Oxaliplatin Group Research Articles

Effects of the compounds resveratrol, rutin, quercetin, and quercetin nanoemulsion on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice.

Oxaliplatin (OXA) is a platinum compound widely used in the treatment of some solid tumors, especially colorectal cancer. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug, and until now, there is no suitable treatment. Chemotherapy with oxaliplatin also increases the rate of developing hepatic damages with inflammatory activity, termed chemotherapy-associated steatohepatitis (CASH). In the present study, we aimed to compare the effects of a series of antioxidant compounds on simultaneous development of oxaliplatin-induced hepato- and neurotoxicity in mice. Mice BALB/c were treated with oxaliplatin for 6 weeks, 10 mg/kg, intraperitoneally, resulting in mechanical allodynia and hepatic steatosis. We administered the following antioxidant compounds--rutin (RT) (20 mg/kg), resveratrol (RVS) (100 mg/kg), quercetin (QT) (20 mg/kg), and quercetin nanoemulsion (NQT) (20 mg/kg)--daily by gavage to BALB/c, and N-acetylcysteine (NAC) was used as positive control. Treatments with RSV, RUT, or NQT were able to prevent mechanical allodynia when compared to the OXA group, and this effect was associated with decreased c-Fos immunopositivity in the lumbar spinal cord. Regarding the effects on steatohepatitis, RVS, QT, and NQT almost completely reversed the mean liver weight increase induced by OXA. In accordance with these previous data, histological evaluation indicated attenuation of all features of hepatic steatosis evaluated in RSV, RUT, QT, and NQT groups. These compounds were able to reduce the immunopositivity for the apoptosis marker caspase-3. On the other hand, only QT and NQT treatments were able to reduce neutrophil migration measured by myeloperoxidase (MPO) activity. These results suggest that the compounds tested, RSV, RUT, QT, and NQT, would be useful for the clinical treatment of neuro- and hepatoxicity induced by oxaliplatin.

Avoidance of Early Post-Operative Intraperitoneal Chemotherapy (EPIC) Following Peritonectomy with Heated Intraperitoneal Chemotherapy (HIPEC) Significantly Reduces Cost and Hospital Stay

Aims: Peritoneal carcinomatosis is treated with Cytoreductive surgery (CRS) and Heated Intraperitoneal Chemotherapy (HIPEC) with or without Early Postoperative Intraperitoneal Chemotherapy (EPIC) depending on the pathology involved. Since 2010 heated intraperitoneal oxaliplatin has been utilised in our institution. Our aim was to determine if there was a significant cost difference between patients receiving oxaliplatin and those requiring five additional days of EPIC. Methods: We retrospectively analysed 30 patients from our database. 15 patients underwent cytoreductive surgery, heated intraperitoneal oxaliplatin (350mg/m 2 ) and 5-fluorouracil (FU) intravenously administered intraoperatively. We compared those patients with 15 patients who underwent CRS, heated intraperitoneal mitomycin C (10-25mg/m 2 ) as well as EPIC with 5-FU (600-800mg/m 2 ) on postoperative days 1 to 5. Patients were matched for age, gender, pathology and peritoneal carcinomatosis index (PCI). Results: There was no significant difference between radiology (p=0.6) and transfusion costs (p=0.4). The chemotherapy costs in the oxaliplatin group were significantly higher (p=0.001) however overall bed costs including ward, HDU and ICU were significantly lower in the oxaliplatin group (p 0.029). There was a higher percentage of patients in the EPIC group that had postoperative ileus (p 0.4), rate of infection (p 0.1), fistula formation (p 0.03), return to theatre (p 0.2) and collection formation (p 0.07) compared to the oxaliplatin group. The overall cost was significantly lower in the oxaliplatin group (p 0.038). There was no significant survival benefit between both groups (p 0.3). Conclusion: In colorectal cancer the cost and complications of EPIC following HIPEC are unjustified. We now use oxaliplatin HIPEC as our standard regimen in colorectal cancer and appendiceal adenocarcinoma.

P19 Cysthionine-β-synthetase inhibition in combination with standard-chemotherapy decreases colorectal cancer metastasis to the liver

Over two-thirds of colorectal cancer patients will develop liver metastases. The current standard-of-care is treatment with the chemotherapeutic agents 5-flurouracil alone or in combination with oxaliplatin (OX) or irinotecan; however, these drugs are often ineffective. We have previously demonstrated that CBS is selectively upregulated in colorectal cancer cells and stimulates hydrogen sulfide (H 2 S)-mediated cell migration and invasion in vitro , processes that define the metastatic phenotype. The aim of this study was to evaluate whether CBS inhibition with aminooxyacetic acid (AOAA) alone or in combination with OX reduced liver metastases in vivo . Human HCT116 colon cancer cells, which express high levels of CBS, were transfected with a luciferase reporter gene. Cells were injected into the cecal submucosa of athymic nude mice. Mice were treated either with vehicle, AOAA (SQ QOD at 9 mg/kg), OX (IP Qwk at 10 mg/kg) or AOAA plus OX (N = 6 per group) for 3 weeks. In vivo metastasis was measured (photons/s) using the IVIS Spectrum Imaging System. Post-harvest, liver metastases were visually counted on serial H& E stained sections and quantified using a weighted scale based on the number of cells within each metastatic focus. In vivo imaging revealed a significant decrease in luciferase activity in the AOAA plus OX group when compared to either AOAA or OX alone ( p = 0.04 and 0.008, respectively). Histological quantification of liver metastasis confirmed the in vivo findings. In conclusion, our data indicate that CBS inhibition enhances the efficacy of OX in reducing metastatic tumor burden.

Nedaplatin or oxaliplatin combined with paclitaxel and docetaxel as first-line treatment for patients with advanced non-small cell lung cancer.

BackgroundBoth nedaplatin and oxaliplatin combined with paclitaxel or docetaxel have demonstrated potent activity in advanced non-small cell lung cancer (NSCLC) patients, but there is no study comparing the difference between these 2 chemotherapy regimens. The aim of this study was to evaluate and compare the efficacy and safety between the combination chemotherapy of nedaplatin or oxaliplatin plus paclitaxel and docetaxel in patients with advanced NSCLC.Material/MethodsWe retrospectively reviewed patients with stage III–IV unresectable NSCLC from 1 January 2010 to 31 December 2013 at Southwest Hospital. They all received nedaplatin (80 mg/m2, nedaplatin group) or oxaliplatin (130 mg/m2, oxaliplatin group) combined with paclitaxel (175 mg/m2) or docetaxel (75 mg/m2) as first-line treatment.ResultsThere are 174 patients enrolled – 123 patients in the nedaplatin group and 51 patients in the oxaliplatin group. The objective response rates were 47.3% and 34.1% and the disease control rates were 87.5% and 79.5% in nedaplatin and oxaliplatin groups, respectively. The progression-free survival time was 10.4 months and 9.6 months (p=0.722) and the overall survival time was 18.5 months and 25.5 months in the nedaplatin and oxaliplatin groups, respectively (p=0.09). Total toxicity was greater in the oxaliplatin group (p=0.008), but there is no significant difference among ¾ grade adverse events between the 2 groups (P=0.595).ConclusionsThe effect of nedaplatin plus paclitaxel and docetaxel is the same as oxaliplatin plus paclitaxel and docetaxel, and the toxicity of nedaplatin is well tolerate as first-line treatment for patients with advanced NSCLC.

Splenic volume may be a useful indicator of the protective effect of bevacizumab against oxaliplatin-induced hepatic sinusoidal obstruction syndrome

The aim of this study was to investigate the relationship between the use of bevacizumab (Bmab) in addition to oxaliplatin (OX), the development of sinusoidal obstruction syndrome (SOS) and the changes in splenic volume as an indicator of the protective effect of Bmab against OX-induced SOS. Seventy-nine patients who received OX-based chemotherapy with (OX + Bmab group: n = 48) or without Bmab (OX group: n = 31) for colorectal liver metastases were included in this study. The changes in splenic volume after chemotherapy were evaluated in the two groups. Furthermore, the relationship between the changes in splenic volume and SOS were analyzed in the 55 patients who underwent hepatectomy. A significant increase in the splenic volume was observed in the OX group, but not in the OX + Bmab group. The increase in the splenic volume relative to baseline was significantly higher in the OX group than in the OX + Bmab group (39.1% vs. 2.3%, p < 0.0001). The incidence of moderate or severe SOS was significantly higher in the OX group than in the OX + Bmab group (50.0% vs. 16.0%, p = 0.0068), and the increase in the splenic volume was significantly higher in the patients with SOS than in those without SOS (42.9% vs. 9.9%, p = 0.0001). A multivariate analysis identified the increase in the splenic volume as an independent predictor of the development of SOS. This study demonstrated that the inhibition of splenic volume enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS.

Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells

Fatty acid synthase is highly expressed in many types of human cancers. Cerulenin, a natural inhibitor of fatty acid synthase, induced apoptosis in the human colon cancer cell lines HCT116 and RKO. Oxaliplatin also induced cell death in these cell lines. Cerulenin treatment was associated with reduced levels of phosphorylated Akt, activation of p38 and induced caspase-3 cleavage and finally caused apoptosis. Oxaliplatin induced activation of the p53-p21 pathway and p38. In combination with cerulenin and oxaliplatin, activation of the p53-p21 pathway and p38 occurred in a smaller concentration and finally induced caspase-3 cleavage in a smaller concentration of cerulenin and oxaliplatin. In xenotransplanted SCID mice, the cerulenin + oxaliplatin group significantly inhibited tumor progression compared to the control, cerulenin and oxaliplatin groups. Based on these studies, inhibiting fatty acid synthase would be an effective strategy to treat unresectable colorectal cancer tumors in combination with oxaliplatin. Fatty acid synthase inhibitor would be one of the best counterparts of oxaliplatin, which reduces the dose and side-effects of oxaliplatin and would make it possible to endure the chemotherapy over a longer period.

Colorectal Cancer Surgery in Portal Hypertensive Patients

Oxaliplatin is used in adjuvant treatment of colorectal cancer and is associated with sinusoidal obstruction syndrome. Few data are available on its effects in patients in whom portal hypertension was diagnosed before cancer treatment. Our aim was to investigate short- and long-term outcomes of surgery for colorectal cancer in patients with portal hypertension with or without cirrhosis, particularly regarding effects of adjuvant chemotherapy with oxaliplatin. This was a prospective cohort study performed at an academic medical center. Patients with stage II or III colorectal cancer and portal hypertension who underwent curative resection were included. All patients received adjuvant chemotherapy with oxaliplatin (FOLFOX 4) or 5-fluorouracil and leucovorin. Potential predictive laboratory and clinical variables and postoperative (30-day) and long-term morbidity and mortality were recorded. Of 63 patients enrolled, 23 (37%) had a total of 82 postoperative complications; 5 patients (8%) died within 30 days postoperatively. Univariate analysis showed that severe portal hypertension, preoperative Child class B, low albumin, the presence of ascites, preoperative upper GI tract bleeding, and high intraoperative blood loss were linked to postoperative morbidity. Presence of postoperative infection (p = 0.004), presence of preoperative ascites (p = 0.01), high intraoperative blood loss (p = 0.02), and preoperative upper GI tract bleeding (p = 0.03) were significantly related to mortality. Of 58 patients receiving adjuvant chemotherapy, 20 received the oxaliplatin regimen and 38 received 5-fluorouracil/leucovorin without oxaliplatin. The median length of follow-up was 26 (range, 6-36) months. Kaplan-Meier analyses showed that patients who received oxaliplatin had higher cumulative incidences of newly developed esophageal varices (p = 0.002), GI tract bleeding (p = 0.02), and newly formed ascites (p = 0.03). Death occurred in 8 of 20 patients (40%) in the oxaliplatin group and in 5 of 38 patients (13%) in the 5-fluorouracil group. Kaplan-Meier estimates of mean survival time were 34.4 months (95% CI, 32.4-36.5) in the 5-fluorouracil/leucovorin group vs 29.9 months (95% CI, 26-33.7) in the oxaliplatin group, and patients receiving oxaliplatin had a significantly higher relative risk of death (HR = 2.98; 95% CI, 1.03-8.65). Cancer-specific mortality was not related to treatment type. The study was limited by the relatively small sample size and lack of randomization, which may have led to selection bias in treatment regimens. Colorectal cancer surgery can be done safely in portal hypertensive patients with good hepatic function; however, higher mortality is expected in patients with compromised hepatic function reserve. Compared with adjuvant chemotherapy without oxaliplatin, oxaliplatin-based chemotherapy does not significantly reduce cancer-specific mortality and may increase overall morbidity and mortality. Therefore, oxaliplatin-based chemotherapy should be used with caution in patients who have portal hypertension, even in those with good liver function.

Treatment of stage IIIb/IV non-small cell lung cancer with Pemetrexed plus Oxaliplatin after failure of Erlotinib as second-line treatment

To determine the efficacy and toxicity of Pemetrexed plus Oxaliplatin in patients suffering from stage IIIb or IV lung adenocarcinoma and being treated with Erlotinib as second-line treatment, a total of 45 patients were randomly divided into two groups. One group was treated with 500 mg/m2 Pemetrexed plus 100 mg/m2 Oxaliplatin, and the other was treated with 500 mg/m2 Pemetrexed plus 75 mg/m2 Cisplatin. All drugs were administered on day one of a 21-day cycle. In the Oxaliplatin group, 3 patients (13.6 %) experienced partial response (PR), 9 patients (41.0 %) showed stable disease (SD), and 10 patients (45.5 %) had progressive disease (PD). In the Cisplatin group, 2 patients (8.7 %) experienced PR, 7 patients (30.4 %) showed SD, and 14 patients (60.9 %) had PD. The PFS of the Oxaliplatin group and the Cisplatin group was 4.45 months (95 % CI 4.10–4.80) and 3.96 months (95 % CI 3.68–4.24) (P = 0.03), respectively. The median overall survival (OS) was 10.8 months (95 % CI 10.2–11.5) and 10.7 months (95 % CI 10.2–11.3) (P = 0.72), respectively. There was no statistically significant difference in the occurrence rate of grades 3 and 4 myelotoxicity between the two groups. However, there was a significant difference in the occurrence rate of grades 3 and 4 gastrointestinal reactions and peripheral neurotoxicity between the two groups (P < 0.05). A regime combining Pemetrexed and Oxaliplatin was marginally effective and well tolerated in patients with stage IIIb or IV lung adenocarcinoma who have received Erlotinib as second-line treatment.

Hepatic histopathology and postoperative outcome after preoperative chemotherapy for Chinese patients with colorectal liver metastases

To assess the effects of preoperative treatment on the hepatic histology of non-tumoral liver and the postoperative outcome. One hundred and six patients underwent hepatic resection for colorectal metastases between 1999 and 2009. The surgical specimens were reviewed with established criteria for diagnosis and grading of pathological hepatic injury. The impact of preoperative therapy on liver injury and postoperative outcome was analyzed. Fifty-three patients (50%) received surgery alone, whereas 42 patients (39.6%) received neoadjuvant chemotherapy and 11 (10.4%) patients received preoperative hepatic artery infusion (HAI). Chemotherapy included oxaliplatin-based regimens (31.1%) and irinotecan-based regimens (8.5%). On histopathological analysis, 16 patients (15.1%) had steatosis, 31 (29.2%) had sinusoidal dilation and 20 patients (18.9%) had steatohepatitis. Preoperative oxaliplatin was associated with sinusoidal dilation compared with surgery alone (42.4% vs 20.8%, P = 0.03); however, the perioperative complication rate was not significantly different between the oxaliplatin group and surgery group (27.3% vs 13.2%, P = 0.1). HAI was associated with more steatosis, sinusoidal dilation and steatohepatitis than the surgery group, with higher perioperative morbidity (36.4% vs 13.2%, P = 0.06) and mortality (9.1% vs 0% P = 0.02). Preoperative oxaliplatin was associated with sinusoidal dilation compared with surgery alone. However, the preoperative oxaliplatin had no significant impact on perioperative outcomes. HAI can cause pathological changes and tends to increase perioperative morbidity and mortality.

Inhibitory effect of nimesulide and oxaliplatin on tumor growth and lymphatic metastasis of transplanted human lung cancer in nude mice

This study was designed to evaluate the inhibitory effect of nimesulide in combination with oxaliplatin on tumor growth, expression of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin, and lymphatic metastasis in lung cancer xenograft in nude mice, and to discuss the possible synergistic effect of nimesulide in combination with oxaliplatin. Human lung cancer A549 cells were injected into BALB/c nude mice subcutaneously. Thirty-three healthy male nude mice were randomly divided into 4 groups: the control group, nimesulide group, oxaliplatin group and nimesulide combined with oxaliplatin group. Transplanted tumor tissues were collected and the expressions of COX-2, VEGF-C, VEGFR-3, survivin, β-catenin protein were detected by immunohistochemistry, and RT-PCR assay was used to assess the expression of tumor COX-2, VEGF-C, VEGFR-3, survivin and β-catenin mRNA. SPSS 16.0 was used for statistical analysis. Data were present as (x(-) ± s), and the means were compared by analysis of variance test. Tumor inhibition rates of the nimesulide group, oxaliplatin group and nimesulide + oxaliplatin group were 39.73%, 48.04% and 65.94%, respectively. Immunohistochemical and RT-PCR analysis showed that compared with the control group, the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin of the nimesulide group were significantly reduced (all P < 0.05). Compared with the control group, statistical analysis of variance showed that the expression levels of COX-2, VEGF-C and VEGFR-3 of the oxaliplatin group were significantly increased (P < 0.05), the expression levels of survivin and β-catenin protein and mRNA of the oxaliplatin group were significantly reduced (P < 0.05). Compared with the control group, the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin of the nimesulide + oxaliplatin group were significantly reduced (all P < 0.05). Both nimesulide alone or in combination with oxaliplatin can significantly inhibit the growth of lung cancer xenografts in nude mice and the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin. Oxaliplatin can significantly inhibit the growth of lung cancer xenografts in nude mice, and the expression of survivin and β-catenin. Nimesulide in combination with oxaliplatin enhances the antitumor effect of oxaliplatin.

Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial

Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. German Cancer Aid (Deutsche Krebshilfe).

Capecitabine plus oxaliplatin compared with 5-fluorouracil plus oxaliplatin in metastatic colorectal cancer: Meta-analysis of randomized controlled trials

The aim of this study was to evaluate the curative effects and safety of capecitabine plus oxaliplatin compared with 5-fluorouracil (5-FU) plus oxaliplatin in patients with metastatic colorectal cancer (MCRC). We searched the Cochrane Central register of Controlled Trials (CENTRAL), PubMed, Ovid, ScienceDirect, EBSCO, EMBASE and conference proceedings for eligible trials. A meta-analysis was performed using Review Manager 5.0. A total of 3,603 cancer patients from 7 trials were analyzed, and the baseline patient characteristics were comparable in all studies. Curative effect outcomes including complete response (CR) (OR=0.78; 95% CI 0.47-1.31; p=0.35), partial response (PR) (OR=0.81; 95% CI 0.65-1.00; p=0.05) and the overall response rate (ORR) (OR=0.85; 95% CI 0.71-1.02; p=0.08) showed similar curative effects between the capecitabine plus oxaliplatin group and the 5-FU plus oxaliplatin group. Moreover, the median overall survival (OS) and progression-free survival (PFS) had no statistically significant differences. Regarding safety, hand-foot syndrome was more frequently observed in the capecitabine plus oxaliplatin group (OR=2.71; 95% CI 2.04-3.61; p<0.00001), while stomatitis and neutropenia were reversed. Other toxic effects had no statistically significant differences between the two groups. Our results showed that capecitabine plus oxaliplatin had similar curative effects to 5-FU plus oxaliplatin, however, it was safer in patients with MCRC.

Suppression of colorectal cancer metastasis by nigericin through inhibition of epithelial-mesenchymal transition

To evaluate the effect of nigericin on colorectal cancer and to explore its possible mechanism. The human colorectal cancer (CRC) cell lines HT29 and SW480 were treated with nigericin or oxaliplatin under the conditions specified. Cell viability assay and invasion and metastasis assay were performed to evaluate the effect of nigericin on CRC cells. Sphere-forming assay and soft agar colony-forming assay were implemented to assess the action of nigericin on the cancer stem cell properties of CRC cells undergone epithelial-mesenchymal transition (EMT). Compared with oxaliplatin, nigericin showed more toxicity for the HT29 cell line (IC50, 12.92 ± 0.25 μmol vs 37.68 ± 0.34 μmol). A similar result was also obtained with the SW116 cell line (IC50, 15.86 ± 0.18 μmol vs 41.02 ± 0.23 μmol). A Boyden chamber assay indicated that a significant decrease in the number of HT29 cells migrating through polyvinylidene fluoride membrane was observed in the nigericin-treated group, relative to the vehicle-treated group [11 ± 2 cells per high-power field (HPF) vs 19.33 ± 1.52 cells per HPF, P < 0.05]. Compared to the control group, the numbers of HT29 cells invading through the Matrigel-coated membrane also decreased in the nigericin-treated group (6.66 ± 1.52 cells per HPF vs 14.66 ± 1.52 cells per HPF, P < 0.05). Nigericin also reduced the proportion of CD133+ cells from 83.57% to 63.93%, relative to the control group (P < 0.05). Nigericin decreased the number of spheres relative to the control group (0.14 ± 0.01 vs 0.35 ± 0.01, P < 0.05), while oxaliplatin increased the number of spheres relative to the control group (0.75 ± 0.02 vs 0.35 ± 0.01; P < 0.05). Nigericin also showed a decreased ability to form colonies under anchorage-independent conditions in a standard soft agar assay after 14 d in culture, relative to the control group (1.66 ± 0.57 vs 7 ± 1.15, P < 0.05), whereas the colony numbers were higher in the oxaliplatin group relative to the vehicle-treated controls (14.33 ± 0.57 vs 7 ± 1.15, P < 0.05). We further detected the expression of E-cadherin and vimentin in cells treated with nigericin and oxaliplatin. The results showed that HT29 cells treated with nigericin induced an increase in E-cadherin expression and a decrease in the vimentin expression relative to vehicle controls. In contrast, oxaliplatin downregulated the expression of E-cadherin and upregulated the expression of vimentin in HT29 cells relative to vehicle controls. This study demonstrated that nigericin could partly reverse the EMT process during cell invasion and metastasis.

6585 POSTER Phase II Study of Low-dose Everolimus Plus Weekly Cisplatin and 24-hour Infusion of High-dose 5-fluorouracil and Leucovorin for First-line Treatment of Metastatic or Recurrent Gastric Cancers

the triplet therapies containing capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with cisplatin. Results: The hazard ratio for death in the capecitabine group was 0.88 (95% confidence interval [CI], 0.81 to 0.98) in comparison to fluorouracil and the hazard ratio for the oxaliplatin group was 0.93 (95%CI, 0.82 to 1.10) in comparison to cisplatin. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.2 months, 9.3 months, 9.1 months, and 11.5 months, respectively; survival rates at 1 year were 36.6%, 38.9%, 40.1%, and 47.5%, respectively. Overall survival was longer with EOX than with ECF. Toxic effects of capecitabine and fluorouracil were almost similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity but with slightly higher incidences of neuropathy. Conclusions: In our experience, oxaliplatin and capecitabine are more effective than cisplatin and fluorouracil, respectively, in patients with previously untreated esophagogastric cancer.

PEG-liposomal oxaliplatin potentialization of antitumor efficiency in a nude mouse tumor-xenograft model of colorectal carcinoma

The non-selectivity of chemotherapeutics between normal tissue and pathological sites poses a challenge for the treatment strategy for advanced colorectal carcinoma. To obtain sufficient antitumor activity, optimization of the therapeutic regimen is of great importance. We investigated PEG-liposomal oxaliplatin potentialization of antitumor efficiency in a nude mouse tumor-xenograft model of colorectal carcinoma. A tumor-bearing nude mouse model, intravenous injections of (Dio)-labeled PEG-liposomes via tail vein and fluorescence imaging with in vivo imaging system were employed. Mice were treated with free L-oHP, PEG-liposomal L-oHP via the tail vein, followed by analysis of the accumulation of L-oHP in tumor tissues by high-performance liquid chromatography (HPLC), observation of the tumor volume and the survival rate. Apoptosis and proliferation of tumors were detected by TUNEL assay and immunohistochemistry. The mRNA and protein levels of Bcl-2, Bax, caspase-3 (P17) and Ki-67 were determined by RT-PCR and Western blotting. Fluorescence imaging with in vivo imaging showed PEG-liposome targeting in tumor tissues. After intravenous injections of PEG-liposomal oxaliplatin, tumor tissue maximum accumulation of L-oHP was 9.37 ± 0.79 µg/g at 24 h; The tumor volume was significantly suppressed, and mice showed longer survival, compared with the free oxaliplatin group. Apoptosis increased, but proliferation decreased in tumor tissues. The mRNA expression of Bcl-2 and Ki-67 was down-regulated, while Bax and caspase-3 expression was up-regulated. Protein expression of Bcl-2 was down-regulated, while Bax and P17 expression was up-regulated. The results indicate that PEG-liposomal oxaliplatin can improve antitumor efficiency in a nude mouse tumor-xenograft model of colorectal carcinoma.

Severe Electrolyte Disturbances After Hyperthermic Intraperitoneal Chemotherapy: Oxaliplatin Versus Mitomycin C

Oxaliplatin (OX) is increasingly used for hyperthermic intraperitoneal chemotherapy (HIPC) for patients with peritoneal metastases. Our aim was to review electrolyte disturbances and complications after HIPC with oxaliplatin (OX) versus mitomycin C (MMC). We included patients enrolled in single-institution prospective clinical trials who underwent cytoreductive surgery and HIPC with MMC or OX. We reviewed patient demographics, pathology, perioperative course, HIPC administration, and postoperative electrolyte disturbances. Measured postoperative sodium values were corrected for systemic hyperglycemia using the formula: (measured Na(+)) × [(glucose - 100/100) × 1.6]. From January 2002 to April 2009 we performed 80 HIPC procedures. A total of 60 patients (75%) received MMC (dose range 12.5-50 mg/m(2)) carried in lactated ringers solution. There were 20 patients (25%) who received OX (dose range 300 × 400 mg/m(2)) carried in 5% dextrose solution. For patients receiving HIPC with OX, electrolyte disturbances were the most common complication. Compared with MMC, patients receiving OX had significant 24-h postoperative uncorrected hyponatremia (P < 0.001), corrected hyponatremia (P < 0.001), hyperglycemia (P < 0.001), and metabolic acidosis (P < 0.001). In the OX group, corrected (mean 130.5) and uncorrected (mean 127.4) sodium levels were significantly lower than preoperatively (mean 139.9, P < 0.001). The overall nonelectrolyte complication rate was 56.2%. (MMC n = 33, 55.0%; OX n = 12, 60%); the 30-day mortality rate was 0% in both groups. Compared with MMC, HIPC with OX was associated with significant but predictable electrolyte disturbances; however, these electrolyte disturbances were not associated with higher overall complication rates. Close monitoring with early correction is imperative to maximize perioperative care. Further studies are needed to provide mechanistic insight.

The integrity of colonic anastomoses following the intraperitoneal administration of oxaliplatin

The purpose of this experimental study was to determine the effect of oxaliplatin on the integrity of colonic anastomoses which were under oxaliplatin administration. Thirty rats were randomized to two groups. After resection of a 1-cm segment of the transverse colon, an end-to-end sutured anastomosis was performed. Rats of the control group were injected with 3 ml of 0.9% sodium chloride solution and in the oxaliplatin group with 2.4 mg/kg of oxaliplatin intraperitoneally immediately after surgery and for seven postoperative days. All rats were sacrificed on the tenth postoperative day, and the anastomoses were examined macroscopically and graded histologically. Rats were measured for anastomotic bursting pressures and tissue hydroxyproline levels. The body weight changes were significantly greater in the oxaliplatin group (p = 0.005). Anastomotic dehiscence occurred only in the oxaliplatin group. The adhesion formation was significantly increased in the group of oxaliplatin compared to the control group (p = 0.001). The colonic bursting pressure was significantly lower in the oxaliplatin group compared to the control group (p < 0.001). The mean inflammatory cell infiltration was significantly lower in the oxaliplatin group (1.00 vs. 2.33, p < 0.001). The mean neoagiogenesis was significantly lower in the oxaliplatin group (0.80 vs. 2.20, p < 0.001). The mean collagen deposition was significantly lower in the oxaliplatin group and the mean fibroblast activity was significantly lower in the oxaliplatin group (1.27 vs. 2.53, p < 0.001). Hydroxyproline concentration was significantly lower in the oxaliplatin group (p < 0.001). Intra- and postoperative intraperitoneal administration of oxaliplatin definitely impairs healing of colonic anastomoses in rats.

Comparison between Intensified Neoadjuvant Treatment and Standard Preoperative Chemoradiation for Rectal Cancer

The aim of the current study was to compare a neoadjuvant regimen containing oxaliplatin with standard preoperative treatment for rectal cancer. From December 2006 to December 2007, 20 patients with rectal cancer were treated at our Institution with the weekly addition of oxaliplatin (50 mg/m(2)) to radiotherapy (50.4-54.0 Gy in 28-30 daily fractions) and continuous infusion of 5-fluorouracil (200 mg/m(2)). The results of the regimen were compared with a historical control group including 21 consecutive patients previously treated with standard 5-fluorouracil treatment from December 2004 to October 2006. Both the rate of sphincter preservation in low rectal cancer (91.7% vs 36.4%, P = 0.009) and the rate of downstaging (84.2% vs 47.6%, P = 0.023) were higher in the oxaliplatin group than in the control group. Pathological complete response was achieved in 8 patients (42.1%) in the oxaliplatin group and in 4 patients (19.0%) in the control group (P = 0.172). When ypT0-pT1 stages were analyzed together, the P value was 0.051. Acute toxicity was increased in the oxaliplatin group, with a higher incidence of G3 diarrhea and pelvic pain than in the control group (30.0% vs 14.3%, P = NS). Our data seem to correlate the addition of oxaliplatin to the standard treatment for rectal cancer with higher rates of sphincter preservation, down-staging and complete response. Toxicity is increased and requires careful monitoring. However, our results refer to a retrospective comparison of a small series of patients and need to be validated by the large, phase III randomized trial currently ongoing.

Oxaliplatin and Leucovorin Plus Fluorouracil Versus Irinotecan and Leucovorin Plus Fluorouracil Combination Chemotherapy as a First-line Treatment in Patients with Metastatic or Recurred Gastric Adenocarcinoma

We performed retrospective study in order to compare oxaliplatin, leucovorin, and fluorouracil (FOLFOX) versus irinotecan, leucovorin, and fluorouracil (FOLFIRI) in recurred or metastatic gastric adenocarcinoma. We investigated 56 patients who were diagnosed with recurred or metastatic gastric adenocarcinoma in a single center during march, 2003 to march, 2008. The patients received either FOLFOX or FOLFIRI chemotherapy. There were no significant difference between the Oxaliplatin group (30 patients) and Irinotecan group (26 patients) in sex, age, and ECOG performance (p<0.05). Oxaliplatin group showed 1 case of CR (3.3%) and 12 cases of PR (40%), making the response rate 43.3%. Irinotecan group showed CR in 2 cases (7.7%) and PR in 10 cases (38.5%), making the response rate 46.2%. The median value of time to progression was 4 months in the oxlaplatin group and 4.5 months in the irinotecan group. The overall survival showed no significant difference (p=0.784), with the irinotecan group (9.7 months) being slightly longer than the Oxaliplatin group (8.3 months). Grade 3/4 neutropenia occurred similarly in both groups (4 cases in the oxalplatin group, 9 in the irinotecan group). Both combination treatment can be used safely and effectively in recurred or metastatic gastric adenocarcinoma.

Capecitabine plus oxaliplatin vs fluorouracil plus oxaliplatin as first line treatment for metastatic colorectal caner – meta‐analysis of six randomized trials

This meta-analysis was performed to evaluate the efficacy and safety of capecitabine plus oxaliplatin vs fluorouracil (FU) plus oxaliplatin as first line treatment for metastatic or advanced colorectal cancer. A total of 2196 patients from six randomized controlled trials were available for analysis, which included 1105 patients in capecitabine plus oxaliplatin group and 1091 patients in FU plus oxaliplatin group. The efficacy data included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), overall response rate (ORR), and the safety data contained specific grade 3 and 4 toxicity such as anaemia, thrombocytopenia, neutropenia, diarrhoea, nausea, asthenia, vomiting, abdominal pain, hand foot syndrome, neuropathy and stomatitis were evaluated. Pooled analysis of OS (hazards ratio HR = 1.04, 95%CI: 0.95-1.14), PFS (1.08, 0.98-1.18), ORR (odds ratio OR = 0.87, 0.73-1.03) in the capecitabine plus oxaliplatin group shows no statistical significance when compared with those in the FU plus oxaliplatin group. The statistically significant differences in pooled estimates suggest a higher incidence of grade 3/4 thrombocytopenia (OR = 1.87, 1.24-2.81), grade 3/4 hand-foot syndrome (3.90, 2.13-7.12) in the capecitabine plus oxaliplatin group and grade 3/4 neutropenia (0.20, 0.07-0.53) in the FU plus oxaliplatin group. No statistically significant difference was noted in the incidence of grade 3/4 anaemia, asthenia, diarrhoea, nausea, vomiting, abdominal pain, neuropathy and stomatitis. The effect of capecitabine plus oxaliplatin regimen is similar to FU plus oxaliplatin regimen as first line treatment for metastatic colorectal cancer, but it offers advantages of simplicity and convenience to administer.