bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of bevacizumab in combination with irinotecan or oxaliplatin as second-line, third-line or later treatment in metastatic colorectal cancer (MCRC) patients
Authors: Lièvre A. , Samalin E. , Senesse P. , Boyer-Gestin C. , Mitry E. , Lepère C. , Bachet J. , Vaillant J. , Ychou M. , Rougier P.
Published: March 2020

14558

Introduction: Bevacizumab (Bev) is efficient in MCRC patients (pts) as first-line treatment (L1) with 5FU±irinotecan, and with FOLFOX as second-line (L2). It has no efficacy in 3rd or later-line, alone or with 5FU. In Europe, Bev was approved by the EMEA (European Medicines Evaluation Agency) in 2005 and many patients could not received it in L1 before this date. This study evaluated the efficacy of Bev combined to polychemotherapy (CT) in L2, L3 or later-line in CT refractory pts. Methods: Between May 2005 and October 2006, 38 pts (median age: 54.5 years, range:25–82) received Bev combined with CT as L2 (n=18), L3 (n=6), L4 (n=7), L5 or later-line (n=7). Tumor response (OR) was assessed according to RECIST criteria by CT-scan. Results: Tumor sites: 28 colon and 10 rectum. Number of metastatic sites were 1, 2 and more in 16, 13 and 9 cases, mostly hepatic (89%) or pulmonary (42%). Bev (5mg/kg/2weeks) was combined with FOLFIRI (n=24) or FOLFOX (n=14); 299 cycles were administered, mean: 7.9 cycles/pt (range:2–14). OR rate was 42,1%, stabilization 42,1% and was not different according to the line or the CT regimen (table). Initial progressions were rare. Tolerance was acceptable (no perforation and no severe Hypertension). Conclusion: This study reports a significant activity of Bev at the dose of 5mg/kg combined with FOLFOX and/or FOLFIRI in CT refractory pts. These results warrant prospective studies of Bev combined with active CT in CT refractory pts who could not received Bev in the setting of the EMEA authorization.

[Table: see text]

No significant financial relationships to disclose.
Altered circadian rhythm in rest and activity (CircAct): Independent prognostic value for survival in patients (pts) with metastatic colorectal cancer (MCC)
Authors: Innominato P. F. , Bjarnason G. A. , Garufi C. , Focan C. , Moreau T. , Gorlia T. , Waterhouse J. , Giacchetti S. , Lévi F. A.
Published: March 2020

14573

Background: Altered CircAct accelerated tumor growth in experimental models (JNCI 2002, 2005; Cancer Res 2004). CircAct was found to be related to survival in two studies (St) in MCC pts (St 1, Clin Cancer Res 2000; St 2, ASCO 2005 #3553). The current study attempted to provide an independent prognostic stratification criteria for survival according to baseline CircAct as a first step toward the development of a comprehensive prognostic model based on circadian physiology. Methods: CircAct was continuously and non- invasively assessed over 72h with a wrist accelerometer (Ambulatory Monitoring, USA), before chemotherapy in two independent datasets of 169 MCC pts (60% pretreated) at Paul Brousse Hospital (St 1) and 130 chemo-naïve MCC pts registered in the international EORTC 05963 trial (St 2). Activity distribution during rest and wakefulness was objectively quantified by I<O (50=no rhythm; 100=marked rhythm). Kaplan-Meier survival curves with logrank tests and Cox regression models were used for analyses. Results: In both St, pts with I<O = 92 (21% in St 1 and 22% in St 2) displayed a significantly poorer survival as compared to those pts with I 92 (Table). The hazard ratios (HR) were 0.37 [95%CI: 0.25 to 0.55] (p<0.0001) in St 1 and 0.56 [0.36 to 0.87] (p=0.01) in St 2. The prognostic value of altered CircAct persisted after adjusting for PS (HR=0.46 [0.30 to 0.69], p=0.0002 in St 1; HR=0.61 [0.38 to 0.97], p=0.04 in St 2). Conclusions: The independent stratification of MCC pts for survival according to baseline altered CircAct occurred using a threshold value of 92 for I<O in both separate datasets. Subsequent studies will involve additional biomarkers of circadian physiology (cortisol, melatonin, clock genes) in order to further improve this prognostic stratification as a step toward tailored treatment of MCC pts.

[Table: see text]

No significant financial relationships to disclose.
Pulmonary and hepatic metastasectomy in colorectal cancer–is it worth it
Authors: Demir G. , Gürsu R. U. , Pekmezci S. , Kaynak K.
Published: March 2020

14574

Forty eight patients (24 males and 24 females) with colorectal carcinoma and lung or hepatic metastasis who had undergone metastasectomy were evaluated retrospectively. The mean age was 58.12±8.34 years (43–79 years). The mean age of the males was 60.16±8.21 years (47–79 years), while it was 56.08±8.13 years in the females (43–71 years). Among the 48 metastasectomies that were performed, 11 were pulmonary metastases, and 37 were hepatic metastases. The mean time to the hepatic metastasectomy after primary surgery was 324.37±420.04. Among the hepatic metastases, one was located in the caudate lobe, 16 were located in the right lobe, and 20 were located in the left lobe. Thirty of the patients had received postoperative chemotherapy after liver metastasectomy. Twenty two of the patients who underwent liver metastasectomy (59%) had a recurrence. In 14 of these, (38%) the recurrence was in the liver. Overall survival of the patients with liver metastasectomy was 914.19±577.08 days. Survival after metastasectomy was 578.80±331.54 days. On the other hand, the mean time to pulmonary metastasectomy after primary surgery was 811.81±552.06 days. Eight of the lung metastases were located in the right lobe, whereas 3 were located in the left lobe. Three patients had concomittant metastases in the right upper and lower lobes, and one patient had additional liver metastasis. Eight of the patients who underwent pulmonary metastasectomy had received postoperative chemotherapy. Five of the patients who underwent pulmonary metastasectomy (45%) had a recurrence. Two of the patients had recurrence in the lung, while 3 had recurrence elsewhere. Overall survival of the patients who underwent pulmonary metastasectomy after initial surgery was 1341.54±816.21 days. Survival after metastasectomy was 528.81±365.45 days while recurrence-free survival after pulmonary metastasctomy was 342.18±125.71 days. Conclusion: This study suggests that patients with pulmonary metastasectomies have even beter clinical outcomes then hepatic metastasectomies in patients with metastatic coloercatla cencer. Every effort should be made to perform both pulmonary and hepatic metastasectomies in this group of patients.

No significant financial relationships to disclose.
Addition of bevacizumab (beva) to xeliri/xelox chemoradiotherapy in neoadjuvant setting for patients (pts) with locally advanced rectal cancer (LARC): A feasibility study
Authors: Privitera G. , Spatola C. , Acquaviva G. , Di Franco G. , Salvo R. , Raffaele L. , Salamone V. , Ettorre G.
Published: March 2020

14583

Background: Preoperative chemo-radiotherapy in pts with LARC has been extensively evaluated, although no standard treatment has been defined. We planned to add the new anti-VEGF monoclonal antibody bevacizumab in the neoadjuvant setting, in order to evaluate whether the modifications induced in normal and tumor microcirculation and vascularity could increase the treatment toxicity profile and induce relevant complications during the surgery. Methods: From Jul 05 to Sept 06, pts with histologically proven uT3–4 N± or uT2 N+ rectal cancer were treated with capecitabine 1,000 mg/m2 bid on days 1–14 before chemoradiation phase and then 825 mg/m2 bid on days 22–55 plus irinotecan 180 mg/m2 (XELIRI) or oxaliplatin 130 mg/m2 (XELOX) on days 1, 22, 43 in combination with BEVA 5 mg/kg q2w starting on day 1 until the completion of the treatment. Radiotherapy was administered according to our previous study (45 Gy to the whole pelvis, plus 9 Gy as conc. boost to the CTV during the last six fractions). Surgery was carried out 8 weeks after the completion of chemoradiation. Results: Eleven pts (7 male/4 female), ECOG PS 0–1, were enrolled in this study. No patient showed systemic disease at the time of diagnosis. Six pts received XELIRI chemotherapy, 5 pts XELOX. Ten pts completed the planned chemotherapy schedule, one patient discontinued chemotherapy administration after the second irinotecan infusion due to GI grade III toxicity. All eleven pts completed the planned radiation treatment, with a total dose of 54 Gy. Three pts reported moderate hypertension, treated with standard anti-hypertensive drugs, and one had epistaxis, but no one required discontinuation of BEVA Conclusions: The use of BEVA in the neoadjuvant setting of pts with LARC is feasible and safe. In combination with XELIRI/XELOX chemoradiation, BEVA does not increase the treatment toxicity profile, nor provoke any surgical delay or modifications. BEVA in this setting should be further evaluated in larger phase II studies, in order to estimate the rates of clinical and pathologic complete and partial response, compared to XELIRI/XELOX chemoradiation schedules.

No significant financial relationships to disclose.
Outcome of metastatic colorectal cancer patients receiving second line chemotherapy in Marmara University Hospital
Authors: Dane F. , Gumus M. , Ozturk A. , Yumuk F. , Iyikesici S. , Basaran G. , Cabuk D. , Teomete M. , Turhal N. S.
Published: March 2020

14588

Background: With the development of oxaliplatin and irinotecan, multiple effective regimens are now available in advanced colorectal cancer (CRC), both as first- and second-line treatment options. Exposure to all of the active drugs is effective in prolonging overall survival (OS) and time to progression (TTP). There are limited studies, if any, analyzing the outcome of second line chemotherapy in metastatic CRC in Turkey. Thus, we aimed to evaluate the outcome of second-line treatments in metastatic CRC patients. Methods: Among 173 patients with metastatic CRC who were given first line chemotherapy 106 (47 female, 59 male) were administered second line treatment after progression. All patients histologically confirmed colorectal adenocarcinoma with ECOG performance score of 2 or lower, and received second line therapy for metastatic CRC after experienced disease progression during or following treatment with first-line therapy were entered the study. The patients were evaluated clinically and radiologically after each three-cycle period, and chemotherapy was changed or stopped if the cancer has progressed. Age, gender, grade, chemotherapy type (combination vs single agent), lymphatic, vascular, and perineural invasion, were analyzed as prognostic factors. Results: At a median follow up of 10 (range 1–40) months from the start of second line chemotherapy median TTP and OS time were 5 and 16 months respectively. Median age was 62 years (range 27–89). After second line therapy 16% of the patient had objective response rate (0.9% complete responses plus 15.1% partial responses), 37.7% had stable disease resulting in a tumor control rate of 53.7%, and 46.2% had progressive disease. One-year progression free survival and OS rates were 15 % and 53.5%, respectively. No difference was seen in the survival of patients received combination or single agent second line chemotherapy (p=0.14). Overall, over 12% of the patients suffered from grade 3 or 4 adverse effects. In multivariate analysis histological grade (p=0.015) was the only independent prognostic factor for survival. Conclusion: The survival outcome and adverse effects of second line treatments in Turkish patients in our department with metastatic CRC is consistent with the worlds’ literature.

No significant financial relationships to disclose.
Weekly low dose irinotecan and daily oral anticancer drug chemotherapy for metastatic colorectal cancer (MCRC) patients more than 75 years old
Authors: Sasaki K. , Takasaka H. , Sawada T. , Ezoe E. , Araya J. , Takada Y. , Furuhata T. , Hirata K.
Published: March 2020

14594

Background: The percentage of CRC patients more than 75 years old is expected to rise in Japan, too. However we have little data on the efficacy and toxicity of chemotherapy in elderly MCRC patients. The aim of this study was to evaluate the objective tumor response rates and toxicities in elderly MCRC patients treated weekly low dose irinotecan and daily oral anticancer drug (UFT or S-1) chemotherapy. Methods: Patients with MCRC were treated on an out-patient treatment basis with irinotecan 60mg/m(2) as an intravenous 90 minutes infusion on weekly plus UFT 300 mg/m(2) or S-1 60 mg/m(2) in 2 divided doses given orally on day 1 to 5 in every week. All the lesions were evaluated with CT and/or MRI scan. Results: From 2001 to 2005, we treated 20 elderly MCRC patients. There were 13 men and 7 women. Fourteen patients were 75∼79 years old and 6 patients were 80 years or more. Chemotherapy was given more than 3 months (3∼30M). To date, 495 cycles (median 24, range 7–98) have been administered. There were 8 PR, 10 SD and 2 PD. The overall response rate was 40% and disease control rate (PR + SD) was seen 90% of pts. Progression free survival time of this regimen is 9.3 months. Median survival time was 16.0 months. One and 2 years survival rates were 72% and 13%. No toxic death was reported. There was no grade III/IV toxicity and all adverse events were manageable. All patients were treated on an out-patient clinic. Conclusions: These results confirmed that this chemotherapy combination is active with acceptable tolerability and QOL maintenance in elderly patients with MCRC. Chemotherapy in elderly patients with MCRC should not be influenced by the chronologic age of the patient.

No significant financial relationships to disclose.
Mitomycin-C and capecitabine as salvage chemotherapy in pre-treated patients with advanced colorectal cancer
Authors: Gennatas C. G. , Michalaki V. , Gennatas S. , Kouvaris J. , Smyrniotis V. , Vasiliou J.
Published: March 2020

14595

Background: To assess the activity and tolerability of the combination of Mitomycin C and Capecitabine in patients with metastatic colorectal cancer after failure of irinotecan, 5-fluorouracil (5-FU), folinic acid and oxaliplatin-containing regimens. Methods: We retrospectively reviewed 31 patients with pre-treated advanced colorectal cancer. At the time of their relapse or progression, cytotoxic chemotherapy, consisting of intravenous mitomycin C, 6 mg/m2 on day 1, and capecitabine, 1000 mg/m2 twice daily on days 1–14, was initiated. Cycles were repeated every 3 weeks. Tumor assessment was performed every 3 cycles, toxicity assessed at each cycle. Results: Main patient characteristics were median age 63 years (range, 45–73); male/female ratio, 19/12. One hundred forty- six courses of therapy were given (median number, 3; range, 2–9). All patients were assessable for response, and all were assessable for toxicity. Fourteen patients had stable disease (45%). Median time to progression was 3 months (range, 1–10) and median overall survival was 8 months (range, 3–28). The regimen was very well tolerated without significant toxicity. Grade 2 toxicities were palmar-plantar erythema 6%, hematological 35%. Conclusions: Our findings suggest that the combination of Mitomycin C and Capecitabine in pre-treated patients with advanced colorectal cancer is safe and effective with an acceptable toxicity profile and a convenient administration schedule. However, further evaluation of other salvage regimens seems to be warranted.

No significant financial relationships to disclose.
Concurrent chemoradiotherapy with S-1 and cisplatin for locally advanced esophageal cancer
Authors: Iwase H. , Shimada M. , Tsuzuki T. , Okeya M. , Kobayashi K. , Watanabe H. , Hibino Y. , Ryuge N. , Goto H.
Published: March 2020

15007

Background: Both oral fluoropyrimidine anti-cancer agent (UFT, S-1) and cisplatin can enhance the effectiveness of radiotherapy. We previously reported a phase II trial of UFT and cisplatin combined with radiotherapy (Int J Clin Oncol 8 (2003): 305–311) and a phase I trial of S-1 and cisplatin combined with radiotherapy (Jpn J Cancer Chemother 33 (2006): 224–229) for advanced esophageal cancer. The present study analyzes the efficacy of concurrent chemoradiotherapy by using S-1 and cisplatin for locally advanced esophageal cancer. Methods: Chemoradiotherapy consisted of two courses. The first course included 30 Gy of radiotherapy given over 3 weeks, together with daily oral administration of S-1 (80 mg/m2/day) for 2 weeks and a 24-h infusion of cisplatin (70 mg/m2) on day 8. The second course of chemoradiotherapy was administered after 2 weeks. For patients who exhibited an objective response to chemoradiotherapy, at least 2 four-week courses consisting of chemotherapy of S-1 and cisplatinon were administered. If a patient was unable to take S-1 as a capsule, S-1 was administered in the powdered form with water. Results: Fifty-nine patients were enrolled. They had the following characteristics: median age 65 years; M/F 52/7; PS 0/1/2: 33/19/7. There were 9 patients with stage II tumors and 50 with stage III. Fifty-four patients (92%) completed 2 courses of chemoradiotherapy. The major toxicity was myelosuppression. Fifteen patients (25%) developed grade 3 leukocytopenia, while 7 patients (12%) developed grade 4 leukocytopenia. Nonhematologic toxicity was moderate: grade 2 nausea/vomiting, pain, oral mucositis, and renal dysfunction occurred in 20%, 12%, 5% and 5% of patients, respectively. In stage II cases, complete response (CR), partial response (PR), and response rates were 78%, 22%, and 100%, respectively. In stage III cases, CR, PR, and response rates were 58%, 32%, and 90%, respectively. All stage II patients survived. In stage III cases, the 1-year survival rate was 70% and the 3-year survival rate was 44%. Conclusions: Chemoradiotherapy with S-1 and cisplatin is convenient, tolerable, and effective, and may be a promising nonsurgical management option for patients with locally advanced esophageal cancer.

No significant financial relationships to disclose.
Preliminary study of three tumor markers for hepatocellular carcinoma: AFP, AFP-L3, and Glypican-3
Authors: Li H. , Qu K. Z. , Ner R. M. , Sferruzza A. D. , Bender R. A.
Published: March 2020

15014

Background: a-Fetoprotein (AFP) is the most widely used biochemical marker for detection of hepatocellular cancer (HCC). AFP is also elevated in acute and chronic liver disease, limiting its utility as an early indicator of HCC. Recently, AFP-L3 and glypican 3 (GPC3) have been reported for early detection of HCC. AFP-L3 is a glycoform of AFP produced by malignant liver cells. Measurement of AFP-L3 as a percentage of total AFP helps distinguish non-malignant hepatic disease from HCC. GPC3 is a heparin sulfate proteoglycan anchored to the plasma membrane. The level of GPC3 in the serum of HCC patients is higher than in the serum of healthy adults or patients with non-malignant hepatopathy. We tested the concordance of AFP, AFP, AFP-L3%, and GPC3and GPC3 to determine if their simultaneous measurement may increase the sensitivity of identifying individuals at risk for HCC. Method: De-identified clinical samples (n = 176) submitted for AFP-L3% measurement were tested. AFP and AFP-L3 levels were measured using the LiBASys automated analyzer (Wako Chemicals USA Inc, Richmond, VA). GPC3 levels were measured with a commercial ELISA kit (BioMosaics, Inc, Burlington, VT). To assess concordance we categorized results according to accepted cut-off values for AFP and AFP-L3, and a clinically established reference range for GPC3. Results: Fourteen of the 176 samples had elevated GPC3 (=180pg/mL), 6 (43%) of which had normal AFP values (<20ng/mL). Forty- seven of the 176 samples had elevated AFP-L3% (L3 =10%), 6 (12.8%) of which had normal AFP levels. Conclusion: These data suggest that GPC3 and AFP-L3% may be used as supplemental markers, and the simultaneous determination of AFP, AFP-L3, and GPC3 may provide a higher sensitivity for identifying individuals with increased risk of HCC.

[Table: see text]

No significant financial relationships to disclose.
Gemcitabine (G) combined with gefitinib in patients with inoperable or metastatic pancreatic cancer. A phase II trial
Authors: Fountzilas G. , Murray S. , Xiros N. , Karayannopoulou G. , Dafni U. , Linardou H. , Kalogera-Fountzila A. , Bobos M. , Koumarianou A. , Kosmidis P.
Published: March 2020

15016

Introduction: Pancreatic cancer is one of the most lethal cancers, with a high incidence of overexpression of EGFR and its ligands. Gemcitabine (G) is the treatment of choice in this tumor. Patients and Methods: From June 2004 to May 2006, 54 patients were registered in the study. Median age was 65 years (range 44–80) and median Karnofsky performance status was 80%. G (1000 mg/m2) was administered weekly for 7 cycles. Gefitinib (250 mg) was given orally. EGFR, HER-2 and PTEN were assessed by IHC and FISH. Biopsies containing =70% tumor were evaluated for the presence of somatic mutations in exons 18–21 of EGFR and exon 2 of RAS by bi-directional sequencing. Results: Ten patients (19%) completed treatment, while 36 patients (67%) progressed before the completion of the treatment. Three patients (6%) had a partial response and 11 patients (20%) had stable disease. After a median follow-up of 9 months, median survival time was 7.4 months, while median time to disease progression (TTP) was 3.9 months. The one-year survival rate was 23%. Rash of any grade was reported in 28 patients (52%). Most common severe toxicities were neutropenia (13%) and leucopenia (6%). RAS mutations were identified in 18/34 patients (53%). Two additional patients had an EGFR point mutation in exon 20. EGFR expression was found in 23/30 patients (77%), while EGFR amplification was not observed. HER-2 gain was detected in 4/20 patients and PTEN deletion in 14/20 patients. PTEN expression was noticed in 7/30 patients and was the only marker associated with significantly increased TTP (p=0.008). Conclusions: The results from this small single arm study were similar to those seen with G plus erlotinib with respect to median and one-year survival. These findings, and the selection of patients with better prognosis based on molecular markers, need to be confirmed in a larger study.

No significant financial relationships to disclose.
Optimized preclinical models for human pancreatic adenocarcinoma therapy research
Authors: Carbó N. , Pérez-Torras S. , Vidal-Pla A. , Miquel R. , Almendro V. , Fernández-Cruz L. , Maurel J. , Navarro S. , Gascón P. , Mazo A.
Published: March 2020

15019

Background: Efforts to find new therapies for human pancreatic ductal adenocarcinoma (PDAC) have not resulted in clear improvements on patient survival. Better knowledge of resistance mechanisms and redefiniton of molecular targets is essential to design more efficient therapies. The multifactorial origin of PDAC points to combined strategies as the therapy of choice, though the effective development of such strategies is hampered by the lack of optimal preclinical models. We have generated and validated optimized human PDAC models by direct implantation of fresh tumoral tissue into the pancreas of athymic mice. Methods: Thirteen pancreatic adenocarcinoma specimens from PDAC patients were obtained by surgical resection. From each specimen, several 10 mg-fragments were used to generate the corresponding intrapancreatic xenografted tumours. Eleven human PDAC orthotopic models have been successfully generated and perpetuated by succesive passages (up to 4). Histological and molecular analyses of both primary and xenografted tumors have been performed by tissue- array, western-blot and DNA sequentiation. Results: Initial engraftment rate ranged from 20 to 100% (mean 59%) and it improved with succesive passages (mean 76% at second and 90% at third generation). Ki67 expression and degree of differentiation in primary tumors correlated with xenograft growth kinetics. Furthermore, their spontaneous metastatic behaviour fairly reproduced the original patient dissemination patterns. Xenografted tumors kept the original architecture and expression patterns of common PDAC markers. Efficacy of several agents was tested on different xenografted tumors, validating this model and underlining its utility to define future therapeutic strategies for drug development and clinical trials. Conclusions: The orthotopic models described here are, probably, the closest resemblance to a patient clinical setting since they preserve human pancreatic structures, genotypic features and biological behaviour. From their use, biological relevant data could be drawn for future clinical trials and for testing new agents and new drug combinations since they represent, very likely, the most reliable animal models at present.

No significant financial relationships to disclose.
Multicenter phase II study of docetaxel plus oxaliplatin combination chemotherapy in patients with advanced gastric cancer
Authors: Kim J. , Song H. , Do Y. , Lee K. , Kim M. , Ryu H. , Bae S. , Park G. , Baek J. , Lee W.
Published: March 2020

15026

Background: The present study was conducted to evaluate the efficacy and safety of a combination regimen of docetaxel plus oxaliplatin in patients with advanced gastric cancer. Methods: Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous docetaxel 65 mg/m2 plus oxaliplatin (Oxalpla®, Yuhan.Co. Seoul, Korea) 120 mg/m2 on days 1 in a 3-week cycle. Treatment was continued until disease progression, patient refusal, or an unacceptable toxicity up to 9 cycles. Results: Forty-two patients were enrolled in the current study. Of these, 39 were assessable for efficacy and 41 assessable for toxicity. Seventeen partial responses were confirmed, giving an overall response rate of 40.5% (95% CI: 26.0% to 54.1%, intention-to-treat analysis). At a median follow-up of 160.5 days, the median time to progression was 6.1 months, whereas median overall survival was not reached yet. Grade 3/4 neutropenia occurred in 10 patients, plus febrile neutropenia was observed in 3 patients. Most common non-hamatologic toxicity was nausea (grade 1/2 56.9%). There were two treatment-related deaths. Conclusions: Docetaxel and oxaliplatin combination was found to be well-tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important first-line treatment option for advanced gastric cancer.

No significant financial relationships to disclose.
A phase I/II study of induction oxaliplatin, 5FU chemoradiation in patients with locally advanced, unresectable pancreatic cancer
Authors: Leung R. C. , Ryan T. , Hochster H. , Newman E. , Chandra A.
Published: March 2020

15027

Background: Newly diagnosed locally advanced and unresectable pancreatic cancer has a 5 yr survival rate of less than 5%. Aggressive local therapy may provide the best means of achieving local control and prolonging survival. We administered concomitant chemoRT with Oxaliplatin and continuous infusional (CIV) 5FU to determine the maximum tolerated dose (MTD) in the phase I portion. Methods: Pts with histologically proven locally advanced pancreatic cancer were enrolled in standard Phase I 3+3 fashion to determine MTD. ChemoRT included 5FU 200mg/m2 CIV and Oxaliplatin wkly X5 wks. Radiation dose was 4500cGy in 25 fractions (180cGy/fx/d) over 5 wks followed by a conedown to the tumor and margin for an additional 540cGy x3 (total dose 5040 cGy in 28 fractions) Oxaliplatin was escalated from 30mg/m2 in 10mg intervals up to 60mg/m2. Following chemoRT, unresectable pts were treated with mFOLFOX6 x 6. Results: 15 pts enrolled in the phase I portion, all completed neoadjuvant therapy. Most hematologic toxicities were gr 1 and 2. There was 1episode of gr 4 lymphopenia. The most common non-hematologic toxicities were gr1–2 fatigue, anorexia, nausea and vomiting. Gr 3 non-hematologic toxicities included 4 episodes hyperglycemia, 1 diarrhea, 1 anorexia, 3 nausea/vomiting and 2 hypokalemia. The highest planned dose level for weekly Oxaliplatin was tolerable and the RPTD is 60mg/m2/wk. Of the 15 pts: 2 progressed, 2 were explored but were unresectable, 2 await exploration and 9 were deemed still unresectable and proceeded to consolidation. 7/9 completed the planned 6 cycles. 1 pt was removed from protocol due to extended delay of treatment due to gr 3 neuropathy. 1 pt died due to progressive disease. 21% of planned cycles were delayed due to gr2 or 3 myelosuppression. 1 pt required dose reduction due to fever in setting of gr4 neutropenia but was able to complete treatment at the reduced dose. Conclusions: Combined modality treatment for locally advanced pancreatic cancer with Oxaliplatin, CIV 5FU and radiation is well tolerated at full doses of Oxaliplatin (60mg/m2/wk) and does not produce substantially more toxicity than standard chemoRT to the pancreatic bed. The phase II portion of the trial is ongoing.

[Table: see text]
Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and down-regulates survivin/BIRC5 gene expression
Authors: Glienke W. , Maute L. , Milz E. , Bauer N. , Bergmann L.
Published: March 2020

15030

The anti-apoptotic gene survivin/BIRC5 plays an important role in cellular proliferation and survival of cancer cells. Regulated by constitutively activated STAT3, Survivin/BIRC5 may be a target for inhibiting cellular proliferation in pancreatic cancer cell lines. The purpose of this study was (a) to determine the effect of curcumin (diferuloylmethane) on survivin/BIRC5 expression and (b) a possible role of STAT3 activation in Survivin/BIRC5 expression in pancreatic cancer cell lines. We have incubated four pancreatic cancer cell lines with different amounts of curcumin. The expression of Survivin/BIRC5 on mRNA and protein level was measured with RT-PCR and western blot analysis. The activation of STAT3 through phosphorylation, contributing to the regulation of survivin was analyzed with western blot analysis. The incubation of the pancreatic cancer cell lines with curcumin resulted in a down-regulation of cellular proliferation in all cell lines tested but with different rates of inhibition. The expression of survivin/BIRC5 on mRNA and protein level was significantly down-regulated after treatment with 30 μM. Curcumin blocked the phosphorylation of STAT3 in a concentration-dependent manner. Treatment of pancreatic cancer cell lines with curcumin resulted in an induction of apoptosis as measured with FacScan analysis. We conclude that curcumin inhibits several key factors in cancer cellular pathways and may have the potential to be investigated in pancreatic cancer.

No significant financial relationships to disclose.
First clinical experience with 90Y-radiolabeled humanized anti-MUC1 antibody (hPAM4) in patients with advanced pancreatic cancer: A phase I study
Authors: Gulec S. A. , Cohen S. J. , Zuckier L. S. , Horne H. , Teoh N. , Wegener W. A. , Gold D. V. , Goldenberg D. M.
Published: March 2020

15034

Background: The humanized antibody, hPAM4, specifically targets an epitope in the mucin glycoprotein MUC1 expressed in most pancreatic cancers, but not normal pancreas or most other normal tissues. This study evaluated the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), dosimetry and preliminary efficacy of 90Y-DOTA-hPAM4 administered as a single dose to patients (pts) with pancreatic adenocarcinoma. Methods: Pts with locally advanced disease and progression on 1 prior therapy (TX) or metastatic disease with 0–1 prior TX’s were eligible if they were ≥ 4 wks beyond prior TX, had adequate hematology/chemistries, with measurable disease, but no lesion >10 cm. Pts initially received 111In-hPAM4 followed by 7 days of serum samples and imaging for PK, biodistribution and organ radiation dose analysis. Pts then received a single infusion of 90Y-hPAM4 with the 90Y dose escalated in cohorts of 3–6 pts (5-mCi/m2 increments) until 2 evaluable pts/cohort encountered DLT. Treatment toxicity was evaluated by NCI CTC v. 3 criteria and tumor response by CT-based RECIST criteria. Results: Fifteen pts (8F/7M; median age 60; 11 metastatic/4 locally advanced;13 with, 2 without prior TX) received 90Y-hPAM4 at a dose level of 15 mCi/m2 (n=4), 20 mCi/m2 (n=7), and 25 mCi/m2 (n=4). Pre-therapy 111In-hPAM imaging showed acceptable biodistribution and organ radiation dosimetry in all pts. Four wks after treatment, 1 pt at 15 mCi/m2 and 2 pts at 20 mCi/m2 had CT responses, with 32–51% shrinkage of their pancreatic mass, while 3 other pts at various dose levels had stable target lesions by CT. All pts showed disease progression at or after wk 8. The only significant drug-related toxicity was hematologic, with >1 DLT (>7 day grade 4 thrombocytopenia and/or neutropenia) encountered at the 25 mCi/m2 level. Conclusions: For 90Y-hPAM administered once as a single agent, hematologic toxicity was dose-limiting, the MTD was established at 20 mCi/m2, and CT demonstrated several transient reductions or stabilization of index lesions. Based on this Phase I experience, combined/sequential treatment with chemotherapy and fractionated radioimmunotherapy is being considered for future trials.

No significant financial relationships to disclose.
Barriers to breast cancer risk screening
Authors: Zwaagstra A. , Hoskins K.
Published: March 2020

1505

Background: The U. S. Preventive Services Task Force has recommended that physicians assess and discuss breast cancer risk with their female patients. With this recommendation comes the need to develop strategies for providing breast cancer risk-screening and a need to identify potential barriers to the successful implementation of a risk-screening strategy. Methods: A personalized breast cancer risk profile was offered to all women presenting for a screening mammogram at a community hospital. The profile included a Gail model estimate and analysis of family cancer history to detect hereditary breast cancer syndromes utilizing a pedigree assessment tool developed by the authors. Women with 5 year Gail estimates ≥ 1.66%, lifetime Gail estimate ≥ 15% or increased score with the pedigree assessment tool were considered at increased breast cancer risk. Women in the increased risk cohort received written notification of their risk status and were advised to undergo formal risk assessment either through a free consultation with an advanced practice nurse with expertise in cancer risk assessment or with their primary physician. We analyzed compliance with this recommendation over the 6 month period of time after subjects received the risk notification letter. Results: For the three month study period, 242 women met criteria for the increased risk cohort. Of these, 201 (83%) failed to follow through with the advanced practice nurse for formal risk assessment. Surveys were mailed to all 201 non-compliant subjects to identify reasons for non-compliance and 80 surveys were returned (40%). Reasons given for failure to follow- through with formal risk assessment included: self-perception of “average” breast cancer risk (75%), recent normal screening mammogram (55%), primary care physician had not referred them (18%), absence of breast symptoms (15%), and time constraints (15%). Only 11 subjects (14%) indicated that they had discussed risk results with their physician. Conclusions: The majority of women in our study who requested breast cancer risk estimates failed to act on that information. These results could have implications for design and implementation of a successful breast cancer risk-screening program, and point to the need for better patient education and involvement of primary care physicians in the risk assessment process.

No significant financial relationships to disclose.
A combination chemotherapy of weekly paclitaxel and doxifluridine (5’-DFUR: an intermediate metabolite of capecitabine) in patients with unresectable or recurrent gastric cancer in an outpatient setting. Final results of a multicenter phase II trial
Authors: Yoshino S. , Nishimura T. , Hazama S. , Oka M. , Ozasa H. , Shimizu R. , Furuya T. , Fukuda S. , Satoh T. , Hara T.
Published: March 2020

15050

Background: Paclitaxel (PTX) and 5’-DFUR have single-agent activity in gastric cancer and have distinct mechanisms of action and no overlap of key toxicities. Synergistic interaction between PTX and 5’-DFUR is mediated by taxane-induced up-regulation of thymidine phosphorylase, which converts 5’-DFUR to 5-FU. We conducted a combination phase II study of PTX and 5’-DFUR in patients with unresectable or recurrent gastric cancer to evaluate the efficacy and safety in an outpatient. Methods: Eligibility criteria included patients with histologically proven unresectable or recurrent gastric cancer who had measurable lesions fitting RECIST, up to one prior chemotherapy, a performance status of 0–2 and adequate organ function. According to our results of phase I study (Proc ASCO 2004, Abstr. 4228), the treatment included PTX 70 mg/m2 i.v. on days 1, 8, and 15 every 4 weeks and 5’-DFUR 600 mg/body p.o. everyday until there was disease progression or the appearance of unacceptable toxicity. Primary endpoint was: RR; and secondary endpoints were OS, PFS, TTF and onset rate of adverse events. Results: Between June 2004 and July 2006, 42 patients were enrolled in this study: including 34 men; 8 women; median age of 70 years (range, 44–85 years); and PS levels were, zero with 27, one with 13 and two with 2 patients. In 42 eligible patients, clinical usefulness was evaluated resulting in response rate of 40.5% (CR, 1; PR, 16; SD, 17; PD, 6; and NE, 2 patients). The first-line therapy involved 28 patients in whom the response rate was 50.0%. The second-line therapy involved 13 patients (all TS-1 failure) in whom the response rate was 23.1%. OS was 371 days, PFS was 170 days and TTF was 147 days. All patients were treated in outpatient. Severe adverse events were found in 2 patients to discontinue the present treatment, though other adverse events were relatively mild without death due to the present therapy. Commonly observed grade 3/4 adverse events were neutropenia (26.2%), appetite loss (4.8%), neuropathy (4.8%), and fatigue (4.8%). Conclusions: The outpatient combination of a weekly PTX and 5’-DFUR chemotherapy is active and well tolerated.

No significant financial relationships to disclose.
Phase II clinical trial of XELOX as first line treatment for patients with unresectable or metastatic gastric cancer
Authors: Xu R. , Han B. , Shi Y. , Xiong J. , Li Y. , Wang F. , Qiu M. , Jiang W. , Lin T. , Zhang L. , He Y.
Published: March 2020

15062

Background: The survival of advanced gastric cancer remains poor, while no chemotherapy regimen was recognized standard. Oxaliplatin and Capecitabine (Xeloda) have demonstrated promising antitumor efficacy in advanced colorectal cancer. The present study was conducted to further evaluate the efficacy and safety of XELOX (Oxaliplatin and Xeloda) regimen in gastric cancer. Methods: Patients with unresectable or metastatic gastric cancer were enrolled into this study. They all receive the XELOX regimens (Oxaliplatin 130mg/ m2 intravenously in 2 hours on day 1 followed by oral capecitabine 1000mg/ m2 twice daily for 14 days every 3 weeks).We evaluated the response every 2 cycles. Results: The median age of the total enrolled 45 patients was 55 years (range, 22–82 years), including 32 male and 13 female. They received a median of 5 cycles (range, 2–8 cycles) of XELOX. 21 of 45 patients (46.7%) achieved an objective response, 1 patient (2.2%) had completed response. 17 patients (37.8%) experienced stable disease. Median time to tumor progression (TTP) and median overall survival were not available yet due to the further follow-up needed. Most toxicity events were mild to moderate in XELOX regimen, with grade 3/4 neutropenia of 8.9 %, thrombocytopenia of 6.7%, anemia of 11.1%, hand-foot syndrome of 6.7 % and diarrhea of 6.7 %. Grade 3 neuropathy was 4.4%. The patients with advanced gastric cancer had a good tolerance to this chemotherapy. Conclusions: XELOX is a highly effective first-line treatment for unrsectable and metastatic gastric cancer. The response rates in this trial seems to be similar to those observed with FU/leucovorin/oxaliplatin combinations. XELOX is tolerable well in the treatment of advanced gastric cancer.

No significant financial relationships to disclose.
Docetaxel (Do) and gemcitabine (Gem) in advanced pancreatic cancer (APC) patients (pts): A multicentre study
Authors: Des Guetz G. , Chauvenet L. , Paraiso D. , Mayeur D. , Aparicio T. , Chirat E. , Boiron C. , Bouleuc-Parrot C. , Pujade- Lauraine E.
Published: March 2020

15065

Background: Gem is the only approved chemotherapeutic drug in the treatment of APC. Do as single agent has shown some activity. Effective cytotoxic combinations with gem are urgently needed. Methods: Combination of Gem 1200 mg/m2/d1 + Do 50 mg/m2/d1 every 2 weeks was evaluated in first line APC pts with Karnovsky Index (KI) > 40, and good organ function. Initial Do dose was modified according to liver biology alterations. Treatment of relapse with Gem-Do or other combinations was allowed. Results: The 45 pts (male=64%) included in 7 centres had a median age of 62 yrs (range 36–81 yrs) and 26 (58%) had metastatic disease. Pts received a median of 4 cycles (0–6) with a median dose of 47 mg/m2 for Do and 1170 mg/m2 for Gem. Neutropenia Gr 3/4 was the most severe toxicity (Tox) (24% of pts) and required G-CSF support, with infection G3 in 14 pts (31%), febrile neutropenia in 1. Others G3 Tox were fatigue (20% of pts), diarrhea (14%), anemia (9%) thrombopenia (7%) and G2 Tox: alopecia (33%), nausea (15%) and edema (11%). During treatment, KI improved or was stable in 33% and 44% of pts, weight increased or was stable in 38% and 23%, pain control was better or stable in 20% and 56%. After panel review, objective RECIST response was observed in 17.7% of pts (CR = 4.4%) and stable disease in 40%. Median progression- free survival (PFS) was 3.8 months (mo) and 14 pts (31%) had PFS between 6 and 14 mo. Median survival was 12.0 mo (95% CI; 10.2–13.8 mo). Conclusions: The combination of Do and Gem every 2 weeks is feasible and should be associated with systematic growth factor support. Subjective and objective criteria of efficacy in APC are encouraging. A direct comparison with Gem single agent is warranted.

No significant financial relationships to disclose.
Dose-dense chemotherapy (CT) with modified TCF regimen (TCF-DD) in metastatic gastric cancer (MGC): A Phase II study
Authors: Dalla Chiesa M. , Tomasello G. , Buti S. , Negri F. , Buononato M. , Longarini R. , Porzio R. , Lazzarelli S. , Brighenti M. , Passalacqua R.
Published: March 2020

15068

Background: Previous studies reported that in lymphomas, early breast and bladder cancer, dose-dense CT is more effective than conventional treatment. We reported for the first time, in 2006 ASCO meeting, the feasibility of an intensified dose-dense TCF regimen (q2w) in MGC. This is the subsequent phase II study. Methods: patients (pts) with histologically confirmed measurable MGC, ECOG PS 0–3, received up to 6 cycles of Docetaxel 85 mg/m2 (75 mg/m2 after first 12 pts, 70 mg/m2 after the 28th patient) day 1, Cisplatin 75 mg/m2 day 1 (60 mg/m2 after the 28th patient) l-Folinic Acid 100 mg/m2 day 1 and 2, followed by 5-Fluorouracil 400 mg/m2 bolus day 1 and 2, and then 600 mg/m2 as a 22 hour continuous infusion day 1 and 2, every 14 days, plus Pegfilgrastim 6 mg on day 3. Pts with a PS > 1 and/or age > 65 years and/or pre-treated for the metastatic disease, received the same schedule with a dose reduction by 30%. Results: 31 consecutive pts were enrolled (81% male, 19% female; median age: 60, range 40–79; median ECOG PS: 1, range 0–3; 3 pts pre-treated). Primary end points were response rate and safety. A median of 4 cycles (range 1–6) per pts were administered. 15 pts (48%) required a dose reduction, mostly because of hematologic toxicity and severe asthenia. 10 pts (32%) were treated with full dose without any delay on at least the first 4 cycles. 25 pts were evaluated for response (3 too early, 1 early suspension because of severe allergic reaction to Docetaxel; 2 early deaths: 1 bowel perforation and 1 sepsis) and 30 for toxicity. 2 CR (multiple liver metastases), 12 PR, 4 SD and 7 PD were observed, for an ORR (RECIST criteria and intention-to-treat principle) of 50% (95% CI 30–65). At a median follow-up of 10 months (range 1–24), overall median survival was 6 months (range 1–20). Frequent grade 3 to 4 toxicities were: neutropenia (65%), thrombocytopenia (31%), anemia (14%) febrile neutropenia (31%), asthenia (62%), diarrhoea (21%) and stomatitis (14%). Conclusions: TCF-DD regimen in MGC is feasible and very active. The recommended dose (with reduction by 30% as above) for further randomised studies comparing TCF-DD with standard TCF is Cisplatin 60 mg/m2 and Docetaxel 70 mg/m2.

No significant financial relationships to disclose.
Daily dose of perifosine less toxic than weekly and active in patients with hepatocellular carcinoma (HCC)
Authors: Campos L. T. , Stephenson J. , Swan F. , Richards D. , Birch R. , Henderson I.
Published: March 2020

15072

Background: P is a novel oral alkylphosphocholine with effects on multiple signal transduction pathways including Akt, MAPK and JNK. Unresectable HCC has a dismal prognosis. In the only large randomized trial, the response rate to single agent chemotherapy was <3% and median progression free survival (PFS) was l0 weeks. In small series response rates up to 25% have been reported with combination regimens Methods: Patients (pts) were accrued to a broad phase 2 trial & randomized to P, 50 mg daily or 1200 mg weekly, between 3/05 and 5/06, at which time the protocol was amended to P 100 mg daily or 900 mg weekly because the daily dose was so non-toxic and the weekly dose too toxic. The amended protocol is still open. A Simon two-stage design was used for each cancer, and HCC is one of several tumor types that have fulfilled criteria for expansion into the second stage. Results: Prior to protocol amendment 241 pts, including 13 with HCC, were entered. The daily dose was very well tolerated; 70% had no or only grade 1 toxicity. The principle toxicities are gastrointestinal and fatigue. (See table ) The weekly dose was significantly more toxic. The median age of the HCC pts was 64(range 22 - 80); 9 patients were male and the median ECOG performance status was 1, range 0–2. Eight had no prior chemotherapy. Eleven were evaluable for response, and 1 without prior chemotherapy who was treated on the 50 mg daily dose had a partial response lasting for 9 months. In addition, 5 (4 on the 50 mg daily dose) were progression free for > 6 months. This included 2 with 2 and 3 prior regimens. Conclusions: This study demonstrated that perifosine has very little toxicity when administered at a dose of 50 mg daily and is active in HCC as well as other cancers

[Table: see text]

No significant financial relationships to disclose.