcitabine 1000 mg/m2 (Day 1) and oxaliplatin 100 mg/m2 (Day 2) were administered every 2 weeks. The primary objective was response rate (RR) by RECIST (one dimension); secondary objectives were progression-free survival (PFS), overall survival (OS), and safety. Here we report an interim analysis of OS and safety. Results: A total of 70 pts were enrolled between April 2003 and April 2005. The median age was 62 years (range 30–83), 40.0% of pts were male, 94.3% had ECOG PS 0–1. Tumor sites were intrahepatic bile ducts (37.1%), gallbladder (31.4%), extrahepatic bile ducts (12.9%), ampulla of Vater (1.4%), intra/extrahepatic bile ducts (1.4%), missing data (15.7%); 98.6% of pts had no prior radiotherapy and 50% had no prior surgery for BTC. Median OS is 8.25 months (68% of pts are dead and 32% have censored data). Sixty-seven pts were evaluable for safety. Grade 3/4 (NCI-CTC v. 2) hematologic toxicities (% of pts) included thrombocytopenia 10.4%, anemia 9.0%, and neutropenia 9.0%. One pt had febrile neutropenia. Grade 3/4 nonhematologic toxicities included pain 10.4%, ALT elevation 9.0%, fatigue 9.0%, infection 10.4%, vomiting 9.0%, sensory neuropathy 4.5%, nausea 4.5%, and diarrhea 3.0%. One patient died during treatment (cause unknown). Conclusions: GEMOX has acceptable toxicity in pts with BTC. Updated efficacy data (RR, PFS, and OS for the entire population and also by tumor sites) will be presented at the meeting.

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Current treatments, determinants of use, and survival for patients with hepatoma in the United States from 1998–2002
Authors: Siegel A. B. , McBride R. , Hershman D. , Brown R. S. , Emond J. , Neugut A. I.
Published: March 2020

4138

Background: Multiple case series have described the use of current therapies for hepatocellular carcinoma (HCC), but recent estimates of treatment utilization in the general population and the impact of various treatments on survival are not known. Methods: We first identified 2898 adults diagnosed with HCC with known tumor size and stage in the Surveillance, Epidemiology, and End-Results Program (SEER), from 1998–2002. Treatment was categorized as transplant, resection, ablation, or none of these. We created a second data set of 1856 HCC patients who were potentially operable, as defined by SEER. We used these patients to construct Kaplan-Meier survival curves and adjusted Cox proportional hazards models. Results: The median age of the larger cohort at HCC diagnosis was 62 (range:18–96). Approximately 42% were white, 32% Asian, 16% Hispanic, and 10% African American. Overall, 10% received a transplant, 18% resection, 8% ablation, and 65% none of these. Only 5% of African Americans with HCC received a transplant, versus 12% of whites, 10% of Hispanics, and 8% of Asians. Asians were most likely to receive resection (24%) and ablation (9%), and least likely to have non-surgical treatment (60%). Using the restricted cohort, improved survival in the multivariate analysis was seen with later year of diagnosis, younger age, female sex, Asian race, smaller tumor size, lower tumor grade, and localized disease. Treatment was highly correlated with survival. This was greatest in the transplanted group (1, 3, and 5-year survivals 93%, 79%, and 71%), followed by resection (70%, 45%, and 29%), and ablation (71%, 33%, and 18%). The non-surgical group had poor survival (33%, 9%, and 0%). Conclusions: Transplantation yields excellent survival on a population scale, similar to reported series, and resection gives relatively good outcomes as well. Asians are more likely to be resected and ablated than other groups. They also had better survival than other groups, perhaps due to underlying etiology of HCC (hepatitis B) and better preserved liver function.

No significant financial relationships to disclose.
Randomized phase II trial of the multi-kinase inhibitor sorafenib versus interferon (IFN) in treatment-naïve patients with metastatic renal cell carcinoma (mRCC)
Authors: Escudier B. , Szczylik C. , Demkow T. , Staehler M. , Rolland F. , Negrier S. , Hutson T. E. , Scheuring U. J. , Schwartz B. , Bukowski R. M.
Published: March 2020

4501

Background: Sorafenib, an oral multi-kinase inhibitor that targets tumor growth and vascularization, significantly prolonged PFS in a Phase III trial with previously treated mRCC patients. This randomized Phase II trial investigated the efficacy and tolerability of sorafenib compared with IFN in first-line therapy of patients with clear-cell RCC. Methods: Untreated patients with mRCC were stratified by MSKCC prognostic score and randomized to receive continuous oral sorafenib 400 mg bid or IFN 9 million units tiw, with an option of dose escalation (600 mg bid sorafenib) or crossover from IFN to sorafenib upon disease progression. The study assessed PFS at 99 events as primary objective, best response (RECIST), overall survival, health-related quality of life, and adverse events (AEs). Results: Baseline characteristics of 188 patients (sorafenib n=97; IFN n = 91) were: median age 62.0 years; MSKCC score: 57% low, 41% intermediate, 1% high; prior nephrectomy: 82%; ECOG 0:1, 55.3%:44.7%. As of January 6, 2006, PFS events have been reported for 64 (34%) patients. Preliminary data showed drug-related AEs of any severity (sorafenib vs IFN) in 50.5% vs 51.6% of patients (≥grade 3: 8.2% vs 11.0%), including diarrhea (24.7% vs 5.5%), fatigue (14.4% vs 20.9%), fever (2.1% vs 18.7%), hypertension (13.4% vs 0%), nausea (5.2% vs 13.2%), flu-like syndrome (1.0% vs 6.6%), hand-foot skin reaction (6.2% vs 0%), and rash/desquamation (4.1% vs 0%). Drug-related metabolic/laboratory abnormalities at grade 3 (no grade 4) comprised hypophosphatemia (21.7% vs. 0%), lipase elevation (5.6% vs. 11.1%), anemia (0% vs. 5.3%) and hypoalbuminemia (0% vs. 3.6%). Five patients receiving IFN withdrew from treatment due to AEs, whereas only one patient withdrew from sorafenib. Conclusions: Sorafenib was generally well tolerated in RCC patients in the first-line setting, with relatively infrequent drug-related AEs ≥grade 3. Full PFS data will be presented at the meeting.

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Bony metastatic disease responses to sorafenib (BAY 43–9006) independent of PSA in patients with metastatic androgen independent prostate cancer
Authors: Dahut W. L. , Scripture C. D. , Posadas E. M. , Wu S. , Arlen P. M. , Gulley J. L. , Wright J. , Chen C. C. , Jones E. , Figg W. D.
Published: March 2020

4506

Background: Sorafenib is a novel bis-aryl urea, multi-kinase inhibitor, approved for the treatment of advanced renal cell carcinoma. It inhibits b- and c-Raf kinase, PDGFR, c-kit, VEGFR, Flt-3 and p38 and demonstrates anti-proliferative and anti-angiogenic activity. Studies have shown a role for anti-angiogenic therapy for androgen-independent prostate cancer (AIPC). Evidence suggests that the Ras-Raf-MAPK-ERK signaling pathway is dysregulated in AIPC and might be targeted by sorafenib. Methods: 22 patients (pts) with progressive metastatic AIPC enrolled in an open-label, single arm phase II study. The primary objective was to determine if sorafenib is associated with a 50% 4 month probability of progression free survival as determined by clinical, radiographic, and PSA criteria. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement occurred every cycle with radiographic measurements every 2 cycles. Results: Baseline patient characteristics included a median (range) age of 64 (51–78), Gleason 8 (6–9), PSA 226.4 ug/l (2–1905), Alk Phos 108 u/l (48–259), Hb 12.7 g/dl (10.2–15.1). 60% of patients had received one prior chemotherapy regimen. Of the 19 pts with progressive disease, 10 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two pts were found to have dramatic disappearance of bone metastatic lesions as demonstrated by bone scan, even though they met PSA progression criteria at the time the scans were obtained. Toxicities likely related to treatment include: one grade 3 hypertension and hand-foot syndrome; grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Conclusion: Sorafenib in AIPC is relatively well tolerated with 2 patients demonstrating evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Further study of sorafenib in metastatic AIPC using clinical and radiographic endpoints is warranted.

No significant financial relationships to disclose.
Long-term outcomes after local treatments for prostate cancer by functional categories: Late changes, different results
Authors: Chen R. C. , Clark J. A. , Mitchell S. P. , Talcott J. A.
Published: March 2020

4507

Background: Although patient-reported treatment outcomes have gained wide acceptance, numerical changes in validated instruments are difficult to interpret by patients and physicians. Using functional categories derived from numerical scales, we report 24- and 36-month outcomes after treatments for localized prostate cancer, presented by patients’ baseline (pre-treatment) functional status, to provide more useful prognostic information and to identify further changes in the third year after treatment. Methods: Using validated symptom indices, we prospectively measured sexual, urinary, and bowel functions of 438 men at baseline, and at fixed intervals post treatment. We translated numerical scores into functional categories: good (normal), intermediate, and poor (severe dysfunction). Results: Abnormal baseline function and surgery in men with normal function uniformly produced poor sexual function ( table ), and more external beam radiotherapy (EBRT) and brachytherapy (BT) patients deteriorated between 24 and 36 months. For those with normal urinary continence, NNSRP (non-nerve sparing radical prostatectomy) produced poor outcomes (26%) more frequently than NSRP (9%) at 24 months and 36 months, despite improvement in some NNSRP patients. Severe incontinence was rare after EBRT (1%) and BT (3%), though slightly more frequent in EBRT patients by 36 months. For patients with normal bowel function, EBRT and BT caused worse outcomes than RP; no change occurred after 24 months. Conclusions: Abnormal baseline sexual function and surgery produced uniformly poor sexual function outcomes and poor function increased significantly between 24 and 36 months after radiation therapy. Significant changes in functional category occurred despite unchanged average numerical scores, indicating that stable numerical indices may conceal significant functional changes.

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No significant financial relationships to disclose.
One course of adjuvant PEB chemotherapy versus retroperitoneal lymph node dissection in patients with stage I non-seminomatous germ-cell tumors (NSGCT): Results of the German Prospective Multicenter Trial (Association of Urological Oncology [AUO]/German Testicular Cancer Study Group [GTCSG] Trial 01–94)
Authors: Albers P. , Siener R. , Krege S. , Schmelz H. , Dieckmann K. , Heidenreich A. , Kwasny P. , Pechoel M. , Lehmann J. , Fimmers R. , Hartmann M.
Published: March 2020

4512

Background: The incidence of relapse was analyzed in patients with clinical stage I (CS I) NSGCT after either retroperitoneal lymph node dissection (RPLND) or one course of adjuvant cisplatin, etoposide, and bleomycin (PEB) chemotherapy. Methods: Between September 1996 and February 2005, 382 patients with stage I NSGCT were included in the German Prospective Multicenter Trial. After orchiectomy, patients were randomized to either RPLND (191 patients) or one cycle of cisplatin 20 mg/sqm d1–5, etoposide 100 mg/sqm d1–5, and bleomycin 30 mg d1, 8, 15 (PEB, 191 patients). Pathological stage II after RPLND (18% of CS I) was followed by adjuvant chemotherapy (2 × PEB). The primary endpoint was relapse rate. The trial was powered to show an advantage for chemotherapy (planned sample size 360 patients, alpha 5%, power 80%) after a median follow-up of 3 years. Results: Thirty-six patients were excluded due to violation of the inclusion criteria. Of the remaining 346 eligible cases, 172 patients were treated by RPLND and 174 patients received one course of PEB. Median time of follow-up was 47 months, with 323 patients (93%) followed-up for at least 1 year. Of the evaluable patients 331 (96%) have remained disease-free. Thirteen (8%) patients experienced relapse after RPLND and 2 (1%) after one course of adjuvant PEB (p = 0.0028). All patients with relapse have been successfully treated. Five patients developed pulmonary metastases, 3 patients relapsed with retroperitoneal metastases, 3 patients showed marker elevations, and 2 patients had an inguino-scrotal relapse after RPLND. The patients with one cycle of PEB relapsed with a tumor marker elevation and a mature teratoma retroperitoneal metastases, respectively. Conclusions: This randomized trial revealed only two relapses among 174 patients treated with one course of PEB. The low risk of recurrence supports one course of PEB over RPLND for the treatment of patients with clinical stage I NSGCT.

No significant financial relationships to disclose.