Continuous Infusion Of 5-fluorouracil Research Articles

Low-Dose Continuous 5-Fluorouracil Combined with Leucovorin, nab-Paclitaxel, Oxaliplatin, and Bevacizumab for Patients with Advanced Pancreatic Cancer: A Retrospective Analysis.

BackgroundContinuous-infusion 5-fluorouracil (5FU) and calcium leucovorin plus nab-paclitaxel and oxaliplatin have been shown to be active in patients with pancreatic cancer. As a protracted low-dose infusion, 5FU is antiangiogenic, and has synergy with bevacizumab. As shown in the treatment of breast cancer, bevacizumab and nab-paclitaxel are also synergetic.ObjectiveIn this paper we retrospectively analyze the survival of 65 patients with advanced pancreatic cancer who were treated with low-dose continuous (metronomic) chemotherapy given in conjunction with conventional anti-VEGF therapy.Patients and MethodsSince July of 2008, we have treated 65 patients with 5FU (180 mg/m2/day × 14 days) via an ambulatory pump. Calcium leucovorin (20 mg/m2 IV), nab-paclitaxel (60 mg/m2) IV as a 30-min infusion, and oxaliplatin (50 mg/m2) IV as a 60-min infusion were given on days 1, 8, and 15. Bevacizumab (5 mg/kg) IV over 30 min was administered on days 1 and 15. Cycles were repeated every 28–35 days. There were 42 women and 23 men, and the median age was 59 years. Forty-six patients had stage IV disease.ResultsThe median survival was 19 months, with 82% of patients surviving 12 months or longer. The overall response rate was 49%. There were 28 patients who had received prior treatment, 15 of whom responded to therapy. Fifty-two patients had elevated CA 19-9 prior to treatment. Of these, 21 patients had 90% or greater reduction in CA 19-9 levels. This cohort had an objective response rate of 71% and a median survival of 27 months. Thirty patients stopped treatment due to disease progression, and an additional 22 stopped because of toxicity. One patient died while on therapy.ConclusionsThis non-gemcitabine-based regimen resulted in higher response rates and better survival than what is commonly observed with therapy given at conventional dosing schedules. Low-dose continuous (metronomic therapy) cytotoxic chemotherapy combined with antiangiogenic therapy is safe and effective.

Pharmacokinetics of continuous transarterial infusion of 5-fluorouracil in patients with advanced hepatocellular carcinoma.

Numerous studies concerning hepatic arterial infusion chemotherapy (HAIC) have been conducted by adopting regimens containing 5-fluorouracil (FU), with a favourable efficacy compared with conventional transcatheter arterial chemoembolisation (TACE) treatment; however, the detailed mechanism of HAIC remains unclear. The present study aimed to evaluate peripheral concentration time curves of 5-FU administered through the hepatic artery, which may additionally explain the mechanism of action of HAIC. A total of 10 eligible patients underwent transcatheter arterial embolization and a 2-day HAIC treatment regimen using a folinic acid, fluorouracil and oxaliplatin regimen. Peripheral venous blood sampling was performed in each patient prior to infusion, and at 0, 0.5, 1, 1.5, 2, 5, 10, 15, 22 and 23 h following the start of infusion. The blood sample at 0 h was analysed for dihydropyrimidine dehydrogenase (DPD) levels by high performance liquid chromatography, and the rest of the samples were analysed for 5-FU by optimised liquid chromatography-mass spectrometry (LC-MS). The lower limit of quantification of optimised LC-MS for 5-FU was 5 ng/ml. The steady-state plasma concentration of 5-FU administered through the hepatic artery was achieved after 15 h. This concentration largely varied, ranging from 8.64–152.00 ng/ml. Optimised LC-MS may detect low concentrations of 5-FU. The steady-state concentration of 5-FU administered through the hepatic artery was achieved after 15 h. DPD levels were analysed through determining the ratio of plasma uracil (U) and dihydrouracil (UH2) by HPLC, and the results indicated a mild DPD deficiency in the patients with HCC. These results may provide a basis for the explanation of the clinical efficacy of HAIC, and to additionally optimise its efficacy.

Phase I and II trial on infusional 5-fluorouracil and gefitinib in combination with preoperative radiotherapy in rectal cancer: 10-years median follow-up

PurposeThe aim of this study is to evaluate the long term survival of the addition of gefitinib to chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). Methods and materialsThis previously published multicentre, open-label, phase I-II study, enrolled patients (pts) with LARC to receive CRT with concurrent 5-fluorouracil continuous intravenous infusion and a dose escalation of orally administered gefitinib, followed 6–8 weeks later by surgery. An intra-operative radiotherapy boost of 10 Gy was planned. Adjuvant chemotherapy was administrated in ypN1-2 pts. After a median f/u of >10 years, we analyzed Local Control (LC), Metastasis Free Survival (MFS), Disease Free Survival (DFS), Disease Specific Survival (DSS) and Overall Survival (OS). Predictive endpoints of clinical outcomes were tested by univariate and multivariate analysis. Variables analyzed included: age, gefitinib dose and interruptions, adjuvant CT, surgery type, ypT, ypN, and TRG grade. We have also analyzed late toxicity according to CTCAEv4. ResultsOf the 41 initially enrolled pts, 39 were evaluable (27M, 12F). With a median f/u of 133 months, LC, MFS, DFS, OS and DSS at 5 years were 84%; 71%; 64%; 87% and 92%, respectively. The OS and DSS at 10 years were 61,5% and 76%, respectively. Grade 3-4 late toxicity occurred in 38% of pts: sexual (28,2%) and gastrointestinal toxicities (10,2%). ConclusionLong term outcomes and late toxicity were similar to previously reported series. The addition of gefitinib did not improve outcomes in LARC. Gefitinib is not recommended for rectal cancer patients who received 5-FU based preoperative CRT. Further studies may identify if gefitinib is beneficial in selected group of patients.

A randomized phase 3 trial comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced esophageal carcinoma\u2014the ESO-shanghai 1 trial protocol

BackgroundConcurrent chemoradiotherapy is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. Cisplatin combined with 5-fluorouracil continuous infusion (PF) remains the standard concurrent chemotherapy regimen. However, radiotherapy concurrent with PF showed a high incidence of severe side effects. Paclitaxel showed a promising radiosensitivity enhancement in the treatment of esophageal carcinoma in both vitro and vivo studies. The ESO-Shanghai 1 trial examines the hypothesis that paclitaxel plus 5-fluorouracil (TF) concurrent with radiotherapy has better overall survival and lower toxicity for patients with local advanced ESCC.MethodFour hundred thirty-six ESCC patients presenting with stage IIa to IVa will be enrolled in a prospective multicenter randomized phase 3 study. Patients will be randomized to either concurrent chemoradiotherapy with PF (cisplatin 25 mg/m2/d, d1–3, plus 5-fluorouracil 1800 mg/m2, continuous infusion for 72 h) once every 4 weeks for 2 cycles followed by consolidation chemotherapy for 2 cycles or concurrent chemoradiotherapy with weekly TF (5-fluorouracil 300 mg/m2, continuous infusion for 96 h plus paclitaxel 50 mg/m2, d1) for 5 weeks followed by consolidation chemotherapy (5-fluorouracil 1800 mg/m2, continuous infusion for 72 h, plus paclitaxel 175 mg/m2 d1) once every 4 weeks for 2 cycles. The radiotherapy dose is 61.2 Gy delivered in 34 fractions to the primary tumor including lymph nodes. The primary end-point is the 3-yr overall survival analyzed by intention to treat. The secondary endpoints are disease progression-free survival, local progression-free survival, and number and grade of participants with adverse events.DiscussionThe aim of this phase 3 study is to determine whether the TF regimen could replace the standard PF regimen for inoperable ESCC patients. An overall survival benefit of 12% at 3 years should be expected in the TF group to achieve this goal.Trial registrationClinicalTrials.gov Identifier: NCT01591135. Registered 18 April 2012.

Continuous infusion fluorouracil (5FU) in heavily pre-treated mCRPC patients.

257 Background: Pts with mCRPC resistant to novel hormones (abi/enza), and taxane chemotherapy are challenging. Extensive pre-treatment typically poses an issue for clinical trials, and there is no consensus regarding how to manage patients who no longer respond to conventional therapies but maintain a good performance status. Methods: 13 mCRPC pts were treated with 5FU at 200mg/m2 continuous infusion as a novel treatment option for those with heavily pretreated mCRPC. Data was retrospectively collected at Tulane Cancer Center for patient treatment history, and laboratory parameters. Results: All treated patients had prior exposure to an average of 8.7 lines of treatment. 5FU was used as median 8th line therapy. All pts had extensive bony disease and 6 had liver involvement. Median PSA at start of treatment was 356 ng/dL. 5 pts progressed within a month of initiation of therapy, and 2 pts did not respond. 8 (61%) patients had treatment for >1 month with 6 having >30% PSA reduction, 4 with a >50% PSA reduction and 2 with a >90% PSA reduction (Table). Median time on therapy was 4.5 months with 2 patients remaining on treatment for >6 months despite multiple pretreatments and far advanced disease. 5FU was well tolerated with improvement in both performance status and symptoms in several patients. Conclusions: Continuous 5FU is active in select highly pretreated pts and targets folate metabolism via inhibition of thymidylate synthase. It is one of the few chemotherapies that can be administered with little myelosuppression, an important issue in far-advanced pts. Prostate specific membrane antigen (PSMA) expression is upregulated in CRPC, especially after abi/enza treatment. PSMA hydrolyzes polyglutamated folates and functions as a folate transporter; its over-expression stimulates both folate transport and prostate cancer cell line growth. We hypothesize that 5FU, functioning as an anti-folate, antagonizes the downstream effects of PSMA over-expression. PSA data for pts on treatment > 1 month. [Table: see text]

A triplet combination with irinotecan, oxaliplatin, continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in RAS wild-type, metastatic colorectal cancer: A phase 1 dose finding study.

856 Background: The FOLFOXIRI regimen (irinotecan, oxaliplatin, 5-fluorouracil and leucovorin) improves the response rate and overall survival compared to FOLFIRI in pts with metastatic colorectal cancer (mCRC), and addition of cetuximab to chemotherapy increases efficacy in pts with RAS wild-type mCRC. We conducted a phase 1 study of FOLFOXIRI plus cetuximab to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety and efficacy in Japanese pts with RAS wild-type mCRC. Methods: Main eligibility criteria were: histologically confirmed colorectal adenocarcinoma; KRAS and NRAS wild-type status; measurable metastatic disease according to Response Evaluation Criteria in Solid Tumors version 1.1; age 20-74 years; Eastern Cooperative Oncology Group performance status 0 or 1. Pts with UDP-glucuronosyltransferase 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded. Pts received an escalating dose of intravenous irinotecan (100, 120, and 150 mg/m2 in the dose levels 0, 1, and 2, respectively) and a fixed dose of intravenous oxaliplatin (85 mg/m2), continuous infusion 5-fluorouracil (2400 mg/m2) plus l-leucovorin (200 mg/m2), and cetuximab (an initial dose of 400 mg/m2 followed by 250 mg/m2 per week). Results: A total of 9 Japanese pts were treated (3 and 9 in the dose levels 1 and 2, respectively). No patients experienced a dose-limiting toxicity (the MTD was not reached), and the dose level 2 (irinotecan 150 mg/m2) was established as the RD. With a median 8 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (44%), paronychia (22%), and acne-like rash (11%). No febrile neutropenia and treatment-related death were observed. Among 9 pts, 1 pt had complete response, 7 pts had partial response, and 1 pt had progressive disease, for an overall response rate of 89%. As of September 24, 2017, median progression free survival was 14.0 (95% CI 7.2-20.7) months. Conclusions: The combination of cetuximab and FOLFOXIRI has shown a favorable toxicity profile and promising antitumor activity in pts with RAS wild-type mCRC. Clinical trial information: UMIN000018217.

Retrospective comparison of modified FOLFIRINOX with full-dose FOLFIRINOX for advanced pancreatic cancer: A Japanese cancer center experience.

469 Background: Various modified FOLFIRINOX (mFFX) regimens have been reported and widely used in clinical practice. Although there are retrospective studies and single-arm phase 2 studies comparing modified regimens to the full-dose regimen of the historical control group, head-to-head comparisons in the same population are limited. This study aimed to compare mFFX with full-dose FOLFIRINOX (fFFX) in patients with advanced pancreatic cancer (APC). Methods: We reviewed 85 patients with APC who received mFFX (no bolus fluorouracil and irinotecan 150 mg per square) or fFFX as first-line chemotherapy between January 2014 and December 2016. mFFX has been used since January 2016 on the basis of results of a Japanese phase 2 study. The efficacy, safety, and dose reduction pattern were evaluated. Results: A total of 56 eligible patients (26 treated with mFFX and 30 with fFFX) were selected. Baseline characteristics of each group were well-balanced. The median relative dose intensities of oxaliplatin, irinotecan, bolus fluorouracil, and continuous infusion fluorouracil were 68.6%, 78.5%, 0%, and 88.5% in the mFFX group, and 80.5%, 76.5%, 25.6%, and 83.6% in the fFFX group, respectively. Second cycle dose reduction occurred in 38% of the patients in the mFFX group and in 62% of those in the fFFX group. The median overall survival (OS) was 19.0 months in the mFFX group, compared to 13.2 months in the fFFX group (HR 0.60, 95% CI 0.25–1.47, P = 0.27). In a multivariate analysis to adjust for prognostic factors for OS, the hazard ratio for death with mFFX was significant (adjusted HR 0.36, 95% CI 0.14–0.93, P = 0.04). The median progression-free survival was 8.3 months in the mFFX group and 5.9 months in the fFFX group (HR 0.83, 95% CI 0.44–1.54, P = 0.55). The response rate was 35% in the mFFX group versus 30% (P = 0.78) in the fFFX group, respectively. Grade 3 or 4 leucopenia (15% versus 40%), neutropenia (42% versus 70%), febrile neutropenia (8% versus 17%), and nausea (4% versus 13%) were decreased in the mFFX group, but the differences were not statistically significant. Conclusions: mFFX had equivalent or higher efficacy and improved safety compared to fFFX in the same population.

Neoadjuvant hyperfractionated accelerated radiotherapy plus concomitant 5-fluorouracil infusion in locally advanced rectal cancer: A phase II study.

AIMTo evaluate the efficacy and tolerability of neoadjuvant hyperfractionated accelerated radiotherapy (HART) and concurrent chemotherapy in patients with locally advanced infraperitoneal rectal cancer.METHODSA total of 30 patients with histopathologically confirmed T2-3/N0+ infraperitoneal adenocarcinoma of rectum cancer patients received preoperative 42 Gy/1.5 Gy/18 days/bid radiotherapy and continuous infusion of 5-fluorouracil (325 mg/m2). All patients were operated 4-8 wk after neoadjuvant concomitant therapy.RESULTSIn the early phase of treatment, 6 patients had grade III-IV gastrointestinal toxicity, 2 patients had grade III-IV hematologic toxicity, and 1 patient had grade V toxicity due to postoperative sepsis during chemotherapy. Only 1 patient had radiotherapy-related late side effects, i.e., grade IV tenesmus. Complete pathological response was achieved in 6 patients (21%), while near-complete pathological response was obtained in 9 (31%). After a median follow-up period of 60 mo, the local tumor control rate was 96.6%. In 13 patients, distant metastasis occurred. Disease-free survival rates at 2 and 5 years were 63.3% and 53%, and corresponding overall survival rates were 70% and 53.1%, respectively.CONCLUSIONAlthough it has excellent local control and complete pathological response rates, neoadjuvant HART concurrent chemotherapy appears to not be a feasible treatment regimen in locally advanced rectal cancer, having high perioperative complication and intolerable side effects. Effects of reduced 5-fluorouracil dose or omission of chemotherapy with the aim of reducing toxicity may be examined in further studies.

Pharmacokinetic Markers of 5-Fluorouracil Toxicity in Clinical Trials and Real World

Background: Fluoropyrimidines remain the cornerstone of several regimens for solid malignancies, despite their administration may result in severe or fatal toxicities. Objective: To review pharmacokinetic markers predictive of fluoropyrimidine- associated toxicities. Shifting from i.v. boluses to both continuous infusions of 5-fluorouracil (5-FU) and oral prodrugs, as well as capecitabine, significantly increased the treatment tolerability. However, a variable percentage of patients still suffer from toxic effects that require the delay of next chemotherapeutic cycles, their definitive discontinuation, or urgent life support because of life-threatening adverse reactions. Methods: Appropriate and pertinent articles were retrieved through PubMed search. Results: Fluoropyrimidine-associated toxicities are mainly due to a dihydropyrimidine dehydrogenase enzymatic deficiency, leading to a reduced excretion of the drug, its increased activation and increased toxic effects against healthy tissues. Among the pharmacokinetic tests, test doses of 5-FU, uracil and thymine have been evaluated in clinical trials, as well as the measurement of uracil (U) and dihydrouracil (UH2) plasma concentrations. The therapeutic monitoring of 5-FU concentrations during i.v. infusions is another tool to optimize drug dosage before the occurrence of toxicities. Advances in technical platforms, as well as chromatography coupled with mass spectrometry, have simplified the implementation of those tests in clinical routine. Conclusion: Several studies have demonstrated that it is possible to predict the occurrence of severe toxicities from fluoropyrimidines, and the review will discuss all those pharmacokinetic approaches. Keywords: 5-fluorouracil, fluoropyrimidines, pharmacokinetics, test dose, therapeutic drug monitoring, toxicity.

Efficacy of sequential sorafenib plus hepatic arterial infusion chemotherapy in patients with Barcelona Clinic Liver Cancer stage B and C hepatocellular carcinoma: a retrospective single-institution study.

Aim of the studyTo evaluate the efficacy of sequential combination therapy using sorafenib and hepatic arterial infusion chemotherapy (HAIC) in patients with Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma (HCC).Material and methodsWe recruited 98 BCLC stage B/C HCC patients at our institute, who received either sorafenib monotherapy or planned sequential sorafenib-HAIC combination therapy. A total of 26 patients (combination group) received sorafenib for one or two months, followed by HAIC with a single dose of cisplatin-lipiodol suspension and a continuous infusion of 5-fluorouracil. Sorafenib-HAIC cycles were repeated every 2–3 months. The remaining 72 patients (control group) were treated with sorafenib alone. Clinical characteristics and treatment outcomes were compared between the groups. Inverse probability weighting (IPW) using propensity scores was applied to adjust for the between-group differences in baseline characteristics.ResultsThe combination group had a significantly lower frequency of extrahepatic metastasis and BCLC stage C disease compared with the control group but had more intrahepatic lesions. The crude median overall survival (OS) was 17.1 months in the combination group compared with 9.7 months in the control group (p = 0.01). The objective response rate was 23.1% in the combination group vs. 6.9% in the control group (p = 0.06). Multivariate analysis identified receipt of sorafenib-HAIC combination (HR: 0.521, 95% CI: 0.297–0.915, p = 0.02) and α-fetoprotein (≥ 400 ng/ml) at baseline as independent factors associated with OS. After adjustment with IPW the combination group still had significantly better OS than the control group (p = 0.04).ConclusionsThe sequential sorafenib-HAIC combination can be an effective and promising treatment option for selected patients with BCLC stage B/C HCC.

Comparative study of concomitant chemoradiation versus concomitant chemoradiation followed by high-dose-rate intraluminal brachytherapy in locally advanced esophageal carcinoma: a single institutional study.

PurposeThe aim of this study is to compare efficacy and toxicity between concurrent chemoradiotherapy (CCRT) followed by high-dose-rate intraluminal brachytherapy (ILBT) and CCRT in inoperable, locally advanced esophageal carcinoma.Material and methodsThirty-four patients with inoperable, locally advanced esophageal carcinoma were randomized into two arms. In the CCRT + ILBT arm (arm A), eighteen patients received 50.4 Gy at 1.8 Gy per fraction over 5.6 weeks, along with concurrent cisplatin (75 mg/m2) intravenously on day 1, and 5-fluorouracil (1000 mg/m2) continuous intravenous infusion on days 1-5, starting on the first day of irradiation and repeated after 28 days. This was followed by ILBT boost with a dose of 10 Gy in 2 fractions, one week apart. In the CCRT arm (arm B), sixteen patients received two cycles of chemotherapy, using the same schedule, along with external beam radiotherapy fractionated in a similar manner without brachytherapy boost. The endpoints were tumor response, acute and late toxicities, disease and progression-free survival.ResultsWith a median follow-up of 13 months, the complete response rate was 88.89% in arm A and 87.50% in arm B (p = 0.71). Acute esophageal toxicity was higher in CCRT followed by ILBT arm (p = 0.60). There was no significant difference between the Kaplan Meier survival plots of disease-free survival (p = 0.68) and progression-free survival (p = 0.55).ConclusionsIn our study, addition of brachytherapy as a boost following concurrent chemoradiation failed to improve treatment outcomes without additional toxicity in locally advanced esophageal cancer.

Comparison of continuous infusional 5-fluorouracil and capecitabine in preoperative chemo radiotherapy for locally advanced rectal cancer: experience from a tertiary cancer centre from Southern India

Background: Neoadjuvant concurrent chemoradiation (CTRT) is the recommended treatment for locally advanced rectal cancer. 5 Fluorouracil (5-FU) has been the standard chemotherapy drug, but recent studies have proved Capecitabine (CA) is as effective as 5-FU in terms of local response, distant recurrences and overall survival except toxicities. We conducted this study to evaluate acute toxicities and local response rates between 5-FU and CA as neoadjuvant treatment modality combined with radiation.Methods: All patients with newly biopsy proven adenocarcinoma of rectum of TNM stage T3N0/ any T with N1,N2 and in whom curative treatment was planned with concurrent chemoradiation dose of 5040cGy in 28 fractions were included in the study. From January 2013 to June 2014, a total of thirty patients were enrolled in this study, fifteen patients received 5-FU (arm A) and fifteen patients received CA (arm B) during concurrent chemoradiation. All patients were evaluated for acute toxicities during treatment using RTOG criteria. Local response was assessed radiographically after four weeks of completion of CTRT utilising RECIST (Response Evaluation Criteria in Solid Tumors) criteria and also assessed for surgery simultaneously. Postoperatively adjuvant chemotherapy was considered in all patients.Results: Grade III toxicities were more in 5-FU arm compared to CA arm. The local response rates were almost same in both the arms, partial response in 5-FU and CA arm were 53.3% and 60% respectively.Conclusions: This is the first Indian study comparing Capecitabine and continuous Infusional 5FU in neoadjuvant CTRT of standard advanced rectal cancer patients. Oral Capecitabine had same efficacy when compared to 5-FU in terms of local response rates as neoadjuvant treatment modality in locally advanced rectal cancer, but CA was better tolerated with better patient compliance and was less toxic.

Clinical effects and safety of intra-arterial infusion therapy of cisplatin suspension in lipiodol combined with 5-fluorouracil versus sorafenib, for advanced hepatocellular carcinoma with macroscopic vascular invasion without extra-hepatic spread: A prospective cohort study.

Although sorafenib and hepatic arterial infusion chemotherapy (HAIC) have been proven to improve prognosis in hepatocellular carcinoma (HCC) patients with macroscopic vascular invasion (MVI), the most appropriate approach remains unclear. The present multicenter, non-randomized, prospective cohort study aimed to compare the efficacy and safety of HAIC and sorafenib in patients with advanced HCC and MVI, without extra-hepatic spread (EHS) and Child-Pugh class A disease. The present study was performed between April 2008 and March 2014, and 64 HCC patients with MVI, without EHS and Child-Pugh class A disease were registered. Of these patients, 44 were treated with HAIC and 20 with sorafenib. HAIC involved cisplatin (50 mg fine powder in 5-10 ml lipiodol) and a continuous infusion of 5-fluorouracil (FU) (1,500 mg/5 days), which is referred to as new 5-FU and cisplatin therapy (NFP). The primary outcome was progression-free survival, and the secondary outcome was overall survival (OS). Clinical factors influencing OS and the therapeutic effect were identified using univariate and multivariate analyses. There were no differences in clinical factors between the two groups. The median progression-free survival was 5.1 and 9.5 months in the sorafenib and NFP groups, respectively (P=0.001). The complete response (CR) or partial response (PR) rates were 10 and 71% in the sorafenib and NFP groups, respectively (P<0.001). The median OS in the sorafenib and NFP groups was 13.2 and 30.4 months, respectively (P=0.013). Multivariate analysis revealed that the independent predictors of survival were Child-Pugh score (5, P=0.022, 95% CI, 0.191-0.892), grade of portal vein invasion (brunch, P=0.009, 95% CI, 0.220-0.752), and therapeutic effect (CR or PR, P<0.001, 95% CI, 0.220-0.752), and the independent predictor of therapeutic effect was therapeutic regimen (NFP, P<0.001, 95% CI, 0.006-0.199). NFP should be the first choice for patients with advanced HCC and MVI, without EHS and Child-Pugh A disease.

Phase 2 Study of Adjuvant Chemoradiation Therapy Using Docetaxel/Cisplatin/5-Fluorouracil Before and After Intensity-Modulated Radiation Therapy With Concurrent Docetaxel in Patients With Completely (R0) Resected Gastric Carcinoma

Complete surgical R0 resection has traditionally been considered the only curative treatment in localized gastric cancer (GC). The INT 0116 study has demonstrated a significant survival benefit for completely resected (R0) GC patients treated with a fluorouracil/leucovorin chemo-radiotherapy regimen. However, this regimen is also toxic and less effective in terms of distant disease control. Therefore, a more efficacious and safer regimen is urgently needed. The eligibility criteria included histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction, complete resection of the tumor defined as surgical resection performed with curative intent and resulting in negative resection margins, disease stage IB through IV (M0). Patients received up to two 21-day cycles of post-operative adjuvant pre- and post-radiation DCF chemotherapy (docetaxel 37.5 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and a continuous infusion of fluorouracil 750 mg/m2 on days 1-5), respectively. Chemo-radiotherapy between pre- and post-radiation chemotherapy was initiated on day 43 and consisted of intensity-modulated radiotherapy (45 Gy) plus concurrent docetaxel 20 mg/m2 weekly for 5 weeks. The clinical tumor volume (CTV) included the tumor bed, anastomoses, and stumps, regional draining lymph nodes. The planning target volume (PTV) consisted of the CTV plus a 0.5-cm margin in all directions to account for daily patient set-up variation. The primary end point was PFS. This single-stage phase II trial was designed to have 93% power to detect a 20% improvement in the 20-month PFS rate from 50 to 70% with a two-sided significance level of exactly 0.05. The accrual goal was 55 patients. A total of 55 patients were evaluated and 76% (42) of patients completed the prescribed therapy. The median age was 59 years (range, 28–75 years). The majority of patients had locally advanced disease (stage T3 or T4, 71%; N1–3, 93%). With a median follow-up of 61 months, the 20-month PFS rate was 75% (95% confidence interval [CI] = 64–86%). The 3- and 5- year progression-free survival rates were 67% (95% CI: 54%-80%) and 59% (95% CI: 46%-72%), respectively; and the 3- and 5-year overall survival rates were 72% (95% CI: 60%-84%) and 61% (95% CI: 48%-74%), respectively. Of 21 documented sites of first treatment failure, local-regional relapse occurred in 5 patients, distant relapse including peritoneal carcinomatosis was observed in 13 patients, and 3 patients had both local-regional and distant recurrences. The most common grade 3 or greater toxicity, during the chemotherapy phase, was neutropenia (24%). Common grade 3/4 toxicities during concurrent chemo-radiotherapy were nausea (32%), vomiting (26%), fatigue (15%), and anorexia (19%). These results demonstrate that this adjuvant regimen is active with an acceptable toxicity profile. A randomized phase 3 trial comparing the INT-0116 chemo-radiotherapy regimen with this regimen is underway.

Adverse drug reaction: a comparative analysis of protocols used for treatment of colorectal cancer

Study design: Cohort study Objective: Analyze the adverse reactions that occurred in Brazilian patients with colorectal cancer submitted to chemotherapy with two different protocols, in order to identify the types and severity of those most frequent recorded. Methods: Sixty-three patients, who started treatment from June 2014 to May 2015, were separated into two groups: mFOLFOX6 (protocol containing oxaliplatin, folinic acid and 5-fluorouracil in bolus and continuous infusion, n= 40) and FOLFIRI (protocol containing irinotecan, folinic acid and 5-fluorouracil in bolus and continuous infusions, n= 23). Data related to the demographic and clinical profile of the patients were collected from the medical record, as well as information about the treatment performed and the adverse reactions manifested. The reactions were classified according to their severity (grades 1, 2, 3 and 4) and causality (definite, probable, possible and doubtful). Results: A high frequency of adverse reactions was observed in both groups, reaching 92.5% of patients with mFOLFOX6 protocol and 95.6% with FOLFIRI protocol. Gastrointestinal and neurological toxicities were the most frequent among the groups. When comparing the occurrence of intergroup reactions, there was difference only for gastrointestinal toxicities (p= 0.035). In 17.5% of patients mFOLFOX6 group (n= 7) and in 8.7% of patients FOLFIRI group (n= 2), grades 3 and 4 adverse reactions were observed and classified as probable. Conclusion: The adverse reactions were more diversified and frequent in the mFOLFOX6 group compared to the FOLFIRI group. However, no difference was observed in the severity and causality of reactions in both groups.

First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials

SummaryBackgroundData suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival.MethodsFOXFIRE, SIRFLOX, and FOXFIRE-Global were randomised, phase 3 trials done in hospitals and specialist liver centres in 14 countries worldwide (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA). Chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation were randomly assigned (1:1) to either oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. In FOXFIRE, FOLFOX chemotherapy was OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m2 oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). In SIRFLOX and FOXFIRE-Global, FOLFOX chemotherapy was modified FOLFOX6 (85 mg/m2 oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). Randomisation was done by central minimisation with four factors: presence of extrahepatic metastases, tumour involvement of the liver, planned use of a biological agent, and investigational centre. Participants and investigators were not masked to treatment. The primary endpoint was overall survival, analysed in the intention-to-treat population, using a two-stage meta-analysis of pooled individual patient data. All three trials have completed 2 years of follow-up. FOXFIRE is registered with the ISRCTN registry, number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov, numbers NCT00724503 (SIRFLOX) and NCT01721954 (FOXFIRE-Global).FindingsBetween Oct 11, 2006, and Dec 23, 2014, 549 patients were randomly assigned to FOLFOX alone and 554 patients were assigned FOLFOX plus SIRT. Median follow-up was 43·3 months (IQR 31·6–58·4). There were 411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group. There was no difference in overall survival (hazard ratio [HR] 1·04, 95% CI 0·90–1·19; p=0·61). The median survival time in the FOLFOX plus SIRT group was 22·6 months (95% CI 21·0–24·5) compared with 23·3 months (21·8–24·7) in the FOLFOX alone group. In the safety population containing patients who received at least one dose of study treatment, as treated, the most common grade 3–4 adverse event was neutropenia (137 [24%] of 571 patients receiving FOLFOX alone vs 186 (37%) of 507 patients receiving FOLFOX plus SIRT). Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group and three treatment-related deaths occurred in the FOLFOX alone group.InterpretationAddition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed.FundingBobby Moore Fund of Cancer Research UK, Sirtex Medical.

Long-term analysis of 2 prospective studies that incorporate mitomycin C into an adjuvant chemoradiation regimen for pancreatic and periampullary cancers

PurposeThe purpose of this study was to report toxicity and long-term survival outcomes of 2 prospective trials evaluating mitomycin C (MMC) with 5-fluorouracil–based adjuvant chemoradiation in resected periampullary adenocarcinoma. Methods and materialsFrom 1996 to 2002, 119 patients received an adjuvant 4-drug chemotherapy regimen of 5-fluorouracil, leucovorin, MMC, and dipyridamole with chemoradiation on 2 consecutive trials (trials A and B). Trial A patients received upfront chemoradiation (50 Gy split-course, 2.5 Gy/fraction) followed by 4 cycles of the 4-drug chemotherapy with bolus 5-fluorouracil. Trial B patients received 1 cycle of the 4-drug chemotherapy with continuous infusion 5-fluorouracil followed by continuous chemoradiation (45-54 Gy, 1.8 Gy/fraction) and 2 additional cycles of chemotherapy. Cox proportional hazards models were performed to identify prognostic factors for overall survival (OS). ResultsOf the 62 trial A patients, 61% had pancreatic and 39% nonpancreatic periampullary carcinomas. Trial B (n = 57) consisted of 68% pancreatic and 32% nonpancreatic periampullary carcinomas. Resection margin and lymph node status were similar for both trials. Median follow-up was longer for trial A than trial B (197.5 vs 107.0 months), with median OS of 32.2 and 24.2 months, respectively. Rates of 3-, 5-, and 10-year OS were 48%, 31%, and 26% in trial A and 32%, 23%, and 9% in trial B. On multivariate analysis, lymph node–positive resection was the strongest prognostic factor for OS. A pancreatic primary and positive margin status were also associated with inferior survival (P < .05). Rates of grade ≥3 treatment-related toxicity in trials A and B were 2% and 7%, respectively. ConclusionsThis is the first study to report long-term outcomes of MMC with 5-fluorouracil–based adjuvant chemoradiation in periampullary cancers. Because MMC may be considered in DNA repair-deficient carcinomas, randomized trials are needed to determine the true benefit of adjuvant MMC.

Abstract 668: Evaluation of α-1-acid glycoprotein as a prognostic marker and as a predictive biomarker for severe neutropenia induced by docetaxel in esophageal carcinoma patients

Abstract Background: Serum α-1-acid glycoprotein (AAG) level is an independent predictor of response and a prognostic factor of survival in patients with non-small cell lung cancer treated with docetaxel chemotherapy. However, whether AAG is associated with the outcomes of esophageal cancer patients treated with docetaxel remains unclear. Methods: Between August 2009 and April 2014, pretreatment serum samples were obtained from patients with clinical stage II/III esophageal cancer. Individuals were subsequently treated with neoadjuvant DCF or CF followed by surgery. DCF consisted of docetaxel and cisplatin on day 1, and continuous infusion of 5-fluorouracil on days 1-5, with this regimen repeated every 3 weeks for up to three cycles. CF consisted of cisplatin and 5-fluorouracil. Patients were divided into groups based on the median value of baseline AAG levels. Response to chemotherapy, survival, and the most severe grade of neutropenia were compared between the high and low AAG groups at each regimen. Results: A total of 129 patients were enrolled (44 received neo DCF and 85 neo CF). The median serum AAG level was 95 g/L (range 57-228 g/L) and 95 g/L (range 46-197 g/L) in the patients with neo DCF and CF, respectively. For all patients, overall survival (OS) was significantly shorter in the high AAG group (AAG ≧ 95 g/L) than the low AAG group (AAG &amp;lt; 95 g/L) (HR 2.18, p=0.03). Both in the neo DCF and neo CF patients, there was a similar trend in OS between individuals with high and low AAG levels. Multivariate analysis demonstrated that AAG level (HR 1.98) and performance status (HR 2.20) were independent prognostic factors. However, the relationship between response to chemotherapy and AAG level were similar both in DCF and CF patients. In addition, grade 4 neutropenia was observed in 50% of patients with low AAG level and 23% with high AAG (p = 0.06) in DCF patients. A correlation analysis revealed a statistically significant correlation between serum AAG level and nadir absolute neutrophil count caused by DCF chemotherapy. However, in CF patients, there was no difference in the frequency of severe neutropenia between individuals with high and low AAG level, and there was no correlation between AAG and nadir neutrophil count. Conclusions: Serum AAG level may be a prognostic marker for survival in stage II/III esophageal cancer patients treated with neoadjuvant chemotherapy. In addition, low serum AAG level is a potential predictive biomarker of docetaxel-induced severe neutropenia. Citation Format: Yusuke Sasaki, Ken Kato, Hidekazu Hirano, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Atsuo Takashima, Tetsuya Hamaguchi, Kengo Nagashima, Narikazu Boku. Evaluation of α-1-acid glycoprotein as a prognostic marker and as a predictive biomarker for severe neutropenia induced by docetaxel in esophageal carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 668. doi:10.1158/1538-7445.AM2017-668

Safety and Efficacy of Pegfilgrastim When Given Less Than 14 Days Before the Next Chemotherapy Cycle: Review of Every 14-Day Chemotherapy Regimen Containing 5-FU Continuous Infusion.

Pegfilgrastim should not be given <14 days from the next chemotherapy because of concerns for cytopenias. Some clinicians are prescribing pegfilgrastim to be given <14 days in patients receiving 5-fluorouracil continuous infusion (5-FUCI) regimens. To determine the effectiveness and safety of pegfilgrastim administered <14 days from the next chemotherapy in patients receiving 5-FUCI administered >46 hours. Single-institution retrospective cohort study of patients who received 5-FUCI administered >46 hours from June 2013 to December 2015. The unit of measurement was chemotherapy cycles. End points included the safety and efficacy of giving pegfilgrastim <14 days from the next chemotherapy (Pegfilgrastim-Less-Than-14-Days-Group) and comparing that to pegfilgrastim given ≥14 days (Pegfilgrastim-More-Than-14-Days-Group), filgrastim only (Filgrastim-Group), and no colony stimulating factors (No-CSF-Group). Generalized estimating equations (GEEs) were used to compare mean absolute neutrophil count (ANC) and white blood cell count (WBC). Poisson regression models with GEE were used to estimate relative risk (RR) for neutropenia. There were no incidences of neutropenia, febrile neutropenia (FN), or hospitalizations for FN with the Pegfilgrastim-Less-Than-14-Days-Group. There was also a high mean ANC of 9.9 (5.7) × 109/L. Mean ANC and WBC were statistically significantly less with the Filgrastim-Group, No-CSF-Group, and Pegfilgrastim-More-Than-14-Days-Group compared with the Pegfilgrastim-Less-Than-14-Days-Group. The Filgrastim-Group and the No-CSF-Group had a 32% (1.10-1.56, P = 0.002) and 8% (1.04-1.12, P < 0.001) increased risk of incidence of neutropenia, respectively, compared with the Pegfilgrastim-Less-Than-14-Days-Group. The risk of incidence of neutropenia was the same with the Pegfilgrastim-More-Than-14-Days-Group and Pegfilgrastim-Less-Than-14-Days-Group (0.95-1.04, P = 0.821). This study shows a promising possibility that administering pegfilgrastim <14 days from the next chemotherapy cycle could be a safe and effective practice. However, better controlled clinical trials are needed.

Multicenter Phase 2 Study of Peri-Irradiation Chemotherapy Plus Intensity Modulated Radiation Therapy With Concurrent Weekly Docetaxel for Inoperable or Medically Unresectable Nonmetastatic Gastric Cancer

To assess the efficacy and feasibility of concurrent chemoradiation therapy (CCRT) plus preradiation and postradiation chemotherapy for patients with nonmetastatic gastric carcinoma who do not undergo surgery. Patients with inoperable (due to medical comorbid conditions or patient's refusal to undergo surgery) or unresectable gastric cancer received up to 2 21-day cycles of preradiation and postradiation chemotherapy (docetaxel 37.5mg/m2 on days 1 and 8, cisplatin 25mg/m2 on days 1-3, and a continuous infusion of fluorouracil [FU] 750mg/m2 on days 1-5), respectively. CCRT between preradiation and postradiation chemotherapy was initiated on day 43 and consisted ofintensity modulated radiation therapy (50.4Gy) plus concurrent docetaxel 20mg/m2 weekly for 6weeks. 36 patients were evaluable; 21 patients with comorbid conditions were unsuitable for surgery (group 1), 8 had unresectable disease (group 2), and 7 refused surgery (group 3). The clinical complete response (cCR) rate for the 36 evaluable patients was 36% (95% confidence interval [CI], 19%-53%) and the overall response rate was 83% (95% CI, 75%-97%). The median survival time and estimated 2-year survival rate were 25.8months (95% CI, 7.1-44.5months) and 52% (95% CI, 38%-67%), respectively. The estimated median OS and 2-year OS rates for groups 1, 2, and 3 were 37.0months (95% CI, 7.9-66.1months) and 52% (95% CI, 31%-73%), 17.7months (95% CI, 7.8-27.6months) and 20% (95% CI, 0%-49%), and 38.9months (95% CI, 16.6-58.3months) and 67% (95% CI, 30%-100%), respectively. Achieving a cCR was associated with significantly better overall survival (P=.004) and progression-free survival (P=.003). The most common grade 3 or greater toxicity during the chemotherapy phase was neutropenia. Common grade 3/4 toxicities during CCRT were nausea and vomiting. This regimen is tolerable and shows promising efficacy in inoperable or medically unresectable GC.