Esterase-Responsive Floxuridine-Tethered Multifunctional Nanoparticles for Targeted Cancer Therapy.

Floxuridine is a potential clinical anticancer drug for the treatment of various cancers. However, floxuridine typically causes unfavorable side effects due to its very poor tumor selectivity, and, hence, there is a high demand for the development of novel approaches that permit the targeted delivery of floxuridine into cancerous cells. Herein, the design and synthesis of an esterase-responsive multifunctional nanoformulation for the targeted delivery of floxuridine in esterase-overexpressed cancer cells is reported. Photopolymerization of floxuridine-tethered lipoic acid results in the formation of amphiphilic floxuridine-tethered poly(disulfide). Self-assembly of the amphiphilic polymer results in the formation of nanoparticles with floxuridine decorated on the surfaces of the particles. Integration of aptamer DNA for nucleolin onto the surface of the nanoparticle is demonstrated by exploring the base-pairing interaction of floxuridine with adenine. Targeted internalization of the aptamer-decorated nanoparticle into nucleolin-expressed cancer cells is demonstrated. Esterase triggered cleavage of the ester bond connecting floxuridine with the polymer backbone, and the subsequent targeted delivery of floxuridine into cancer cells is also shown. Excellent therapeutic efficacy is observed both in vitro and also in the 3D tumor spheroid model. This noncovalent strategy provides a simple yet effective strategy for the targeted delivery of floxuridine into cancer cells in a less laborious fashion.

A Modified Floxuridine Reduced-Dose Protocol for Patients with Unresectable Colorectal Liver Metastases Treated with Hepatic Arterial Infusion.

BACKGROUND: Most patients treated with the standard dosing protocol (SDP) of hepatic arterial infusion (HAI) floxuridine require dose holds and reductions, thereby limiting their HAI therapy. We hypothesized that a modified dosing protocol (MDP) with a reduced floxuridine starting dose would decrease dose holds, dose reductions, and have similar potential to convert patients with unresectable colorectal liver metastases (uCRLM) to resection. PATIENTS AND METHODS: We reviewed our institutional database of patients with uCRLM treated with HAI between 2016 and 2022. In 2019, we modified the floxuridine starting dose to 50% (0.06 mg/kg) of the SDP (0.12 mg/kg). We compared treatment related outcomes between the SDP and MDP cohorts. RESULTS: Of n = 33 patients, 15 (45%) were treated on the SDP and 18 (55%) with our new institutional MDP. The MDP cohort completed more cycles before a dose reduction (mean 4.2 vs. 2), received more overall cycles (median 7.5 vs. 5), and averaged 39 more days of treatment (all P < 0.05). The SDP experienced more dose reductions (1.4 vs. 0.61) and dose holds (1.2 vs. 0.2; both P < 0.01). Of the patients in each group potentially convertible to hepatic resection, three patients (23%) in the SDP and six patients (35%) in the MDP group converted to resection (P = 0.691). Overall, four patients (27%) in the SDP developed treatment ending biliary toxicity compared with one patient (6%) in the MDP. CONCLUSIONS: A 50% starting dose of HAI floxuridine provides fewer treatment disruptions, more consecutive floxuridine cycles, and a similar potential to convert patients with initially uCRLM for disease clearance.

Tumor-penetrating iRGD facilitates penetration of poly(floxuridine-ketal)-based nanomedicine for enhanced pancreatic cancer therapy.

Efficient intratumoral penetration is essential for nanomedicine to eradicate pancreatic tumors. Although nanomedicine can enter the perivascular space of pancreatic tumors, their access to distal tumor cells, aloof from the vessels, remains a formidable challenge. Here, we synthesized an acid-activatable macromolecular prodrug of floxuridine (FUDR)-poly(FUDR-ketal), engineered a micellar nanomedicine of FUDR, and intravenously co-administered the nanomedicine with the tumor-penetrating peptide iRGD for enhanced treatment of pancreatic tumor. A FUDR-derived mono-isopropenyl ether was synthesized and underwent self-addition polymerization to afford the hydrophobic poly(FUDR-ketal), which was subsequently co-assembled with amphiphilic DSPE-mPEG into the micellar nanomedicine with size of 12 nm and drug content of 56.8 wt% using nanoprecipitation technique. The acetone-based ketal-linked poly(FUDR-ketal) was triggered by acid to release FUDR to inhibit cell proliferation. In an orthotopic pancreatic tumor model derived from KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx1-Cre) cells that overexpress neuropilin-1 (NRP-1) receptor, iRGD improved penetration of FUDR nanomedicine into tumor parenchyma and potentiated the therapeutic efficacy. Our nanoplatform, along with iRGD, thus appears to be promising for efficient penetration and activation of acid-responsive nanomedicines for enhanced pancreatic cancer therapy.

Robotic Biliary Stricturoplasty and Roux-en-Y Hepaticojejunostomy After Hepatic Artery Infusion Pump Injury.

BACKGROUND: Hepatic artery infusion pump (HAIP) with floxuridine/dexamethasone and systemic chemotherapy is an established treatment regimen, which had been reported about converting 47% of patients with stage 4 colorectal liver metastasis from unresectable to resectable.1,2 To this effect, HAIP chemotherapy contributes to prolonged survival of many patients, which otherwise may not have other treatment options. Biliary sclerosis, however, is a known complication of the HAIP treatment, which occurs in approximately 5.5% of patients receiving this modality as an adjuvant therapy after hepatectomy and in 2% of patients receiving HAIP treatment for unresectable disease.3 While biliary sclerosis diffusely affects the perihilar and intrahepatic biliary tree, a dominant stricture maybe found in select cases, which gives an opportunity for a local surgical treatment after failure of endoscopic stenting/dilations. While the use of minimally invasive approach to biliary surgery is gradually increasing,4 there have been no descriptions of its application in this scenario. In this video, we demonstrate the use of minimally invasive robotic technique for biliary stricturoplasty and Roux-en-Y (RY) hepaticojejunostomy to treat persistent right hepatic duct stricture after HAIP chemotherapy. PATIENT: A 68-year-old woman with history of multifocal bilobar stage 4 colorectal liver metastasis presented to our office with obstructive jaundice and recurrent cholangitis that required nine endoscopic retrograde cholangiopancreatographies (ERCPs) and a placement of internal-external percutaneous transhepatic biliary drain (PTBD) by interventional radiology within the past 2 years. Her past surgical history was consistent with laparoscopic right hemicolectomy 3 years prior, followed by a left lateral sectorectomy with placement of an HAIP for adjuvant treatment. The patient had more than ten metastatic liver lesions within the right and left lobe, ranging from 2 to 3 cm in size at the time of HAIP placement. The patient had a histologically normal background liver parenchyma before the HAIP chemotherapy treatment. The patient did not have any history of alcohol use, diabetes mellitus, metabolic syndrome, nonalcoholic steatohepatitis, or other underlying intrinsic liver disorders, which are known to contribute to the development of hepatic fibrosis. Despite a radiologically disease-free status, the patient started to have episodes of acute cholangitis 1 year after the placement of HAIP that required multiple admissions to a local hospital. The HAIP was subsequently removed once the diagnosis of biliary sclerosis was made despite dose reductions and treatment with intrahepatic dexamethasone for almost 1 year. In addition to this finding, the known liver metastases have shown complete radiological resolution. Therefore further treatment with HAIP was deemed unnecessary, and pump removal was undertaken. Magnetic resonance imaging showed a dominant stricture at the junction of the right anterior and right posterior sectoral hepatic duct. The location of the dominant stricture was confirmed by an ERCP and cholangioscopy. Absence of neoplasia was confirmed with multiple cholangioscopic biopsies. Multiple endoscopic and percutaneous attempts with stent placement failed to dilate the area of stricture. Postprocedural cholangiographies showed a persistent significant narrowing, which led to multiple recurrent obstructive jaundice and severe cholangitis. While the use of surgical approach is rarely needed in the treatment of biliary sclerosis, a decision was made after extensive multidisciplinary discussions to perform a robotic stricturoplasty and RY hepaticojejunostomy with preservation of the native common bile duct. TECHNIQUE: The operation began with a laparoscopic adhesiolysis to allow for identification of HAIP tubing (which was later removed) and placement of robotic ports. A peripheral liver biopsy was obtained to evaluate the degree of hepatic parenchymal fibrosis. Porta hepatic area was carefully exposed without causing an inadvertent injury to the surrounding hollow organs. Biopsy of perihepatic soft tissues was taken as appropriate to rule out any extrahepatic disease. The common bile duct and common hepatic duct with ERCP stents within it were identified with the use of ultrasonography. Anterior wall of the common hepatic duct was then opened, exposing the two plastic stents. Cephalad extension of the choledochotomy was made toward the biliary bifurcation and the right hepatic duct. The distal common bile duct was preserved for future endoscopic access to the biliary tree. After lowering the right-sided hilar plate, dense fibrosis around the right hepatic duct was divided sharply with robotic scissors, achieving a mechanical release of the dominant stricture. An intraoperative cholangioscopy was performed to confirm adequate openings of the right hepatic duct secondary and tertiary radicles, as well as patency of the left hepatic duct. A 4-Fr Fogarty catheter was used to sweep the potential biliary debris from within the right and left hepatic lobe. Finally, a confirmatory choledochoscopy was performed to ensure patency and clearance of the right-sided intrahepatic biliary ducts and the left hepatic duct before fashioning the hepaticojejunostomy. A 40-cm antecolic roux limb was next prepared for the RY hepaticojejunostomy. A side-to-side double staple technique was utilized to create the jejunojejunostomy. The common enterotomy was closed in a running watertight fashion. Once the roux limb was transposed to the porta hepatic in a tension-free manner, a side-to-side hepaticojejunostomy was constructed in a running fashion by using absorbable barbed sutures. The index suture was placed at 9 o'clock location, and the posterior wall of the anastomosis was run toward 3 o'clock location. This stabilized the roux limb to the bile duct. The anterior wall of the anastomosis was next fashioned by using a running technique from both corners of the anastomosis toward the middle (12 o'clock), where both sutures were tied together. This completed a wide side-to-side hepaticojejunostomy anastomosis encompassing the upper common hepatic duct, biliary bifurcation, and the right hepatic duct. A closed suction drain was placed before closing.5 RESULTS: The operative time was approximately 4 hr with 60 ml of blood loss. The postoperative course was uneventful. The patient was discharged home on postoperative Day 5 after removal of the closed suction drain, confirming the absence of bile leak. The patient had developed periportal/periductal fibrosis, cholestasis, and moderate-severe parenchymal fibrosis (F3-F4) based on liver biopsy, often seen in patients treated with a long course of floxuridine HAIP chemotherapy. The patient is clinically doing well at 1 year outpatient follow-up without any evidence of recurrent cholangitis at the time of this manuscript preparation. CONCLUSIONS: Robotic biliary stricturoplasty with RY hepaticojejunostomy for treatment of biliary sclerosis after HAIP chemotherapy is safe and feasible. Appropriate experience in minimally invasive hepatobiliary surgery is necessary to achieve this goal.

A Randomized Phase II Trial of Adjuvant Hepatic Arterial Infusion and Systemic Therapy With or Without Panitumumab After Hepatic Resection of KRAS Wild-type Colorectal Cancer.

OBJECTIVE/BACKGROUND: The purpose was to determine whether adding Pmab versus no Pmab to an adjuvant regimen of hepatic arterial infusion (HAI) of floxuridine (FUDR) plus systemic (SYS) leucovorin, fluorouracil, and irinotecan (FOLFIRI) improves 15-month recurrence-free survival for patients with RAS wild-type colorectal cancer. Secondary endpoints included overall survival, toxicity, and influence of predictive biomarkers. METHODS: This phase II trial randomized patients with KRAS wild-type resected colorectal liver metastases to adjuvant HAI FUDR + SYS FOLFIRI +/- Pmab (NCT01312857). Patients were stratified by clinical risk score and previous chemotherapy. Based on an exact binomial design, if one arm had ≥24 patients alive and disease-free at 15 months that regimen was considered promising for further investigation. RESULTS: Seventy-five patients were randomized. Patient characteristics and toxicity were not different in the 2 arms, except for rash in +Pmab arm. Grade 3/4 elevation in bilirubin or alkaline phosphatase did not differ in the 2 arms. Twenty-five (69%; 95% CI, 53-82) patients in the Pmab arm versus 18 (47%; 95% CI, 32-63) patients in the arm without Pmab were alive and recurrence-free at 15 months. Only the Pmab arm met the decision rule, while the other arm did not. After median follow-up of 56.6 months, 3-year recurrence-free survival was 57% (95% CI, 43-76) and 42% (95% CI, 29-61), and 3-year overall survival was 97% (95% CI, 90-99) and 91% (95% CI, 83-99), +/- Pmab, respectively. CONCLUSIONS: The addition of Pmab to HAI FUDR + SYS FOLFIRI showed promising activity without increased biliary toxicity and should be further investigated in a larger trial.

Combination of HAI-FUDR and Systemic Gemcitabine and Cisplatin in Unresectable Cholangiocarcinoma: A Dose Finding Single Center Study.

BACKGROUND: Unresectable cholangiocarcinoma has a poor prognosis and treatment options are limited. Combined systemic and intrahepatic chemotherapy may improve local control and enable downsizing. The aim of this study was to determine the maximum tolerated dose (MTD) of intravenous gemcitabine combined with intravenous cisplatin and hepatic arterial infusion (HAI) with floxuridine (FUDR) in patients with unresectable intrahepatic or hilar cholangiocarcinoma. METHODS: Twelve patients were treated within a 3 + 3 dose escalation algorithm with 600, 800, or 1,000 mg/m2 gemcitabine and predefined doses of cisplatin 25 mg/m2 on days 1 and 8, q21, for 4 cycles, and FUDR 0.2 mg/kg on days 1-14 as continuous HAI, q28, for 3 cycles. Safety and toxicity as well as resectability rates after 3 months and preliminary survival data are reported. RESULTS: The determined MTD for gemcitabine was 800 mg/m2. Dose limiting toxicities were neutropenic fever and biliary tract infections. In total, 27% of the patients showed partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, the 3-year overall survival rate was 33%, median overall survival 23.9 months (range 1-49), and median progression-free survival 10.1 months (range 2-40). CONCLUSIONS: Intravenous gemcitabine/cisplatin plus HAI-FUDR is feasible and appears effective for disease control. Larger prospective studies evaluating this triplet combination are warranted.

Co-delivery of 5-fluorodeoxyuridine and doxorubicin via gold nanoparticle equipped with affibody-DNA hybrid strands for targeted synergistic chemotherapy of HER2 overexpressing breast cancer.

Combination chemotherapy is still of great importance as part of the standard clinical care for patients with HER2 positive breast cancer. As an attractive component, gold nanoparticles (AuNPs) have been extensively studied as biosafety nanomaterials, but they are rarely explored as drug nanocarriers for targeted co-delivery of multiple chemotherapeutics. Herein, a novel affibody-DNA hybrid strands modified AuNPs were fabricated for co-loading nucleoside analogue (5-fluorodeoxyuridine, FUdR) and anthracycline (doxorubicin, Dox). FUdRs were integrated into DNA hybrid strands decorated on AuNPs by DNA solid phase synthesis, and Dox molecules were intercalated into their duplex regions. Affibody molecules coupled to the DNA hybrid strands were distributed the surface of AuNPs, giving them targeting for HER2. The new dual-drug-containing affibody-DNA-AuNPs (Dox@affi-F/AuNPs) owned compact and stable spherical nanostructures, and precise drug loading. Cytotoxicity tests demonstrated that these nanoparticles caused a higher inhibition in HER2 overexpressing breast cancer cells, and showed better synergistic antitumor activity than simple mixture of the two drugs. The related mechanistic studies proved that Dox@affi-F/AuNPs achieved a remarkable combined antitumor activity of Dox and FUdR by promoting more cells to enter apoptosis pathway. Our work provided a nanomedicine platform for targeted co-delivery of nucleoside analog therapeutics and anthracycline anticancer drugs to achieve synergistic treatment of HER2+ cancer.

Reproductive outcomes after floxuridine-based regimens for gestational trophoblastic neoplasia: A retrospective cohort study in a national referral center in China.

OBJECTIVE: To analyze the reproductive outcomes of gestational trophoblastic neoplasia (GTN) patients who were cured only by floxuridine-based regimens. METHODS: This was a retrospective analysis of 464 patients who were treated with only floxuridine-based regimens at Peking Union Medical College Hospital between January 2002 and December 2013 and retained their reproductive ability. Their reproductive outcomes were analyzed. The factors affecting pregnancy intention were identified by logistic regression. RESULTS: Of the 464 patients (average age, 28.0 ± 5.7 years; median follow-up = 85 months), the livebirth rate was 72.2%, while the rates of spontaneous abortion, induced abortion and ectopic pregnancy were 9.2% (n = 41), 8.7% (n = 39) and 1.8% (n = 8), respectively. The GTN recurrence rate was 2.1%. The time from chemotherapy completion to first conception in the induced abortion group was significantly shorter than those in spontaneous abortion, full-term/premature, and ectopic pregnancy groups (P ≤ 0.001, <0.001, =0.015, respectively). The logistic analysis showed that the age at onset of GTN (OR = 0.899, 95% CI 0.851-0.951, P < 0.001), parity at onset of GTN (parity = 1, OR = 0.123, 95% CI 0.068-0.225, P < 0.001; parity = 2-3, OR = 0.058, 95% CI 0.014-0.232, P < 0.001) and interval from the index pregnancy to chemotherapy were independent factors affecting pregnancy intention. Among the 36 pregnancies occurring within 12 months postchemotherapy, only one choriocarcinoma occurred, and 20 culminated in induced abortions (55.6%). CONCLUSIONS: After floxuridine-based chemotherapy, the pregnancy rate of GTN patients after fertility-preserving treatment is comparable to that of the normal population. Pregnancy losses within one year after chemotherapy completion are mainly caused by induced abortion.

Floxuridine-chlorambucil conjugate nanodrugs for ovarian cancer combination chemotherapy.

Due to no specific symptoms and lack of early diagnosis for ovarian cancer, most diagnosed patients are often in the terminal stage resulting that tumor tissue is unable to be resected completely by operation. So postoperative chemotherapy has become an important and indispensable treatment procedure for them. Up to date, it remains a challenge to treat ovarian cancer by an effective chemotherapy strategy. Recently, the strategy of ADDC has been regarded as a highly effective chemotherapy strategy to treat various cancers without any drug carriers. Here a novel ADDC is synthesized by linking a water-soluble antitumor drug floxuridine (Fud) and a water-insoluble antitumor drug chlorambucil (Cb) through the esterification. Then the Fud-Cb conjugate can form stable nanodrugs in water with an average size around 103.0 nm through molecular self-assembly. After internalization of cells, the ester bonds in nanodrugs can be degraded to release free Fud and Cb at a fixed ratio under the intracellular acid conditions, which exhibits the high synergistic effect on ovarian cancer cells. The cytotoxicity test results show that Fud-Cb nanodrugs can efficiently inhibit the growth of ovarian cancer cells. The apoptosis data exhibit that the cell necrotic and apoptotic rate treated with Fud-Cb nanodrugs is about 73.7 % and 18.76 % within 24 h. These results suggest that Fud-Cb nanodrugs based on ADDC strategy can effectively enhance synergistic anticancer efficacy to ovarian cancer.

Hepatic artery infusion pump for nasopharyngeal carcinoma with liver metastasis.

To evaluate the benefits and risks of hepatic artery infusion (HAI) gemcitabine and floxuridine (FUDR) in patients with nasopharyngeal carcinoma liver metastases. HAI catheter systems were implanted under the guide of digital subtract angiography (DSA) in 16 patients with unresectable nasopharyngeal carcinoma liver metastases. HAI gemcitabine and FUDR in combination with radiotherapy and systemic chemotherapy were delivered. Disease control rate (DCR) of intrahepatic lesions is 100%, objective response rate (ORR) of intrahepatic lesions is 87.5%, including 4 patients (25%) with complete response (CR), 10 patients (62.5%) with partial response (PR) and 2 patients (12.5%) with stable disease (SD). The median overall survival (mOS) was 30 months. There was no significant difference between patients with < 9 intrahepatic lesions and patients with ≥ 9 intrahepatic lesions (31 months vs. 24 months, P = 0.562). Patients without extrahepatic metastases has longer survival than patients with extrahepatic metastases (31 months vs. 17 months, P = 0.005). In all 72 cycles of HAI, the main grade 3/4 toxicities related to HAI include: leukopenia occur in 8 cycles (11.1%), thrombocytopenia in 5 cycles (6.9%), AST/ALT elevation in 12 cycles (16.7). Catheter related complications occurred in 2 patients (12.5%). HAI gemcitabine and FUDR is effective to improve DCR of intrahepatic lesions and prolong mOS for patients with nasopharyngeal carcinoma liver metastases, and is associated with a relative low rate of toxicity.

Evaluation of 5-[18F]fluoro-2'-deoxycytidine as a tumor imaging agent: A comparison of [18F]FdUrd, [18F]FLT and [18F]FDG.

One of the hallmarks of cancer is increased cell proliferation. Measurements of cell proliferation by estimation of DNA synthesis with several radiolabeled nucleosides have been tested to assess tumor growth. Deoxycytidine can be phosphorylated by deoxycytidine kinase (dCK) and is incorporated into DNA. This study evaluated a radiofluorinated deoxycytidine analog, 5-[18F]fluoro-2'-deoxycytidine ([18F]FdCyd), as a proliferation probe and compared it with 5-[18F]fluoro-2'-deoxyuridine ([18F]FdUrd), 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT), and [18F]fluorodeoxyglucose ([18F]FDG) in a tumor-bearing mouse model. [18F]FdCyd was synthesized from two precursors by direct electrophilic substitution. The serum stability and partition coefficient of [18F]FdCyd were evaluated in vitro. Positron emission topography (PET) imaging of Lewis lung carcinoma (LLC)-bearing mice with [18F]FdCyd, [18F]FdUrd, [18F]FLT, and [18F]FDG were evaluated. [18F]FdCyd was stable in mouse serum and normal saline for up to 4 h. With all radiotracers except [18F]FLT, PET can clearly delineate the tumor lesion. [18F]FdCyd and [18F]FdUrd showed high accumulation in the liver and kidney. The SUV and tumor-to-muscle (T/M) ratios derived from PET imaging of the radiotracers were [18F]FDG > [18F]FdCyd > [18F]FdUrd > [18F]FLT. Selective retention in tumors with a favorable tumor/muscle ratio makes [18F]FdCyd a protential candidate for further investigation as a proliferation imaging agent.

Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

Transarterial chemoembolization with raltitrexed-based or floxuridine-based chemotherapy for unresectable colorectal cancer liver metastasis.

PURPOSE: To evaluate and compare the efficiency and safety of raltitrexed- or floxuridine (FUDR)-based transarterial chemoembolization (TACE) in patients with unresectable colorectal cancer liver metastasis (CRCLM). METHODS: We conducted a retrospective analysis of 81 patients with unresectable CRCLM who failed systemic chemotherapy and were treated with TACE in our department from Oct 2014 to Oct 2017. Of these, 61 patients received TACE using raltitrexed, oxaliplatin, and pirarubicin (raltitrexed group), and 20 received TACE using FUDR, oxaliplatin, and pirarubicin (FUDR group). The objective response rate (ORR), disease control rate (DCR), overall survival (OS, from the first TACE), progression-free survival (PFS, from the first TACE), and adverse reactions were evaluated and compared between the two groups, and prognostic factors for OS were analyzed. RESULTS: The ORRs of the raltitrexed group and FUDR group were 67.2 and 45.0%, respectively (P = 0.076), and the DCRs were 86.9 and 80.0%, respectively (P = 0.452). The median OS (from first TACE) was 14.0 months in the raltitrexed group and 13.0 months in the FUDR group (P = 0.556). The median PFS (from first TACE) was 2.1 months in the raltitrexed group and 2.4 months in the FUDR group (P = 0.878). Univariate and multivariate analyses showed that the primary tumor site, Child-Pugh class, and combination with local ablation (RFA or CRA) were independent significant factors affecting survival. There were no significant differences in adverse reactions between the two groups (P > 0.05), and no treatment-related death occurred in either group. CONCLUSION: TACE treatment based on raltitrexed or FUDR is an efficient and safe alternative choice for treating unresectable CRCLM.

Implementation and early outcomes for a surgeon-directed hepatic arterial infusion pump program for colorectal liver metastases.

INTRODUCTION: Hepatic arterial infusion pump (HAIP) therapy for colorectal liver metastases (CRLM) is beneficial in selected patients yet wide acceptance in the oncology community is lacking. METHODS: A surgeon-led team implemented a HAIP program in 2012. Pumps were placed by laparotomy for CRLM and fluorodeoxyuridine was infused via HAIP every 28 days without systemic chemotherapy supervised by the operating surgeon. RESULTS: Sixty patients were treated with HAIP, either in the adjuvant setting after liver resection or ablation of CRLM in 26 (43%) patients or with the unresectable disease in 34 (57%). Perioperative complications occurred in 19 (32%) and pump-specific complications in 14 (23%) that included intrahepatic biliary stricture in one (2%). Time to liver progression was a median 9.2 months (95% CI, 3.1-15.3 months) in unresectable patients and liver recurrence was a median 24.7 months (2.5-46.9 months) in the adjuvant group. Estimated 3-year overall survival from the time of HAIP placement was 64% in the adjuvant group and 37% in the unresectable group. Sarcopenia was prevalent (48%) and was associated with a worse survival (HR 2.4, 95% CI, 1.1-5.0). CONCLUSION: A surgeon-led HAIP program may achieve outcomes on par with those of experienced centers and foster strong relationships between surgical and medical oncologists.

Loading Lovastatin into Camptothecin-Floxuridine Conjugate Nanocapsules for Enhancing Anti-metastatic Efficacy of Cocktail Chemotherapy on Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a malignant and refractory disease with high morbidity and mortality. The TNBC shows no response to hormonal therapy nor targeted therapy due to the lack of known targetable biomarkers. Furthermore, the TNBC also exhibits a high degree of heterogeneity that leads to cancer evolution, drug resistance, metastatic progression, and recurrence, arising from the tumor-initiating properties of cancer stem cells (CSCs). Thus, the development of radical therapeutic regimens with high efficacy and limited side effects is crucial. In this study, we designed an innovative ternary cocktail chemotherapy by using Lovastatin (L)-loaded Janus camptothecin-floxuridine conjugate (CF) nanocapsules (NCs) with ultrahigh drug loading capacity. The obtained LCF NCs were shown to be able to suppress growth of TNBC, including inhibition of growth and metastasis of CSCs, both in vitro and in tumor-bearing mice. Moreover, in animal experiments, the LCF NCs showed sustained and synchronous drug release (half-life > 300 min), 85.2% reduction in pulmonary metastases, and no cancer recurrence during one-month observation post-treatment. Thus, this innovative LCF NC design provides a simple and synergistic strategy for the development of simultaneous triple chemotherapy and could be an efficacious, safe, and amenable choice with higher therapeutic relevance and fewer toxic complications than conventional multidrug delivery systems for TNBC treatment in the future.

[Impact of chemotherapy on ovarian function and quality of life of patients with gestational trophoblastic neoplasia].

Objective: Using a questionnaire to evaluate different regimens of chemotherapy on ovarian function and quality of life of patients with gestational trophoblastic neoplasia (GTN) . Methods: At least 6 months after completion of chemotherapy, 200 patients with GTN treated in Peking Union Medical College Hospital from January 2010 to June 2017 were randomly selected to fill up the questionnaire. The questionnaire items were included the patient's menstrual cycles, sexual life, gestational issues and common health. The patients were divided into 3 groups by chemotherapy regimens: actinomycin D (Act-D) group, floxuridine+Act-D+vincristine (FAV) or floxuridine+Act-D+etoposide+vincristine (FAEV) group (FAV-FAEV group) , and etoposide+methotrexate+Act-D (EMA) /vincristine+cyclophosphamide (CO) or EMA/ etoposide+cisplatin (EP) group (EMA/CO-EMA/EP group) . Chi-square test was used with a significance level of P-value less than 0.05. Results: One hundred and seventy-three (86.5%,173/200) of the patients completed the questionnaire. Forty three point two percent (43.2%, 19/44) in the EMA/CO-EMA/EP group had a normal menstrual cycle, which were significantly lower than those of Act-D group (84.6%,22/26) and FAV-FAEV group (71.2%, 37/52; all P<0.05) . Amenorrhea rate was also significantly higher in EMA/CO-EMA/EP group (25.0%, 11/44) than in Act-D group (0) and FAV-FAEV group (17.3%, 9/52; all P<0.05) . The sexual life parameters were comparable among 3 groups. Ten out of thirty-two patients conceived after chemotherapy, 2 had miscarriages and 8 had full-term delivery of healthy babies. The common health and labor capacity were significantly decreased after chemotherapy (all P<0.05) . Conclusions: EMA/CO or EMA/EP regimen have a worse impact on ovarian function than Act-D and FAV or FAEV regimen. Gynecologic oncologist should be concerned about the ovarian function and quality of life of GTN patients.

Floxuridine-containing nucleic acid nanogels for anticancer drug delivery.

Herein, we report the self-assemblies of floxuridine-containing DNA and RNA nanogels with a precise drug loading ratio as effective drug delivery systems. Based on the structural similarity between the nucleoside analogue floxuridine (F) and the natural nucleoside thymidine (T), F can be incorporated into nucleic acid strands via either solid-phase synthesis or enzyme-mediated transcription. With the retained property of molecular recognition, the synthesized F-integrated DNA or RNA strands can be used as building units and further assembled into nucleic acid based spherical nanogels, which can be efficiently taken up by cancer cells and then release the therapeutic agents. As such, the drug-containing nucleic acid nanogels exhibit excellent inhibitory activity against cancer cells.

Phase I Trial of Dose-escalated Whole Liver Irradiation With Hepatic Arterial Fluorodeoxyuridine/Leucovorin and Streptozotocin Followed by Fluorodeoxyuridine/Leucovorin and Chemoembolization for Patients With Neuroendocrine Hepatic Metastases.

OBJECTIVES: We have previously shown that refractory neuroendocrine tumors can respond to moderate doses of chemoradiotherapy. We completed a dose-escalation phase I/II trial combining hepatic arterial (HA) chemotherapy, chemoembolization, and dose-escalated whole liver radiotherapy to determine the maximum safe dose of radiation that could be delivered and to make a preliminary assessment of response. MATERIALS AND METHODS: From 2002 to 2009, 19 patients with symptomatic neuroendocrine liver metastases who failed somatostatin analog therapy were enrolled. HA fluorodeoxyuridine, leucovorin, and streptozotocin were delivered, as concurrent whole liver radiotherapy was dose escalated from 24 to 32 Gy in 2 Gy fractions, with a target rate of dose-limiting grade ≥3 radiation-induced liver disease of 10%. Eight weeks later, for patients without grade ≥3 liver or grade ≥4 any toxicity, a 72-hour infusion of HA fluorodeoxyuridine and leucovorin was given, followed by transarterial chemoembolization. RESULTS: Eleven patients completed the entire protocol and received 24 to 32 Gy. No patients developed radiation-induced liver disease; 7 had grade 3 to 4 transiently increased liver function tests, and 4 had other grade 4 toxicities. Three patients (14%) had partial response, 16 (84%) stable disease. Median freedom from local progression and overall survival were 35.3 and 54.6 months, respectively. CONCLUSIONS: Thirty-two in 2 Gy daily fractions can be delivered safely when combined with HA chemotherapy and subsequent transarterial chemoembolization. However, although objective responses were observed, this combination was not significantly better than our prior approaches. Further treatment intensification strategies, including individualized dose escalation for radiation-tolerant livers, and improved radiosensitization should be investigated, along with improved systemic therapy.