Intraperitoneal Administration Of Paclitaxel Research Articles

Phase II clinical study evaluating the efficacy and safety of disitamab vedotin combined with sintilimab and S-1 in the conversion treatment of HER2-overexpression unresectable gastric cancer.

TPS428 Background: Gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA) is the fifth commonest cancer and the fourth leading cause of cancer deaths worldwide. In about 30% to 40% of patients with advanced gastric cancer have lost the opportunity for radical surgery at the first diagnosis, and the overall 5-year survival rate is less than 50%. In recent years, conversion therapy has shown great promise. Disitamab vedotin is an antibody-drug conjugate comprising a novel HER2-directed monoclonal antibody, In previous study C008, RC48 showed a good safety profile and promising activity towards GC, and showed equivalent efficacy for HER2 IHC 2+ or HER2 IHC 3+ tumors. Methods: This study is a single-arm, phase II trial carry out at 16 academic hospitals in China, and will evaluate DV combined with Sintilimab and S-1 in patients with HER2-expressing unresectable gastric cancer. Eligible patients are at ≥ 18 to ≤ 75 years old; histologically confirmed, unresectable stage IV GC or GEJA; Single initial unresectable factor. For example, peritoneal metastasis (P1), Intraperitoneal free cancer cells positive (CY1), Paraaortic lymph node metastasis, liver metastasis (≤ 3 lesions, and ≤ 5 cm for a single lesion), ovarian metastasis; and documented histologically confirmed HER2 IHC 3+ or 2+; ECOG 0-1; at least one unresectable, measurable tumor lesion according to the RECIST version 1.1; adaptable function of the heart, liver, and kidney. 30 patients will be enrolled in this trial and receive Disitamab Vedotin(2.5mg/kg, IV, Q3W), Sintilimab (200 mg, IV, Q3W) and S-1 (twice daily on D1-14 are given at a dose calculate according to the body surface area and repeated every 3 weeks), until patients assessed by MDT to meet the criteria for surgical resection undergo gastrectomy. And the patients with peritoneal dissemination will combine with intraperitoneal administration of paclitaxel (60mg / m2, Q3W). The primary endpoint is R0 resection rate, Secondary endpoints include cORR, OS, RFS and safety. Seven patients have been enrolled in this study. Clinical trial information: NCT05627414 .

The antinociceptive effects of selective TRPV1 antagonist RCI002 against chemotherapy-induced peripheral neuropathy.

e15111 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect experienced by cancer patients receiving chemotherapy. Recent reports showed that transient receptor potential (TRP) channels are involved in paclitaxel- or oxaliplatin-induced neuropathic pain. TRP vanilloid 1 (TRPV1) may contribute to the development of mechanical allodynia and thermal hyperalgesia after cisplatin or oxaliplatin treatment. Moreover, paclitaxel-induced behavioral hypersensitivity is prevented and reversed by administration of TRPV1 antagonists. RCI002 is a potent and selective TRPV1 antagonist, blocking capsaicin activation of the target, with a little affect pH or heat activation. We found that RCI002 relieves neuropathic pain by inhibiting TRPV1, an important nociceptor involved in pain signal transduction, and does not cause thermoregulation, a problem with existing TRPV1 antagonists. In this study, Calcium imaging and patch clamp were employed to examine effects of RCI002 on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1. We also investigated RCI002 associated paclitaxel-induced peripheral neuropathic pain using a rat model. Methods: Dorsal root ganglion (DRG) neurons and TRPV1-transfected human embryonic kidney-derived (HEK) 293 cells were used for calcium imaging or whole-cell patch-clamp recording. CIPN was induced by intraperitoneal administration of paclitaxel 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. RCI002 were administered intraperitoneal and the paw withdrawal thresholds were measured using von Frey filaments. Results: We previously showed that RCI002, a novel TRPV1 antagonist that could be referred to as a new class of TRPV1 modulators that produce a significant analgesic effect formalin-induced behavior and improved mechanical allodynia undergoing spinal nerve ligation(SNL) in rats without hyperthermic effect. In the present study, The selective TRPV1 inhibitor RCI002 impaired capsaicin-induced calcium influx in DRG neurons. hTRPV1 expressed in HEK293 cells mediated a hemin-induced calcium influx which was blocked by RCI002. Behavioral assessment using the von Frey filaments. SD rat that received paclitaxel developed mechanical hypersensitivity to Von Frey filament stimulations of their hindpaws. Paclitaxel-induced hypersensitivity inhibited by TRPV1 antagonist RCI002(RCI002 EC50 = 0.85mg/kg). RCI002 significantly increased the paw withdrawal threshold more than pregabalin in CIPN rats(Pregabalin EC50 = 14.77mg/kg). Conclusions: Our findings suggest that RCI002 may be a promising approach to reduce paclitaxel-induced hyperexcitability and thereby to reduce neuropathy pain.

Oral Administration of Glutathione Trisulfide Increases Reactive Sulfur Levels in Dorsal Root Ganglion and Ameliorates Paclitaxel-Induced Peripheral Neuropathy in Mice.

Peripheral neuropathy is a dose-limiting side effect of chemotherapy with paclitaxel. Paclitaxel-induced peripheral neuropathy (PIPN) is typically characterized by a predominantly sensory neuropathy presenting with allodynia, hyperalgesia and spontaneous pain. Oxidative mitochondrial damage in peripheral sensory neurons is implicated in the pathogenesis of PIPN. Reactive sulfur species, including persulfides (RSSH) and polysulfides (RSnH), are strong nucleophilic and electrophilic compounds that exert antioxidant effects and protect mitochondria. Here, we examined the potential neuroprotective effects of glutathione trisulfide (GSSSG) in a mouse model of PIPN. Intraperitoneal administration of paclitaxel at 4 mg/kg/day for 4 days induced mechanical allodynia and thermal hyperalgesia in mice. Oral administration of GSSSG at 50 mg/kg/day for 28 days ameliorated mechanical allodynia, but not thermal hyperalgesia. Two hours after oral administration, 34S-labeled GSSSG was detected in lumber dorsal root ganglia (DRG) and in the lumber spinal cord. In mice treated with paclitaxel, GSSSG upregulated expression of genes encoding antioxidant proteins in lumber DRG, prevented loss of unmyelinated axons and inhibited degeneration of mitochondria in the sciatic nerve. In cultured primary neurons from cortex and DRG, GSSSG mitigated paclitaxel-induced superoxide production, loss of axonal mitochondria, and axonal degeneration. These results indicate that oral administration of GSSSG mitigates PIPN by preventing axonal degeneration and mitochondria damage in peripheral sensory nerves. The findings suggest that administration of GSSSG may be an approach to the treatment or prevention of PIPN and other peripheral neuropathies.

Ayurveda-based Botanicals as Therapeutic Adjuvants in Paclitaxel-induced Myelosuppression.

Chemotherapy-induced myelosuppression is one of the major challenges in cancer treatment. Ayurveda-based immunomodulatory botanicals Asparagus racemosus Willd (AR/Shatavari) and Withania somnifera (L.). Dunal (WS/Ashwagandha) have potential role to manage myelosuppression. We have developed a method to study the effects of AR and WS as therapeutic adjuvants to counter paclitaxel (PTX)-induced myelosuppression. Sixty female BALB/c mice were divided into six groups—vehicle control (VC), PTX alone, PTX with aqueous and hydroalcoholic extracts of AR (ARA, ARH) and WS (WSA, WSH). The myelosuppression was induced in mice by intraperitoneal administration of PTX at 25 mg/kg dose for three consecutive days. The extracts were orally administered with a dose of 100 mg/kg for 15 days prior to the induction with PTX administration. The mice were observed daily for morbidity parameters and were bled from retro-orbital plexus after 2 days of PTX dosing. The morbidity parameters simulate clinical adverse effects of PTX that include activity (extreme tiredness due to fatigue), behavior (numbness and weakness due to peripheral neuropathy), body posture (pain in muscles and joints), fur aspect and huddling (hair loss). The collected samples were used for blood cell count analysis and cytokine profiling using Bio-Plex assay. The PTX alone group showed a reduction in total leukocyte and neutrophil counts (4,800 ± 606; 893 ± 82) when compared with a VC group (9,183 ± 1,043; 1,612 ± 100) respectively. Pre-administration of ARA, ARH, WSA, and WSH extracts normalized leukocyte counts (10,000 ± 707; 9,166 ± 1,076; 10,333 ± 1,189; 9,066 ± 697) and neutrophil counts (1,482 ± 61; 1,251 ± 71; 1,467 ± 121; 1,219 ± 134) respectively. Additionally, higher morbidity score in PTX group (7.4 ± 0.7) was significantly restricted by ARA (4.8 ± 1.1), ARH (5.1 ± 0.6), WSA (4.5 ± 0.7), and WSH (5 ± 0.8). (Data represented in mean ± SD). The extracts also significantly modulated 20 cytokines to evade PTX-induced leukopenia, neutropenia, and morbidity. The AR and WS extracts significantly prevented PTX-induced myelosuppression (p < 0.0001) and morbidity signs (p < 0.05) by modulating associated cytokines. The results indicate AR and WS as therapeutic adjuvants in cancer management.

Participation of transient receptor potential vanilloid 1 in the analgesic effect of duloxetine for paclitaxel induced peripheral neuropathic pain

Painful peripheral neuropathy is a common dose-limiting side effect of chemotherapeutic paclitaxel (PTX) treatment. The American Society of Clinical Oncology (ASCO) recommends duloxetine (DUL) as a promising treatment alternative for chemotherapy-induced peripheral neuropathic pain. However, this recommendation lacks a robust theoretical basis and supporting data. To elucidate the involvement of transient receptor potential vanilloid 1 (TRPV1) in the analgesic effect of DUL for PTX-induced neuropathic pain, TRPV1 expression in the lumbar dorsal root ganglion (DRG) and spinal cord was evaluated following intraperitoneal administration of PTX (2 mg/kg/day) for four alternate days in rats. Western blot and immunohistochemistry suggested that a cumulative dosage of PTX (8 mg/kg) upregulated TRPV1 expression in the lumbar DRG and spinal dorsal horn (SDH) at day 14 post treatment. TRPV1 upregulation in the DRG was mainly expressed in calcitonin gene-related peptide (CGRP) and IB-4 positive small-size sensory neurons. Additionally, PTX increased CGRP and substance P (SP) expression in the DRG and SDH, induced SDH microglia and astrocyte activation, and upregulated spinal tumor necrosis factor-α (TNF-α) but not IL-1β or IL-10 expression. Behavioral detection showed that PTX-related mechanical and thermal hyperalgesia was significantly inhibited by consecutive administration of DUL 20 mg/kg/day greater than 10 mg/kg/day for 5 days starting at day 10 post PTX injection. Furthermore, DUL (20 mg/kg/day) for 5 days markedly ameliorated PTX-induced TRPV1, CGRP, and SP upregulation in the DRG and SDH, and mitigated PTX-induced spinal cord glia activation and TNF-α expression. Moreover, the pharmacological blockade of TRPV1 resulted in an analgesic effect on PTX-induced hyperalgesia. Collectively, these results suggest that DUL alleviates PTX-induced peripheral neuropathic pain by suppressing TRPV1 upregulation in the lumbar DRG and SDH, which is followed by a reduction in CGRP and SP release, as well as spinal glia activation and TNF-α expression.

Efficacy of conversion surgery after a single intraperitoneal administration of paclitaxel and systemic chemotherapy for gastric cancer with peritoneal metastasis.

The prognosis of gastric cancer patients with peritoneal metastasis (PM) remains dismal with standard systemic chemotherapy. Intraperitoneal (i.p.) chemotherapy with paclitaxel (PTX) has local effects on intra-abdominal cancer cells. According to this phenomenon, we have developed regimens combining single i.p. PTX administration with systemic chemotherapy. This treatment strategy is very promising; however, the effect of "conversion surgery" in patients responding to this chemotherapy is unclear. Therefore, we performed a retrospective study to evaluate the safety and efficacy of conversion surgery for gastric cancer patients with PM. We enrolled 52 gastric cancer patients with PM who were treated with single i.p. PTX plus systemic chemotherapy between 2005 and 2015. Conversion surgery was performed where PM was eliminated by combination chemotherapy. Among 52 gastric cancer patients, the disappearance of PM was confirmed in 33 patients (63.5%). Gastrectomy with D2 lymph node dissection was performed in all these patients. Histological response of grade ≥ 1b was achieved in 13 patients (39%). Clavien-Dindo grade II postoperative complications occurred in three patients (9%). There were no treatment-related deaths. The median survival time and 1-, 3-, and 5-year overall survival rates of the 33 patients who underwent conversion surgery were 30.7months and 78.8%, 36.3%, and 24.2%, respectively, and those of the 19 patients who did not undergo surgery were 12.5months and 52.6%, 5.2%, and 0%, respectively. Conversion surgery is safe and may prolong survival for gastric cancer patients with PM who have responded to single i.p. PTX plus systemic chemotherapy.

Doxorubicin Embedded into Nanofibrillated Bacterial Cellulose (NFBC) Produces a Promising Therapeutic Outcome for Peritoneally Metastatic Gastric Cancer in Mice Models via Intraperitoneal Direct Injection.

Natural materials such as bacterial cellulose are gaining interest for their use as drug-delivery vehicles. Herein, the utility of nanofibrillated bacterial cellulose (NFBC), which is produced by culturing a cellulose-producing bacterium (Gluconacetobacter intermedius NEDO-01) in a medium supplemented with carboxymethylcellulose (CMC) that is referred to as CM-NFBC, is described. Recently, we demonstrated that intraperitoneal administration of paclitaxel (PTX)-containing CM-NFBC efficiently suppressed tumor growth in a peritoneally disseminated cancer xenograft model. In this study, to confirm the applicability of NFBC in cancer therapy, a chemotherapeutic agent, doxorubicin (DXR), embedded into CM-NFBC, was examined for its efficiency to treat a peritoneally disseminated gastric cancer via intraperitoneal administration. DXR was efficiently embedded into CM-NFBC (DXR/CM-NFBC). In an in vitro release experiment, 79.5% of DXR was released linearly into the peritoneal wash fluid over a period of 24 h. In the peritoneally disseminated gastric cancer xenograft model, intraperitoneal administration of DXR/CM-NFBC induced superior tumor growth inhibition (TGI = 85.5%) by day 35 post-tumor inoculation, compared to free DXR (TGI = 62.4%). In addition, compared with free DXR, the severe side effects that cause body weight loss were lessened via treatment with DXR/CM-NFBC. These results support the feasibility of CM-NFBC as a drug-delivery vehicle for various anticancer agents. This approach may lead to improved therapeutic outcomes for the treatment of intraperitoneally disseminated cancers.

P-159 First-in-human phase 1 dose-escalating study protocol of pressurized intraperitoneal aerosol chemotherapy with paclitaxel in peritoneal carcinomatosis (PIPAC2 study)

Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) is a relatively novel laparoscopic intraperitoneal chemotherapy delivery technique, with advantages such as the homogeneous distribution of aerosol and deeper tissue penetration. Thus far, PIPAC paclitaxel has not been administered in humans. However, intra-peritoneal paclitaxel administration has shown promising results in selected patients. We aim to determine the dose-related safety profile and tolerability of PIPAC paclitaxel using an evidence-based approach.

Involvement of the Sodium Channel Nav1.7 in Paclitaxel-induced Peripheral Neuropathy through ERK1/2 Signaling in Rats.

Paclitaxel treatment is a major cause of chemotherapy-induced peripheral neuropathy. The sodium channel Nav1.7 plays a critical role in pain perception. However, whether Nav1.7 in the dorsal root ganglion (DRG) is involved in paclitaxel-induced peripheral neuropathy remains unclear. Thus, our study aimed to evaluate whether Nav1.7 participates in the pathogenesis of paclitaxel-induced neuropathy. Paclitaxel-induced peripheral neuropathy was generated by intraperitoneal administration of paclitaxel on four alternate days. The results showed that DRG mRNA and protein expression levels of Nav1.7 were upregulated between days 7 and 21 after the administration of paclitaxel. Besides, paclitaxel upregulated extracellular signal-regulated kinase (ERK1/2) phosphorylation in DRG. Intrathecal injection of U0126 (a MEK inhibitor) blocking ERK1/2 phosphorylation blunted up-regulation of Nav1.7 in the DRG and correspondingly attenuated hyperalgesia. These results indicated that the sodium channel Nav1.7 in the DRG exerted an important function in paclitaxel-induced neuropathy, which was associated with ERK phosphorylation in neurons.

Pathological complete response after intraperitoneal paclitaxel and systemic combined chemotherapy in a patient with peritoneal metastases from gastric cancer: a case report

BackgroundDespite recent progress in systemic chemotherapy, the prognosis of patients with peritoneal metastases from gastric cancer is still poor. Efficacious intraperitoneal and systemic combination chemotherapy regimens to treat patients with peritoneal metastases have recently been developed.Case presentationA 74-year-old man with gastric cancer T4b (transverse mesocolon) N3 M1 (peritoneum) received combination chemotherapy with intraperitoneal administration of paclitaxel, intravenous oxaliplatin, and oral S-1. Eight courses of combined chemotherapy had remarkable anti-tumor effects on the primary lesion, lymph node metastases, and peritoneal metastases. Total gastrectomy with regional lymph node dissection was performed. Pathological examination revealed no viable tumor cells in the resected specimens. After gastrectomy, the patient received 25 courses of the same chemotherapy without oxaliplatin and has no evidence of recurrence 24 months later.DiscussionTherapeutic approaches including systemic chemotherapy, extended resection, and heated intraperitoneal chemotherapy have been used to treat patients with peritoneal metastases. Repeat therapy with intraperitoneal paclitaxel has been used recently. Intraperitoneal administration of paclitaxel results in prolonged retention in the peritoneal cavity with effects against peritoneal metastases. Repeated administration of paclitaxel does not cause adhesions in the peritoneal cavity. When combination chemotherapy is effective, salvage gastrectomy is a promising option with minimal morbidity and mortality.ConclusionCombined chemotherapy with intraperitoneal paclitaxel and systemic chemotherapy followed by gastrectomy is a promising strategy for patients with advanced gastric cancer and peritoneal metastases.

Phase I/II Clinical Trial of Weekly Intraperitoneal Paclitaxel (IP-PTX) with Monthly Intravenous Carboplatin (IV-CBDCA) for Minimal Residual Disease of Ovarian, Tubal, and Peritoneal Carcinoma

We conducted weekly intraperitoneal administration of paclitaxel (IP-PTX) with monthly intravenous administration of carboplatin (IV-CBDCA), as a prospective phase 1/2 setting. The purpose of this study was to assess the pharmacokinetics and to decide the recommended dose (RD) according to modified Fibonacci method. Patients aged 20-75 years old with histological confirmed mullerian cancers (epithelial ovarian cancer; EOC, fallopian tubal cancer; FTC, and primary peritoneal cancer; PPC) from stage IC to IV or the patients with recurrent disease with small residual disease (including retention of ascetic fluid, para-aortic nodes recurrence after optimal debulked after interval debulking surgery; IDS) were eligible. The protocol regimen consisted of IP-PTX on day1 (D1), 8, and 15, at a starting dose level 1(DL1) of 45 mg/m2, with 15 mg/ m2 incremental, and IV-CBDCA was fixed dose AUC 5.0 mg/mL.min on D1, monthly. The accrual period was from August 2000 until September 2005. As for result, twelve patients were enrolled. No dose limiting toxicity (DLT) was observed in DL1. In dose level 2 (DL2, 60 mg/m2), one grade 3 (G3) hypersensitive reaction to CBDCA was detected. Further 5 patients had been enrolled but additional DLT was not identified. The RD was decided as DL2, which was the same dose of RD in weekly IP-PTX reported by Francis et al. The serum AUCs of PTX in DL1 and DL2 were 1605 nM.min and 2365 nM.min, respectively. By serum CA125, five complete responses were observed out of 8 evaluable patients by Rustin’s criteria. In conclusion, the combination of weekly IP-PTX and monthly IV-CBDCA at AUC 5.0 mg/mL.min was feasible and the recommended dose of IP-PTX was 60 mg/m2. The therapy was moderate effective for optimal debulking mullerian carcinomas. From our pharmacokinetic results, as for the patients with extra-pelvic lesions, additional IV-PTX would be necessary like GOG 172 experimental arm.

Intraperitoneal Administration of Paclitaxel Followed by Paclitaxel, Cisplatin, and S-1 Chemotherapy for Cytology-positive Gastric Cancer: A Feasibility Study.

A preliminary study evaluating the feasibility of single intraperitoneal (IP) administration of paclitaxel followed by paclitaxel and cisplatin with S-1 (PCS) systemic chemotherapy for cytology-positive (CY1) gastric cancer. Staging laparoscopy was performed to confirm CY1 and P0 status. Initially, patients received IP paclitaxel. Beginning 7 days later PCS was given every 3 weeks followed by second-look laparoscopy. Nine patients were enrolled. The toxic effects of IP and systemic chemotherapy were acceptable. After chemotherapy, 8 patients converted from CY1P0 to CY0P0 and 1 patient from CY1P0 to CY1P1. Gastrectomy was performed on 8 patients except for the CY1P1 patient. Four patients were alive without recurrence. The 2-year overall and progression-free survival rates were 76% and 65%, respectively. Combination chemotherapy with IP paclitaxel and sequential PCS is safe and may be effective for CY1 gastric cancer.

Clinical significance and practice points of conversion therapy for gastric cancer with peritoneal metastasis

Gastric cancer with peritoneal dissemination is usually considered to be oncologically unresectable and is known to have a very poor prognosis. Despite recent advances in systemic chemotherapy, peritoneal dissemination due to advanced gastric cancer (AGC) still remains the most life-threatening type of metastasis and recurrence, which usually causes ascites accumulation, intestinal obstruction, or hydronephrosis, and then seriously impairs the quality of life. In general, the median survival time of these cases is reported to be just only 6-9 months. Recently, conversion therapy for gastric cancer with peritoneal dissemination has been highly concerned. It is defined as a conversion surgery aiming at an R0 resection after chemotherapy for both primary gastric cancer and distant metastatic cancerous foci including peritoneal dissemination, which were originally unresectable due to technical and/or oncological reasons. In numerous clinical practices, the results of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) have been reported to be more satisfactory in comparison with traditional systemic chemotherapy alone. Some clinical trials have demonstrated the clinical efficacy of intravenous and intraperitoneal administration of paclitaxel (PTX) combined with oral S-1 for peritoneal dissemination of gastric cancer with or without malignant ascites. Particularly, a longer period of survival can be expected when conversion R0 gastrectomy is successfully performed after observing significant responses of NIPS. Some clinical practice key points of conversion therapy for AGC patients with peritoneal dissemination are reviewed, including the importance of intraperitoneal and systemic synchronous chemotherapy, the reasonable choice of intraperitoneal chemotherapy drugs, the evaluation of primary gastric cancer and metastatic foci before and after conversion therapy, some special complications of NIPS, the indications of conversion surgery and the adjuvant therapy after conversion surgery, ect.

Feasibility of weekly intraperitoneal versus intravenous paclitaxel therapy delivered from the day of radical surgery for gastric cancer: a preliminary safety analysis of the INPACT study, a randomized controlled trial

Peritoneal carcinomatosis is common after curative resection of gastric cancer. Intraperitoneal administration of paclitaxel (PTX) is known to control ovarian peritoneal metastases. Patients with either linitis plastica or T4 cancer with high risk of peritoneal metastasis or recurrence but whose cancer was considered resectable were preregistered. After their cancer had been confirmed intraoperatively as resectable, the patients were randomized into either group A (PTX at 60mg/m2 intraperitoneally on the day of surgery and on days 14, 21, 28, 42, 49, and 56) or group B (PTX at 80mg/m2 administered intravenously by the identical schedule) before being treated by evidence-based chemotherapy. The primary end point was the 2-year survival rate. Safety, the secondary end point, was also analyzed. The study has been registered as UMIN000002957. Of 177 preregistered patients, 83 underwent treatment (39 by intraperitoneal administration and 44 by intravenous administration). There was no difference in patient demographics between the two groups. The incidences of surgical complications were similar between the groups, except for transient bowel obstruction observed exclusively in group A. The relative dose intensity of PTX was 81.4% for group A and 76.3% for group B. There was one death due to pulmonary thrombosis and a case of anaphylaxis that led to termination of the protocol treatment (group B). Other adverse events were mild and manageable. Intraperitoneal administration of PTX from the day of gastrectomy did not result in a higher incidence of surgical complications and adverse reactions when compared with intravenous administration of PTX.

Cell-free and Concentrated Ascites Reinfusion Therapy (CART) for management of massive malignant ascites in gastric cancer patients with peritoneal metastasis treated with intravenous and intraperitoneal administration of Paclitaxel with Oral S-1.

e15042 Background: Peritoneal metastasis is the most frequent and life-threatening types of metastasis in gastric cancer (GC). Massive malignant ascites are often associated with peritoneal metasta...

Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

The intraperitoneal administration of paclitaxel has been shown to be a promising treatment strategy for peritoneal malignancy. The present study evaluated the effects of intraperitoneal administration of NK105, a paclitaxel-incorporating micellar nanoparticle, which has been shown to have a remarkable effect in a mouse model of gastric cancer. Intraperitoneal NK105 significantly reduced peritoneal tumors in vivo compared with the conventional paclitaxel formulation of paclitaxel solubilized in Cremophor EL and ethanol (PTX-Cre). Moreover, intraperitoneal NK105 significantly reduced the size of subcutaneously inoculated tumors, whereas no such effect was seen with PTX-Cre. Similar systemic toxic effects were observed following the intraperitoneal administration of both NK105 and PTX-Cre. Although NK105 disappeared rapidly almost within a day from the peritoneal cavity, the paclitaxel concentration in peritoneal nodules 4 h after intraperitoneal administration was significantly higher in the NK105 group than in the PTX-Cre group (P < 0.05), whereas there were no significant differences in liver paclitaxel concentrations between the two groups. We also evaluated the pharmacokinetics following intraperitoneal administration of NK105 and PTX-Cre. Serum paclitaxel concentrations 6, 12, 24, and 48 h after the intraperitoneal administration of the drugs were significantly higher in the NK105 than the PTX-Cre group. Furthermore, the peak serum concentration was higher in the NK105 than PTX-Cre group (24 100 ± 3560 vs 108 ± 25 ng/mL, respectively; P < 0.001), as was the area under the concentration-time curve from 0 to 48 h (191 000 ± 32 100 vs 1500 ± 108 ng·h/mL, respectively; P < 0.001). Therefore, intraperitoneal chemotherapy with nanoparticulate paclitaxel NK105 may offer a novel treatment strategy for improving drug delivery in gastric cancer with peritoneal dissemination because of enhanced drug penetration into peritoneal nodules and its prolonged presence in the systemic circulation.

Impact of Intraperitoneal Chemotherapy after Gastrectomy with Positive Cytological Findings in Peritoneal Washings

Background: There is no standard treatment available for gastric cancer patients whose sole ‘non-curative factor’ is positivecytological findings in peritoneal washings (CFPW). The aim of this study was to examine the safety, pharmacokinetics and efficacy for free intraperitoneal cancer cells of intraperitoneal chemotherapy with paclitaxel after gastrectomy with en bloc D2 lymph node dissection in cases of gastric cancer with positive CFPW. Methods: Ten patients with gastric cancer who underwent gastrectomy and systemic lymphadenectomy with D2 dissection, without any other non-curative factors besides positive CFPW, were treated with early postoperative intraperitoneal paclitaxel. Intra-chemotherapeutic toxicity and operative complications were measured using NCI-CTC version 3.0. Intraperitoneal and plasma paclitaxel concentrations were measured using a high-performance liquid chromatographic assay. Results: Grade 3/4 toxic effects included anemia (20%) and neutropenia (10%) that required no treatment. Operative complications were, for example, superficial surgical site infections (10%) that were treated with antibiotics. No viable cancer cells were observed in the intra-abdominal fluid 24 h after intraperitoneal administration of paclitaxel. The intraperitoneal/plasma area under the drug concentration-time curve ratio was 2,003.3:1. Conclusion: Intraperitoneal chemotherapy with paclitaxel is a safe and effective treatment modality for free intraperitoneal cancer cells.

Intraperitoneal administration of a small interfering RNA targeting nuclear factor‐kappa B with paclitaxel successfully prolongs the survival of xenograft model mice with peritoneal metastasis of gastric cancer

Activation of nuclear factor-kappa B (NF-kappaB) has been detected in various malignant tumors, including gastric carcinoma, and is associated with tumor growth, metastasis, resistance to chemotherapeutic agents and poor prognosis. Therefore, NF-kappaB is a potential target for antitumor therapy. In this study, we used a small interfering RNA (siRNA) to knockdown NF-kappaB p65 expression and determined whether intraperitoneal administration of NF-kappaB p65 siRNA and paclitaxel was effective for treating peritoneal metastasis of gastric cancer. Western blot analysis revealed that NF-kappaB p65 expression was diminished by NF-kappaB p65 siRNA. Apoptotic cells were increased after transfection of NF-kappaB p65 siRNA compared with control siRNA in the treatment with paclitaxel. In a murine xenograft model, abundant fluorescence was observed on the surface of intraperitoneal nodules of gastric cancer after siRNA administration. Moreover, intraperitoneal administration of NF-kappaB p65 siRNA reduced NF-kappaB expression in intraperitoneal nodules of gastric cancer. Finally, mice treated by intraperitoneal administration of NF-kappaB p65 siRNA and paclitaxel survived for a significantly longer time than mice treated by intraperitoneal administration of paclitaxel alone (p = 0.0002). Taken together, the present results demonstrate that intraperitoneal administration of NF-kappaB p65 siRNA and paclitaxel inhibited cancer growth in mice with peritoneal metastasis of gastric cancer. Therefore, intraperitoneal administration of NF-kappaB p65 siRNA and paclitaxel may provide a breakthrough in the treatment of peritoneal metastasis of gastric cancer.

Intra-peritoneal administration of paclitaxel with non-animal stabilized hyaluronic acid as a vehicle – A new strategy against peritoneal dissemination of gastric cancer

Background and aim: Intra-peritoneal administration (i.p.) of Taxanes has recently been reported to be effective for the treatment of peritoneal dissemination, presumably because extremely high concentration of the drug is achievable onto the disseminated nodules as compared to intra-venous administration. Here, we aimed to investigate the ability of non-animal stabilized hyaluronic acid (NASHA) to retain the anti-cancer drugs in the peritoneal cavity, and, consequently, improve the efficacy of i.p. administration of paclitaxel. Methods: Mice were inoculated i.p. with MKN45P gastric cancer cells. The mice received i.p. administrations of paclitaxel, without or with NASHA, once a week for 3 consecutive weeks, and the intra-peritoneal nodules were counted after 4 weeks. The ability of NASHA to retain the i.p. administered liquid and paclitaxel in abdominal cavity was also investigated. Finally, the concentration of paclitaxel in metastatic nodule was measured with HPLC. Results: In the group receiving paclitaxel with NASHA, the number of disseminated nodules were significantly smaller than in those receiving paclitaxel without NASHA. The fluid volumes and concentration of paclitaxel recovered from the abdominal cavity as well as the concentrations of paclitaxel in metastatic nodule were significantly increased by the addition of NASHA. Conclusion: Our results indicate that NASHA improves the exposure time of i.p. administrated paclitaxel to disseminated nodules by retaining the drug in the abdominal cavity. Since the material is used in cosmetic surgery with few adverse effects, NASHA can be clinically used as the vehicle for the i.p. administration of anti-cancer agents for advanced gastric cancer with peritoneal dissemination.

Intraperitoneal administration of paclitaxel and oral S-1 for a patient with peritoneal dissemination and hydronephrosis due to advanced gastric cancer

We report a patient with type 3 gastric cancer with peritoneal dissemination and hydronephrosis who was successfully treated with intraperitoneal infusion of paclitaxel and oral administration of S-1. He was diagnosed with unresectable gastric cancer with severe peritoneal dissemination by staging laparoscopy. We selected combined chemotherapy with both paclitaxel and S-1. Paclitaxel at 60 mg/m(2) was administered intraperitoneally on days 1 and 8, and S-1 at 100 mg/body was administered orally for 14 days, followed by 7 days' rest, as one course. After five courses, primary tumor reduction was confirmed and no cancer cells were detected on pathocytological investigation at second-look laparoscopy. The patient underwent total gastrectomy with lymph node dissection. He died from liver metastasis 29 months after the initial treatment, but he had not suffered from peritoneal metastases and had kept a good quality of life (QOL) since that treatment. This chemotherapy can be applied as one of the promising candidates for the treatment of patients with peritoneal metastasis of gastric cancer.