bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II study of capecitabine (X), irinotecan (I) and oxaliplatin (O) as first-line therapy in patients (pts) with advanced or metastatic colorectal cancer (MCRC)
Authors: Maroun J. A. , Jonker D. , Goel R. , Cripps C. , Lister D. , Chiritescu G.
Published: March 2020

13540

Background: Triplets of I, O and infusional 5-FU/Leucovorin (LV) are associated with high response rates and long survival in first-line MCRC [Falcone et al. JCO 2002;20:4006–14]. The oral fluoropyrimidine X has proved higher response rates and improved safety vs. 5-FU/LV in MCRC. Methods: This ongoing dose-escalation study aims to establish dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase II doses (RPIID) of I and O in combination with X as first-line therapy for MCRC and to assess the efficacy and safety of this XIO combination. Starting doses were: I (180mg/m2 i.v. on day 1), O (85mg/m2 i.v. on day 1), and X (850mg/m2 bid orally on days 2–15). Dose escalations are based on toxicity observed at the previous dose level (DL), until DLT, MTD and RPIID are documented, at which time a phase II component begins. Results: We enrolled 18 pts (13 men, 5 women), median age 61 (range 44–74) at 4 DLs. ECOG PS was 0 or 1 in 17 pts, and 2 in 1 pt. Pts received a median of 7 cycles (range 1–15) of XIO. All pts are evaluable for toxicity and 14 for response. The most common adverse events were: neutropenia (83% all grades (G) with 4 G3, 4 G4), diarrhea (67%, 4 G3, one of which was a DLT). Nausea (78%) and vomiting (56%) were mild and controlled with anti-emetics. Fatigue occurred in 50% pts, with 1 G3. The DLT was febrile neutropenia (3 pts at DLs 1, 3, & 4 respectively). One pt at DL4 developed severe neutropenia and sepsis during cycle 3, had aspiration pneumonia and died in hospital from respiratory and cardiac complications. MTD has not yet been reached. Responses were observed at all DLs: 11 partial responses with 2 still unconfirmed (79%, 95% CI 54–100), and 2 stable disease (14%). Progression-free survival and overall survival have not been reached. Conclusions: XIO is well tolerated and demonstrated significant efficacy as first-line treatment in MCRC. Severe neutropenia was significant but was of short duration and manageable. It is likely to be the main DLT. MTD has not yet been identified but is expected in the next few pts. A phase II study to confirm the efficacy and safety of the XIO combination will follow. Supported by Roche, Sanofi Aventis, and Pfizer Canada Inc.

[Table: see text]
Multicenter phase II study of cetuximab and irinotecan as third line chemotherapy in patients (pts) with metastatic colorectal cancer (MCRC) previously treated with both irinotecan and oxaliplatin regimens
Authors: Grande C. , Mel J. R. , Salgado M. , Reboredo M. , Candamio S. , Fernandez I. , Quintero G. , Huidobro G. , Firvida J. L. , Valladares M.
Published: March 2020

13551

Background: Pts with chemotherapy-resistant MCRC have a really poor prognosis with few therapeutic options. Cetuximab (Erbitux®) is an IgG1 monoclonal antibody targeting the EGFR, shown to be effective in pts with EGFR-expressing MCRC refractory to prior irinotecan-based chemotherapy (Cunningham NEJM 2004). Methods: The goal of this multicenter phase II study is to investigate the safety and efficacy of cetuximab in combination with irinotecan as third line treatment in 40 pts with heavily pre-treated MCRC. From Jan to Dec 2005, 40 pts with EGFR-expressing MCRC, refractory to irinotecan, pre-treated with both irinotecan and oxaliplatin with fluorouracil or capecitabine combinations, and PS 0–2, were included to receive cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) plus irinotecan (180 mg/m2 every 2 weeks) until tumour progression or unacceptable toxicity. Pts were analysed weekly for toxicity and every 12 weeks for response. Recruitment is completed. Currently, 38 pts are evaluable for toxicity (2 pts recently recruited) and 23 pts for response (16 pts on treatment for <12 weeks and 1 pt withdrew at week 6 due to lung thromboembolism not related to study treatment). Results: M/F 24/14, median age 63 years (range: 33–78), colon/rectum 23/15, ECOG PS=0/1/2 9/23/6, Metastatic sites 1/2/>2 16/19/3 (Liver 43%, lung 23%, nodes 17%, pelvic 5%, others 12%). A total of 418 weekly infusions were administered (mean: 11; range: 3–37). Preliminary efficacy data is as follows: 3 PR, 3 SD, 17 PD with an overall response rate of 13% (95% CI: 3–34%) and disease control rate of 26% (95% CI: 10–48%). Major toxicities (G 1–2/G 3–4) were: Acne-like skin rash 58/11%, Anemia 32/3%, Neutropenia 16/13%, Nausea-vomiting 32/0%, Diarrhoea 32/11%. Median time to progression was 3.5 months (Range: 1–10+) and median overall survival was 7.3 months (Range: 1.5–12+). Conclusions: These preliminary results suggest that cetuximab and irinotecan combination, is a reasonably effective treatment for pts with highly pre-treated MCRC with an acceptable toxicity profile

No significant financial relationships to disclose.
Impact of the size of metatases on the outcome of patients with non-resectable colorectal liver metastases treated with percutaneous laser-induced thermoablation (pLIT)
Authors: Aprile Esq. G. , Sponza M. , Vit A. , Pella N. , Gasparini D. , Zanon E. , Iaiza E. , De Pauli F. , Marzio A. , Piga A.
Published: March 2020

13556

Background: whenever surgical resection of liver metastases from colorectal cancer is not possible, thermal ablation is a mini-invasive local treatment that can be considered as an alternative approach. Complete thermal ablation can be achieved by laser treatment. When thermoablation is obtained by radiofrequency, patients treated for a small dominant lesion (less than 3 cm) experience a better outcome. This evidence is less clear when pLIT is used. Patients and Methods: 30 patients (22 with a single lesion, 8 with up to three metastases) were consecutively treated. Maximum diameter of the dominant lesion was less than 3 cm in 20 pts and more than 3 cm in ten. With mild sedation and local anaesthesia, optical fibers were inserted directly into the tumor with echo-guided percutaneous needle placement. Each optical fiber was connected to a neodymium:yttrium-aluminium-garnet (ND:YAG) laser, which delivers concentrated light at a wave-length of 1064 nm, with a 5-Watt power and a 1800-Joule energy per single fiber. A minimum of two and a maximum of four needles were used, with a 5 to 8 mm distance from one needle to another. Results: all patients tolerated LIT procedure well, without major complications. Post-treatment CT-scan demonstrated complete thermonecrosis in 39 out of 44 (87%) of the treated lesions, and almost complete in the remaining 5, 4 of which of diameter larger than 3 cm. Local failure was reported in 12% of the lesions at six-month follow-up. The median Kaplan-Meier survival for all patients was 607 days, with survival rate of 82% at one year and 55% at three years. Patients treated for a smaller dominant lesion had a significantly better survival than the others (850 vs 420 days, p=0.04, logrank). Conclusions: pLIT permitted in most cases a complete ablation of liver metastases with a high local tumor control rate and a low complication rate. Patients with a smaller dominant lesion do best after pLIT procedure. Local treatment coupled with systemic chemotherapy offers a chance of prolonged survival in patients not amenable to hepatic surgery.

No significant financial relationships to disclose.
Pharmacokinetics of Irinotecan and SN38 after intra-arterial liver perfusion according to infusion time and circadian patient pattern in metastatic colorectal cancer
Authors: Pirovano M. , Nasisi A. , Paraboni L. , Sestini S. , Masseroni S. , Gherardi F. , Martignoni G. , Meregalli M. , Fornasari D. , Scaglione F. , Tabiadon D.
Published: March 2020

13557

Chronotherapy studies in pretreated CRC cancer pts showed that 6 hrs chronomodulated CPT11 infusion from 2 to 8 a.m., alone or combined with 5FU+AF±OHP, is less toxic than the standard 90 min. infusion, and CPT11-SN38 convertion efficency is improved with an higer objective response rate. Objective of this study was evaluation of CPT11 pharmacokinetics after hepatic i.a. perfusion according to infusion time and circadian patient pattern. To evaluate patient circadian pattern, serum levels of prolactin and cortisol were detected at 2–6, 4 pm and 2–6, 4 -8 pm respectively. CPT11 and SN38 serum levels were detected, according to two different time schedules, following the HPLC method. Every pt received 240 mg/mq i.a. CPT11 perfusion alternating daily with nightly schedule: from NOV04 to FEB05 5 metastatic CRC patients were treated. All pts concluded all programmed cycles. No cycle was delayed due to toxicity. Haematological, hepatic and g.i. G 3–4 (NCI) toxicity were not observed (only neutropenia G1 in the female subject). Circadian organization seems to be progressively lost according to cycle number. At 3rd cycle, cyrcadian levels of cortisol and prolactin are lost in all pts. Kinetic data suggests for a progressive reduction of liver enzymatic capability; this is probably due to cumulative liver drug toxicity: this phenomenon is clearly evidenced in female subject but is also signicative in the male subjects (see Table). These preliminary data show enormous PK/PD interpatient variability and a significative AUC reduction 2nd cycle vs 1st and 3rd vs 2nd; due to this unespected observation we are not able to evaluate cyrcadian oscillation of enzymatic systems: in order to fully understand these data we decided to perform polimorphism assesment for UGT1A1,Carboxil Esterase isoform2 and ABC transporters genes.This analysis will be performed on paraffin included samples for the first 5 pts and on fresh tissue for the next pt set. [Table: see text]

No significant financial relationships to disclose.
Tegafur combined with oxaliplatin and 5-FU versus FOLFOX4 for advanced colorectal cancer: a randomized controlled study
Authors: Lingxiang L. , Yongqian S. , Ping L. , Puwen H. , Yongmei Y.
Published: March 2020

13566

Background: To determine the activity and side-effect of tegarfur injection combined with L-OHP and 5-FU, comparing with FOLFOX4 as the therapy for advanced colorectal cancer. Methods: 60 patients, proved pathologically, were divided into 2 groups at random. Group A received the intravenous administration of tegafur(800mg/m2 IV 3hrs qd d1–5),leucovorin(100mg/m2 IV 2hrs qd d1–5) and L-OHP(130mg/m2 IV 2hrs d1) every 21 days. FOLFOX4 was applied in the group B. The endpoint included response rate (RR), progression free survival (PFS), overall survival(OS) and quality of life(QOL). Results: The response rate was 39.3% in the group A, while median time to progression was 9.5 months with median survival time of 11.6 months. In the group B, the response rate was 48.1% and median time to progression was 9.4 months with median survival time of 12.1 months. No significant differences were found between treatment arms in curative effect, survival time and side effect(P>0.05). With respect to QOL, the group A achieved higher PS than B during treatment (P<0.001). Conclusions: The intravenous administration of tegafur, leucovorin and L-OHP is a well-tolerated, effective, and feasible schedule for advanced colorectal cancer that yields comparable efficacy and side effect compared with FOLFOX4. Meanwhile, the former achieves the better QOL.

No significant financial relationships to disclose.
Capecitabine plus irinotecan (CAPIRI) as first-line treatment for patients (pts) with metastatic colorectal cancer (MCRC)
Authors: Laudani A. , Agostara B. , Savio G. , Leonardi V. , Salvagno L. , Palmisano V. , Usset A.
Published: March 2020

13573

Background: Twice-daily oral capecitabine mimics 5-FU infusion and has superior efficacy, improved safety and convenience compared with 5-FU/LV in MCRC and early-stage colon cancer. Preclinical and phase I/II clinical data suggest supra-additive efficacy of X + irinotecan and no significant pharmacokinetic interactions. We evaluated the efficacy and safety of X plus weekly irinotecan (CAPIRI) in 3-week cycles as first-line treatment for MCRC. Methods: Pts with no prior treatment for MCRC received irinotecan 80 mg/m2 i.v. infusion on d1&8 + capecitabine 1000 mg/m2 orally bid d1–14, q3w. Results: Baseline characteristics of the 39 enrolled pts (22 men/17 women) were: median age 59.9 years (range 38–76), ECOG PS 0–1, colon cancer (n=25), rectal cancer (n=14), metastatic sites (liver 74%, pelvis 20%, nodes 23%, lung 18%, peritoneum 10%, primary tumor 20%). Previous treatments were as follows: adjuvant chemotherapy (36%), radiotherapy (5%), neoadjuvant chemotherapy (3%). Pts received a total of 199 cycles (mean 5.1 per pt, range 1–13). All 39 pts were evaluable for safety and 38 for efficacy. The most common treatment-related grade 3/4 adverse events were nausea/vomiting (23% of pts), diarrhea (10%), and leucopenia (5%). The overall response rate was 45%, including 3 complete and 14 partial responses. A further 8 pts (21%) had stable disease. The duration of response in pts with a complete response was >10 months. Conclusions: These early findings indicate that this combination is effective and well tolerated as first-line treatment for MCRC. Replacing 5-FU with capecitabine in XELIRI offers benefits to the pt in terms of efficacy, safety, convenience, reduced discomfort and avoidance of central venous access compared with infusional 5-FU/LV-based regimens (IFL and FOLFIRI).

No significant financial relationships to disclose.
Adjuvant CCRT for locally advanced rectal cancer: Uracil-tegafur? Or intravenous fluorouracil?
Authors: Hsieh C. H. , Chen Y. J. , Chang K. H. , Hsu H. H. , Liu C. K. , Hung S. K. , Chen H. W. , Lai Y. L. , Hsu T. C.
Published: March 2020

13582

Background: This prospective, nonrandomized study was conducted to compare the efficacy and toxicity of postoperative concurrent chemoradiation therapy (CCRT) using daily oral uracil-tegafur plus leucovorin (UFUR/LV) vs. weekly intravenous fluorouracil plus leucovorin (5-FU/LV) in patients with locally advanced rectal cancer. Methods: From November 1996 through December 2004, 30 patients with stage II or III rectal cancer were enrolled. Seventeen received oral UFUR/LV regiment and thirteen with intravenous 5-FU/LV regiment during CCRT. A weekly infusion of 400 to 450 mg/m2 of 5-FU plus a bolus injection of 80 to 100 mg/m2 of LV and 250 to 300 mg/m2/d of oral UFUR plus 30 to 45 mg /m2/d of oral LV were given separately during RT and for an additional 42 weeks thereafter. Forty-five Gy of whole-pelvis irradiation was followed by a local boost of 5.4 to 14.4 Gy to the tumor bed delivered in 33 fractions. Analytical method was Kaplan-Meier method. Results: Mean survival in the UFUR/LV group was 36 months compare with 30 months in the 5-FU/LV group. The 2-year OS, DFS and LCR were 68.1% vs. 65.8%, 54.9% vs. 50.4%, and 79.4% vs. 83.9%, (p > 0.05), respectively. There were no treatment-related deaths and grade 4 toxicity in both groups. Grade 3 of dermatitis, gastrointestinal, and hematologic toxicity was noted in the 5-FU/LV group. Conclusions: Postoperative CCRT with oral UFUR/LV in locally advanced rectal cancer provides an alternative way for those who have difficulty with an intravenous regimen due to it was more tolerable and less toxicity and has similar survival rate.

No significant financial relationships to disclose.
Upregulation of thymidine phosphorylase (TP) by radiation (XRT): Phase II study of capecitabine (CAP) with XRT in pts with locally advanced (LA) pancreatic cancer
Authors: Roy S. , Russo S. , Black G. , Eloubeidi M. A. , Steg A. , Zelterman D. , Johnson M. R. , Diasio R. B. , Saif M. W.
Published: March 2020

14001

Background: Preliminary studies have shown that XRT unregulates TP, the main enzyme responsible for activity of CAP. The objectives of this phase II study were to further evaluate effect of XRT on TP, DPD, and TNF-alpha as well as response and efficacy of CAP with concurrent XRT in pts with LA pancreatic cancer. Methods: Pts received 50.4 Gy XRT with CAP at 1600 mg/m2 M-F × 6 wks determined from our phase I study (JCO, Dec 2005). Following CAP-XRT, stable and responding pts on CT scan were treated with CAP 2000mg/m2 × 14 days q 3 wks till progression. Restaging was performed every 9 wks. Tumor specimens were procured with EUS-FNA 1 wk prior and 2 wks after CAP-XRT to evaluate TP, DPD, and TNF-alpha mRNA levels by RT-PCR. A sample size of 20 was selected (mean 1 vs. S with mean 0=13.5; alpha = 0.05; power = .99; t-test). Results: 19 pts (median age: 67; M/F: 7/12) were enrolled at UAB between March 2004 and June 2005. 4 pts (21%) had confirmed partial responses and 13 (68%) had stable disease. 2 pts underwent surgery (Ro in 1; extensive fibrosis in 1). Six-month survival rate was 89%. We have not met enough deaths to estimate median survival. Grade 3 and 4 toxicities included: nausea/vomiting (5%), thrombosis (5%), hyperbilirubinemia (5%), and grade 3 GI bleeding (5%). No hematological toxicities except grade 1 thrombocytopenia (5%) and grade 1 anemia (10%). All pts completed full CAP-XRT with 3 dose reductions (by 20%). Pts received mean of 5.4 cycles (range: 3–15) of CAP alone with a total of 104 cycles with dose reductions in 7 cycles (by 25%). TP was elevated during wk 2 when compared to pre-XRT TP (P = .005) but DPD was not (P = .13) nor was TNF-alpha (P = .37). No correlation between TP and TNF-alpha was noticed. No association between TP/DPD ratio and efficacy of CAP was identified. Tumor TP expression was higher (183.16) in pt with GI bleeding. Conclusions: This Phase II study further confirms our Phase I results that CAP-XRT is an effective, tolerable, and an easy alternative to infusional 5-FU regimen for pts with LA pancreatic cancer. Also TP upregulation by XRT was statistically significant. While these results support use of CAP-XRT in pancreatic cancer, there appears to be additional genes (other than TP, DPD) associated with response to CAP and CAP-XRT.

[Table: see text]
A multicenter phase II study of pemetrexed and cisplatin in patients with advanced gastric cancer (AGC)
Authors: Bang Y. , Kim Y. , Chung H. C. , Kang W. , Park S. , Yang S. , Park H. , Kim C. , Park B. , Otero J. C.
Published: March 2020

14008

Background: Pemetrexed is a novel folate antimetabolite, and it inhibits a number of folate-dependent enzymes. This agent has demonstrated activity in a variety of tumor types including AGC. This study was performed to evaluate the combination of pemetrexed and cisplatin in the treatment of AGC. The primary endpoint was response rate, and secondary endpoints were duration of response, time to progressive disease, time to treatment failure, overall survival, and toxicity. Methods: Patients with stage IV AGC not to be amendable to curative surgery and measurable disease were eligible. Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 were given on day 1, every 21 days. Treatment was supplemented with folic acid, vitamin B12, and dexamethasone. Response was assessed by RECIST, and toxicity was assessed by NCI-CTC v 2.0. Results: From October 2003 to September 2004, 51 patients were enrolled, but 1 did not meet the eligibility criteria. There were 37 men and 13 women with a median age of 56 years (range, 24–69) and an ECOG PS 0/1 for 14/36 patients; all had metastatic disease. Of 50 evaluable patients, there were no complete responses, and 13 had confirmed partial responses (26%; 95% CI, 14.6%-40.3%). Fifteen patients (30%) had stable disease, and 21 (42%) progressed, and 1 (2%) was unknown. Among 13 responders, the median durarion of response was 3.60 months (95% CI, 2.80–9.40). Median time to progressive disease was 2.8 months (95% CI, 2.20–4.40), and median overall survival was 6.6 months (95% CI, 4.80–10.40). The median time to treatment failure was 2.10 months (95% CI, 1.00–2.80). Survival estimates were 32.0% at 3 months and 7.0% at 6 months. A total of 212 cycles were administered to 51 patients (median 4 [range, 1–13]). Based on 51 patients, most common grade 3/4 hematologic toxicities were neutropenia (49.0%), leukopenia (19.7%), and anemia (13.7%); the most common grade 3/4 nonhematologic toxicities were hyponatremia (15.7%), anorexia (9.8%), nausea (7.8%), and vomiting (7.8%). Conclusions: : The combination of pemetrexed and cisplatin in the current dose and schedule has a modest activity and a mild toxicity profile in patients with AGC. Further study is warranted using a different dose and treatment schedule.

[Table: see text]
Hepatic arterial infusion (HAI) of oxaliplatin in advanced hepatocellular cancer (HCC): A phase I study
Authors: Rathore R. , Iannitti D. , Soares G. , Wanebo H. , Maia-Aucna C. , Safran H.
Published: March 2020

14010

Background: We performed this phase I study is to evaluate the feasibility and determine the Maximally Tolerated Dose of HAI-oxaliplatin given every 3 weeks in advanced HCC. Methods: Patients (pts) with unresectable or recurrent HCC were eligible for therapy on this protocol. HAI-oxaliplatin was administered over 2 hours via a percutaneously placed hepatic arterial catheter or a surgically inserted hepatic arterial infusion pump. Therapy was continued until disease progression or excessive toxicity not amenable to appropriate modifications. Restaging was performed after every 2 cycles. Dose escalation levels for HAI-oxaliplatin are 90 mg/m2, 110 mg/m2, 130 mg/m2 and 150 mg/m2 given every 3 weeks. Results: A total of 16 patients have been enrolled and toxicity data are available for all patients. Median age was 61 yrs (range 47–84 yrs), there were 15 men and 1 woman. The stage distribution is: stage II-3 pts, stage III- 7 pts, stage IV- 6 pts. Prior therapies including chemoembolization (CE) in 3 pts, radiofrequency ablation (RFA) in 3 pts, and both RFA and CE in 1 pt. A total of 37 cycles (range 1–3) have been delivered. Levels 1 and 3 had to be expanded to 6 pts each due to major toxicity in 2 pts at each level. Level 2 was expanded as 1 pt was non-compliant. Major toxicities are shown below. One patient developed embolic bowel ischemia after his HAI procedure. There was one episode each of duodenal perforation and duodenal ulceration. Traditional grade 3/4 hematologic and gastrointestinal toxicities were infrequent. Among 13 pts receiving at least 2 cycles, 3 pts had partial responses (PR) and 4 pts had stable disease (SD). Greater than 50% reduction in AFP was seen in the 3 pts with PR and 2 pts with SD. Conclusions: HAI-oxaliplatin is feasible, well tolerable, and demonstrates activity in this population of pts with advanced HCC. [Table: see text]

No significant financial relationships to disclose.
Phase II study of conventional fractionated radiotherapy versus hyper-fractionated accelerated radiotherapy concomitant with low dose gemcitabine for patients with pancreatic cancer
Authors: Maemura K. , Takao S. , Shinchi H. , Noma H. , Hiraki Y. , Nakajo M. , Aikou T.
Published: March 2020

14017

Background: Concurrent radiotherapy and chemotherapy with gemcitabine (GEM) has been reported to improve the median survival of patients with unresectable pancreatic cancer. Although hyperfractionated accelerated radiotherapy (HART) was administered to pancreatic cancer recently, the efficacy is unclear. Phase II study was conducted to evaluate the efficacy and the toxicity of HART concomitant with twice-weekly low dose GEM compared with conventionally fractionated radiotherapy (CRT) for unresectable pancreatic cancer. Methods: Between April 2001 and April 2004, 34 untreated eligible patients with histologically proven unresectable pancreatic cancer were enrolled. In CRT group (n=15), 50.4Gy was delivered in 28 fractions of 1.8Gy/day. In HART group (n=19), 50Gy was delivered in 40 fractions of 1.25Gy twice a day. All patients were treated with conformal radiation using 5mm multileaf collimeter. Concurrent chemotherapy with GEM (40mg/m2) was administered twice a week to both groups. Chemotherapy was suspended for Grade 3 toxicities or increase in temperature more than 38 °C. Response evaluations were conducted at six weeks after the treatment. Maintenance chemotherapy composed of GEM (1000mg/m2/week) for 3weeks was repeated every 4 weeks thereafter. Results: The median survival time (MST) was 11.3 months in CRT group and 12.9 months in HART group. The 1- and 2-year survival rates were 42.9% and 28.6% in CRT group, 52.9% and 17.6% in HART group. There was no significant difference in response rate between CRT and HART group (35.7% vs. HART; 35.3%). The median time to progression (TTP) was significantly prolonged in HART group (9.7months) compared with CRT group (5.9 months) (p=0.02). Overall treatment time was significantly shorter in HART group (37days) than CRT group (45days) (p=0.002). There was no significant deference in toxicity between CRT and HART group. Conclusions: HART concomitant with low dose GEM was well tolerated with acceptable toxicity and prolonged median TTP and MST with shortening of treatment time compared with conventional radio-chemotherapy. This regimen appears to be one of the crucial therapies for patients with unresectable pancreatic cancer.

No significant financial relationships to disclose.
Glufosfamide (GLU) plus gemcitabine (GEM) in advanced solid tumors: Phase 1 results
Authors: Chiorean E. G. , Dragovich T. , Hamm J. T. , Langmuir V. K. , Kroll S. , Jung D. T. , Colowick A. B. , Loehrer P. J.
Published: March 2020

14022

Background: Glufosfamide is glucose linked to isophosphoramide mustard, the active metabolite of ifosfamide. Cancer cells use glucose at a higher rate than normal cells, which may lead to preferential metabolic targeting by GLU. GLU has shown activity in patients (pts) with pancreatic cancer in Phase 1/2 studies with the dose-limiting toxicities (DLT) being nephrotoxicity and neutropenia. The MTD was 4500 mg/m2. In preclinical studies, GLU has shown additive activity when combined with GEM. The objectives of this study are to establish the maximum tolerated dose (MTD) and to evaluate the safety, efficacy and PK of GLU + GEM in advanced solid tumors. Methods: Eligible pts had Karnofsky Performance Status ≥70, no prior GEM, at least one lesion by RECIST, creatinine clearance (CrCL) ≥60 mL/min and acceptable hematologic and liver function. Cohorts of 3–6 patients were treated with GLU 1500–4500 mg/m2 IV over 4 hours on Day 1 and GEM 1000 mg/m2 IV over 30 minutes on Days 1, 8 and 15 of every 28-day cycle for up to 6 cycles. CT scans were obtained every 8 weeks. Detailed PK sampling was performed. Results: Nineteen pts with pancreatic (8), gall bladder (4) and other (7) cancers were enrolled. Two DLTs have occurred: Grade 3 fatigue at 2500 mg/m2 and Grade 4 thrombocytopenia at 4500 mg/m2. Both cohorts were expanded. No DLTs occurred in the 1500 or 3500 mg/m2 cohorts. Three pts completed all 6 cycles and 3 pts continue on study. Reasons for early discontinuation were progressive disease (10), clinical deterioration (1), AE (1) and death (1). Grade 3/4 neutropenia occurred in 7 pts (5 during Cycle 1) and Grade 3/4 thrombocytopenia in 5 pts (2 during Cycle 1). The CrCL fell below 60 mL/min in one patient. No objective tumor responses have been reported; 10 of 18 (56%) evaluable pts had stable disease (SD) at 8 weeks, including 1 pt with heavily pretreated ovarian cancer with ongoing SD after 8 months on therapy. PK analyses suggest no interaction between GLU and GEM. Conclusions: Phase 1 data indicate that full dose GLU (4500 mg/m2) can be given safely in combination with GEM. Both early and delayed Grade 3/4 thrombocytopenia and neutropenia have been observed. A Phase 2 cohort of 28 pts with pancreatic adenocarcinoma is currently enrolling. Studies with GEM/GLU in other tumor types are planned.

[Table: see text]
Chemotherapy in advanced biliary tract carcinoma (BTC): A comprehensive analysis
Authors: Eckel F. , Schmid R. M.
Published: March 2020

14036

Background: BTC are uncommon but highly fatal malignancies in the United States and Europe. Unfortunately, most BTC are diagnosed at advanced stages when the tumor is unresectable. Due to the lack of phase III studies there is no standard regimen for palliative chemotherapy of BTC. The aim of this study was to analyze existing data of published clinical trials, even small and non-randomized, and identify superior regimens, which may represent a quasi standard of care of palliative chemotherapy in this disease. Methods: Data for this analysis were identified by searches of PubMed and references from relevant articles using the search terms “biliary tract neoplasms”, “bile duct neoplasms”, “cholangiocarcinoma”, and “gallbladder neoplasms”. Only papers published in English since 1985 were included. Additionally abstracts from ASCO meetings presented since 1999 were included. Results: 88 trials were analyzed. The overall response rates (OR) of this trials were in the range of 0–83%. There were 497 responders out of 2137 patients corresponding to a pooled OR of 23.3% (95%CI 21.5–25.2%). The median progression free survival (PFS) and overall survival (OS) for all patients was 4.1 and 8.0 months, respectively. There was a significant correlation between OR and PFS (r=0.49; p=0.001) and PFS and OS (r=0.76; p=0.000) but not between OR and OS. Gemcitabine (GEM) and platinum analogs (P) had a significant positive impact on OR, whereas the impact of taxanes and irinotecan was negative. OR of subgroups defined by 5-FU, GEM, and P were analyzed in detail. There was only a trend of an increased OR between 5-FU and GEM without P (17 vs 22%). Combination with P increased significantly the OR of 5-FU by 10% (17 vs 27%) and of GEM by 20% (22 vs 42%). Conclusions: The pooled OR of mostly small trials of palliative chemotherapy in BTC is about 23%. With GEM alone no significant improvement could be achieved compared to 5-FU or capecitabine. However, doublets of GEM in combination with P synergistically increased OR. Results of GEM plus P are promising and should be further evaluated by large RCT. In the meantime GEM plus P may represent at least a good option for patients in good general condition.

No significant financial relationships to disclose.
Selection of induction chemotherapy (CT) in esophageal and gastroesophageal junction cancer by positron emission tomography (PET)
Authors: Irigoyen A. , Delgado J. , Rodriguez A. , Ferron J. , Luque R. , Reche P. , Gonzalez E. , Conde V. , Rodriguez C. , Pleguezuelos J.
Published: March 2020

14041

Background: Preoperative CT improves survival in esophageal cancer. 50% of patients (pts) do not respond to cisplatin+5-FU (C+F). The reduction of fluorodeoxyglucose uptake after 14 days (d) of CT predicts clinical response (rsp). Our objective was to measure the rsp (rsp) rate after CT adjusted according to PET rsp. Methods: Eligible pts were ≥ stage II esophageal cancer and able to tolerate CT. By adjusting CT according to PET rsp, we expected an increase of rsp rate by 25%. Taking into account a confidence level of 90%, an error β of 20% and a minimal error of 15% (even with such a high error rate the data will exceed the standard results), we calculated a sample size of 23 pts. All underwent esophagoscopy, computed tomography and PET scan prior to C (100mg/m2 d1) +5-FU (1,000mg/m2 d1–5). If PET rsp after first cycle (uptake decreased ≥ 35%), we continued up to third C+F cycle, then if endoscopy rsp: C+F + concurrent radiation only if stage II or III. If no endoscopy rsp, surgery only if stage II or III. On the other hand, if the pts had no rsp in PET after first C+F cycle they continued with 2 cycles of docetaxel (35mg/m2 d 1 & 8) and irinotecan (50mg/m2 d 1 & 8) (D+I) every 21 d and then if endoscopy rsp: radiation + docetaxel only if stage II or III. If no endoscopy rsp, surgery. Results: Since 2/04, 23 pts have been enrolled. Location: 2 cervical, 4 upper thoracic, 7 mid-thoracic, 10 GE junction. PET stage: 7 IIA, 6 IIB, 2 III, 2 IVA, 6 IVB. Up-staging with PET in 6 pts, down-staging in 4 pts. Histology: 10 Adenocarcinoma, 13 squamous carcinoma. Improved swallowing function: from a total of 12 PET responders, 9 had a clinical rsp after C+F, 3 did not. From 11 PET non-responders, 7 had a clinical rsp after D+I, 4 did not. Global clinical rsp = 16/23 (70%). Endoscopy rsp (frequent inaccuracy by overstaging): from a total of 12 PET responders, 6 had a clinical rsp after C+F, 6 did not. From 11 PET non-responders, 7 had a clinical rsp after D+I, 4 did not. Global clinical rsp = 13/23 (57%). Conclusion: Our results suggest that it is possible to significantly increase the percentage of pts who respond to induction CT adjusted according to PET in esophagogastric cancer before concurrent chemoradiotherapy or esophagectomy, or both.

No significant financial relationships to disclose.
Influence of first line treatment in the 5 (5yS) and 10-year (10yS) survival outcomes of patients with gastroenteropancreatic neuroendocrine tumors (GNETs): 2001–2005 Spanish task force GNET group
Authors: Vilar E. , Martinez M. , Alonso V. , Sevilla M. , Sastre J. , Castellano D. , Marazuela M. , Diaz J. , Villabona C. , Salazar R.
Published: March 2020

14058

Background: Data on incidence, morbidity and mortality of GNETs is limited due to the low frequency of these tumors. However this survival data is critical to design studies with new agents. Methods: Data was obtained from medical records of 262 patients with GNETs and centralized in an online registry at www.retegep.net . Among the study parameters were histology, localization, stage, diagnostic workup, 1st line and subsequent treatments, 5yS and 10yS for the whole dataset and for different stages, tumor types and 1st line systemic treatment. Results: Mean age 58, 58% male. Primary tumors: 49% Carcinoids (C), 19% non-functioning pancreatic tumors (PT), 9% insulinomas, 6% gastrinomas and 8% unknown primary. Localizations: midgut (36%), head (17%) and body of pancreas (10%). Functioning symptoms led to diagnosis in 38% of cases. 4% were associated to MEN1. Stage at diagnosis was advanced (Adv) in 46%, localised (L) in 30% and locorregional (LR) in 13% (unknown in 11%). Diagnostic workup were CT Scan (84%), Octreoscan (52%) and US (52%) and serum hormone tests (65%). Treatments for Adv disease included somatostatin analogues (SA) (47%), surgery (S) (43%), chemotherapy (CT) (35%) and interferon (IFN) (34%), embolization (7%) and radiofrequency ablation (3%). 5yS and 10yS for the whole group was 61.6% (SD: 5.2%) and 49.8% (SD: 7.7%) respectively. 5yS and 10yS for the L/LR and Adv stages were 78.1% (SD: 7.3%) and 71% (SD: 10%), and 48.9% (SD: 7.7%) and 29% (SD: 12.4%), respectively. LR PT and C had similar 5 and 10yS but Adv PT did worse than Adv C (5yS of 36.2% and 61.1%, respectively). 1st line systemic treatment for LR and Adv disease (n=90) included SA (39%), CT (34.4%), IFN (5.6%), combinations of SA+IFN (13.3%), A+CT (4.4%) and other combinations (3.3%), with a 10yS rate of 69%, 79%, 50%, 89%, 66% and 50%, respectively. Adv PT perform worse than C regardless of treatment choice. As second line systemic treatment (n=43) 30% received SA, 30% CT, 26% inmunotherapy and 14% combinations. Conclusions: An extensive use of systemic therapy and a scarce use of non-surgical LR treatments is observed in the Adv stages. Choice of 1st line systemic treatment does not seem to influence survival outcomes.

No significant financial relationships to disclose.
Phase I/II trial of continuous hepatic arterial infusion (HAI) of Irinotecan in patients with hepatocellular carcinoma (HCC). Preliminary results
Authors: Pantaleo M. , Derenzini E. , Piscaglia F. , Golfieri R. , Bolondi L. , Mirarchi M. G. , Danesi R. , Biasco G. , Brandi G.
Published: March 2020

14061

Background: No standard therapies are available for HCC patients (pts) who are not eligible for curative treatments (surgery, RF, TACE or PEI). Methods: This dose finding phase I/II study investigates the tolerability of increasing doses of continuous HAI of CPT-11 (during days 1–5 every 21) in pts with histologically confirmed Child A/B HCC, confined to the liver, not eligible for curative treatments. Secondary endpoints are pharmacokinetics and efficacy. To date, 5 dose levels (DL) of CPT-11 have been investigated (from 7,5 to 17,5 mg/m2/die) and the 6th (20 mg/m2/die) being evaluated. An arterial port-a-cath was placed in the hepatic artery by percutaneous catheterization of the femoral or axillary artery. Before each cycle an angiography was performed to define the optimal liver perfusion. DLT was defined as one G4 hematogical and/or two G3 nonhematological toxicities or liver function impairment (Child C). AEs were graded using NCI-CTC. Responses were evaluated after the 3rd cycle with ultrasonography or CT scan (WHO criteria). Results: To date 16 pts have been enrolled and evaluated for tolerability. Median age is 63, 8 years (range 41–80), M/F 11/5, median ECOG 1 (0–2), Child-Pugh A/B 10/6 . Total n° of courses was 41 (median 2, range 1–10). DLT was not reached. Two grade 3 toxicities were reported at DL 4: diarrhea in 1 pt and anemia in another pt. There were no G4 toxicities. Most common G1–2 toxicities at any DL were: neutropenia 5 pts (31%), nausea/vomiting 4 pts (25%), diarrhea 3 pts (18%), thrombocytopenia 2 pts (12.5%). In two pts (DL3 and DL4) treatment was discontinued because of chemotherapy induced arteritis after 1 and 3 courses respectively. 12 pts were assessable for response: 3 PR, 6 SD, 3 PD. α-fetoprotein levels decreased significantly in 6 pts (50%). Pharmacokinetics data will be presented later. Conclusions: To date MTD hasn’t been reached. At DL 1–5 this schedule shows little and manageable toxicity - without impairment of liver function - and promising activity (PR+SD=75%).

No significant financial relationships to disclose.
Radiochemotherapy followed by gemcitabine and capecitabine in extrahepatic bile duct cancer (EBDC): A phase I/II-trial
Authors: Schoppmeyer K. , Wiedmann M. W. , Liebmann A. , Miethe S. , Mossner J. , Caca K. , Witzigmann H. , Hildebrandt G.
Published: March 2020

14087

Background: The 5-year survival rate of patients with resected EBDC is less than 30%. Phase II trials demonstrated that advanced EBDC responds to both chemotherapy with gemcitabine and capecitabine and to radiotherapy. Our objective was to define a feasible and effective postoperative therapy in patients with EBDC. Methods: Patients were eligible after surgery for EBDC. Surgery included resection of lymph node positive cancer, incomplete resections and diagnostic laparotomy in unresectable tumors. Patients received a fractionated radiotherapy with 49.6 Gy accompanied by gemcitabine 100 mg/m2 weekly × 5. After a two week rest patients were treated with gemcitabine (1000 mg/m2 IV D1+8 q3w) and capecitabine (1500 mg/m2 PO D1–14 q3w) on a 3-week cycle. Treatment continued for 6 cycles in nonmeasurable disease or until disease progression or intolerable toxicity. Primary endpoint was toxicity; secondary endpoints were response rate in measurable disease and overall survival. Results: 18 Patients (resectable/unresectable disease 7/11) were enrolled. Radiotherapy was completed in all patients and a total of 66 cycles of chemotherapy were applied. Anemia, fatigue, and nausea were the most common mild adverse events in 16, 14, and 16 patients, respectively. Grade 3 and 4 toxicity was rare after resection but frequent in unresectable disease and consisted of fatigue, nausea, duodenal ulcer, cachexia and cholangitis in 1, 2, 2, 4, and 4 patients, respectively. We observed a 50% disease stabilization rate in patients with measurable disease. Median overall survival was 7.9 months in patients with unresectable tumors. Median overall survival in patients after resection has not been reached after a median follow-up of 19.5 months. Conclusions: Radiochemotherapy with gemcitabine followed by gemcitabine and capecitabine is an active regimen with manageable toxicity after resection of EBDC but has significant toxicity in unresectable disease.

No significant financial relationships to disclose.
Irinotecan with 5-FU/FA in advanced biliary tract adenocarcinomas—A two-center phase II trial (GBFiri)
Authors: Feisthammel J. , Schoppmeyer K. , Wiedmann M. , Mossner J. , Schulze M. , Caca K.
Published: March 2020

14088

Background: The majority of patients with biliary tract cancer present with advanced, unresectable tumors. Irinotecan and 5-Fluorouracil/folinic acid (FOLFIRI) have synergistic activity in gastrointestinal cancers. The aim of this study was to determine the tolerability and activity of systemic chemotherapy with FOLFIRI in patients with intrahepatic cholangiocarcinoma (CCC) or gallbladder cancer (GBC). Methods: This was a prospective, multicenter, non-randomised, open-label, phase II trial. Eligibility criteria: Inoperable adenocarcinoma of the biliary tract, measurable disease, age 18–80 years, ECOG PS 0–2. Patients received irinotecan 80 mg/m2 as a 30 min infusion, followed by folinic acid 500 mg/m2 over 2 h and 5-FU 2000 mg/m2 over 24h weekly × 6 followed by a 2 week rest. Treatment was continued until progression or limiting toxicity. Response to therapy was assessed after every other cycle according to RECIST criteria. Primary end point was response rate, secondary end points were overall survival, progression free survival and toxicity. Results: 30 pts (CCC 17, GBC 13) were enrolled. A total of 387 doses (Median 12.9; 1 to 36) were administered with an overall relative dose intensity of 98%. 30 patients are evaluable for safety. WHO grade 3/4 drug related adverse events occured in 7 patients (23%): Leukopenias in 2, anemia in 1, and diarrhea in 4 patients. 14 patients completed 2 cycles and were evaluable for response. Response rates: CR 0/30, PR 3/30 (10%) and SD 3/30 (10%). 8 patients presented with disease progression at restaging. Median overall survival: CCC 166 days, GBC 327 days. Progression-free-survival: CCC 84 days, GBC 159 days. Conclusions: FOLFIRI is a well tolerated regimen in patients with biliary cancer that can be safely administered on an outpatient basis. FOLFIRI has no substantial activity in CCC and moderate activity in GBC. Further studies are required to define a standard palliative chemotherapy for treatment of biliary cancer.

No significant financial relationships to disclose.
Pancreatic cancer survivorship: Intrathecal drug delivery system for pain management
Authors: Stearns L. J. , Poling W. H. , Kiser J. , Nasternak J. , Berryman E.
Published: March 2020

14100

Background: Pancreatic cancer is predominantly unresectable at diagnosis and is most frequently fatal. Nationally the average survivorship is 10 months. Among pancreatic cancer patients, pain is associated with decreased survival rates. Quality of life and survivorship are the principal outcome measures for these patients. Successful pain management may be a significant predictor of prolonged survivorship. No study has demonstrated an impact on survivorship secondary to the treatment of pancreatic cancer pain and the use of Intrathecal Drug Delivery Systems (IDDS). Methods: A retrospective chart review identified all pancreatic cancer patients treated at a cancer pain treatment center between January 2002 and June 2005. 43 patients had known dates of diagnosis and known dates of death. The Arizona Department of Health Services Cancer Registry provided similar information for pancreatic cancer patients residing in Maricopa County for that time period. 713 Maricopa county residents had known dates of diagnosis and known dates of death. Results: Among the Maricopa County pancreatic cancer patients, the mean survivorship was 5 months. Among the treatement center patients who did not receive the IDDS for pain, 10 (23.3%), the mean survivorship was 10.8 months. Among the pancreatic cancer patients receiving IDDS for pain management, 33 (76.7%), the mean survivorship was 14.2 months. Mean survivorship among the treatment center patients receiving IDDS for pain management is nearly 3 times greater than the general survivorship of pancreatic cancer patients in Maricopa County. Among the treatement center patients the mean survivorship is nearly 50% greater for patients receiving IDDS versus those that did not. Conclusions: The implantable IDDS for pain management among pancreatic cancer patients may be a significant predictor of increased survivorship. A larger sample size may be needed to detect significant differences in survivorship. Controlled studies examining survivorship as the primary outcome for patients with unresectable pancreatic cancer by evaluating the implantable IDDS as compared to usual care modalities such as comprehensive medical management (CMM) or neurolytic celiac plexus block (NCPB) for pain management are warranted.

No significant financial relationships to disclose.
Preliminary results of a phase II-study: Vaccination therapy of pancreatic carcinoma patients with autologous, tumor lysate pulsed dendritic cells
Authors: Bauer C. , Dauer M. , Schnurr M. , Junkmann J. , Bauernfeind F. , Conrad C. , Bruns C. , Jauch K. , Emmerich B. , Endres S. , Eigler A.
Published: March 2020

14102

Background: Vaccination trials in the experimental and in the clinical setting have shown that it is possible to use dendritic cells (DC) to induce a specific antitumoral immune response. In this study, a protocol for the treatment of patients with metastasised pancreatic carcinoma with autologous, tumor-lysate pulsed dendritic cells was established. Methods: Patients with strong suspicion of pancreatic carcinoma receiving abdominal surgery are recruited to the study. Tumor-lysate is derived by freeze-taw-cycles from surgically derived tissue specimens. After recurrence of histologically verified pancreatic carcinoma or in a primarily palliative situation, patients are eligible for DC vaccination. DC are derived from PBMC according to a six-day protocol, loaded with tumor lysate and stimulated with TNF-alpha and PgE2. DC are applicated intracutaneously into the groin region three times in twice weekly cycles, then in monthly cycles. Immune response is controlled by DTH skin testing. Samples of non adherent cells are frozen for future MLR and ELISPOT assays. Main study end point is partial or complete remission four months after the start of vaccination. Alternative end points are adverse effects, quality of life, one-year survival and immuno-monitoring. Results: Tumor material of 49 patients has been worked up to tumor lysate and stored for future vaccinations. Four patients have received dendritic cell vaccination. Two of these patients have received their four months staging CT. In one case local disease was stable. The other patient showed progressive disease. A more pronounced proliferation of specific T cells compared to the control setting could be demonstrated by MLR assay. Discussion: A protocol for vaccination with tumor lysate pulsed dendritic cells of patients with pancreatic carcinoma has been established. Four patients have been vaccinated with dendritic cells according to a phase II study protocol. Vaccination was tolerated well. Because of a severe adverse reaction after the beginning of gemcitabine therapy, vaccination had to be omitted intercurrently with this patient. Results of most immuno monitoring assays are pending. One patient receiving DC vaccination therapy showed stable local disease.

No significant financial relationships to disclose.