CDDP Group Research Articles

Comparison of cisplatin (CDDP) and radiation (RT) to cetuximab (C) and RT for locally advanced head and neck cancer (LAHNC): A preliminary analysis

6042 Background: Both concurrent CDDP/RT and C/RT have been shown in randomized trials to yield superior disease control compared to RT alone in LAHNC, but no randomized trial has compared them. We evaluated our center's experience with these regimens. Methods: From 3/1/06 - 4/1/08, 175 patients were retrospectively identified who received definitive treatment for LAHNC with CDDP (planned total dose 100 mg/m2 Q3 weeks X 3) and RT (n = 125) or C (400 mg/m2 load; 250 mg/m2 weekly) and RT (n = 50). Patients who received prior RT, additional systemic therapy, and/or surgery to the primary site were excluded. C was given for the following reasons: auditory 30%, renal 4%, cardiac 2%, performance status 18%, patient choice 16%, neuropathy 4%, unknown 2%, and a combination of factors 24%. The median age: CDDP group 56, 6% >71; C group 66.5, 40% >71. Additional CDDP and C features: male sex, 86 v 78%; stage IV, 70 v 68%; and oropharynx, 78 v 70%. Median RT dose (70 Gy), RT length (46 days), and Karnofsky performance status (KPS) (90%) were the same; alcohol/tobacco use was similar. Results: At a median follow up of 18.7 months, with death without local failure (LF) as a competing risk, the 18 month LF incidence rate was 2.5% in the CDDP group and 43.3% in the C group (p < 0.0001), with the latest event occurring at 16.5 months. The 18 month disease-free survival (DFS) and overall survival (OS) rates were 85.7 v 40.9%, and 96.8 v 73.1%, in favor of CDDP (p < 0.0001 for both). Initially, 21 variables were assessed for significance, and when Cox proportional hazards model was used for multivariate analysis to address prognostic imbalances, treatment with CDDP still predicted for improved LF, DFS, and OS (p < 0.0001 for LF and DFS; p = 0.0017 for OS). For OS analysis, the concordance probability estimates were .67 for using drug choice alone and .80 for using drug choice, T stage, RT dose, and KPS. Conclusions: CDDP/RT and C/RT were used to treat somewhat different populations with LAHNC. The observed superiority of CDDP/RT compared to C/RT in LF, DFS, and OS may reflect patient selection issues. However, preliminary multivariate modeling suggests that CDDP/RT remains the preferred option for fit patients pending further analyses and prospective studies comparing these regimens. [Table: see text]

Role of Panaxoside on regulating intestinal bacteria balance of hydroperitonia mice and alleviating side effect of chemotherapy

Usually, the intestinal bacteria balance of hydroperitonia mice was modulated by panaxoside (PA) to alleviate the chemo‐treatment side effect. Hepatocarcinoma hydroperitonia model was induced by injecting H22 cells intraperitoneally. The mice were either exposed with PA before model induced or with PA and CDDP after model induced. The results showed that the rates of successful implantation of H22 cells in PA group decreased significantly compared to the control group. The quantity of the intestinal predominant ballicus and Enterococcus in the PA+CDDP group (PC) were improved, while the quantity of the Enterobacter decreased significantly. Ascitic liquid was observed on the 6th day in CDDP group, but on the 9th day in PC group. The survival time of CDDP and PC group is 16±2.1days and 38.4±2.31days respectively. The rate of bacterial translocation in liver was decreased significantly in the PC group. The splenomegaly was more obvious in PC group than in CDDP group. The spleen index also increased significantly in PC group (1.43±0.16). The quantity of lymphocytes, macrophages and platelet increased in the PC group. So panaxoside could not only regulate intestinal microecology balance, improve immune function, but also prevent the formation of hepatocarcinoma hydroperitonia, relieve the side effects of chemotherapy, reduce the incidence of cancer.

Clinical development of S-1 plus cisplatin therapy as first-line treatment for advanced gastric cancer

We reviewed the clinical development of S-1 and S-1 plus cisplatin (CDDP) therapy for advanced gastric cancer (AGC). S-1 is an active oral fluoropyrimidine in patients with AGC. Phase I/II clinical trials of S-1 plus CDDP for AGC have yielded high response rates and the agents were well tolerated. On the basis of these phase I/II studies, we performed a randomized phase III study comparing S-1 plus CDDP with S-1 alone in patients with AGC. In the S-1 plus CDDP group, S-1 was given orally, twice daily for 3 consecutive weeks, and 60 mg/m2 CDDP was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. In the S-1 alone group, S-1 was given orally, twice daily for 4 consecutive weeks, followed by 2 weeks of rest, within a 6-week cycle. Median overall survival was significantly longer in the S-1 plus CDDP group (13.0 months) than in the S-1 alone group (11.0 months; P = 0.04). Progression-free survival was significantly longer in the S-1 plus CDDP group (median, 6.0 months vs 4.0 months; P < 0.0001) and the response rate was also significantly higher (54.0% vs 31.1%; P = 0.002). There were more grade 3 or 4 adverse events, including leukopenia, neutropenia, anemia, nausea, and anorexia in the S-1 plus CDDP group, but the events were manageable. No treatment-related deaths were observed. As a result of this study, S-1 plus CDDP therapy has become a standard first-line treatment for AGC in Japan.

Replacement of cisplatin with nedaplatin in a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma

The effects of replacing cisplatin (CDDP) with cis-diammineglycolatoplatinum (nedaplatin, NDP), a second-generation platinum complex, on the pharmacokinetics of 5-fluorouracil (5-FU) were investigated in Japanese patients with esophageal squamous cell carcinoma, who were treated with a definitive 5-FU/CDDP-based chemoradiotherapy. Fifty-six patients were enrolled, 49 treated with CDDP and 7 treated with NDP. A course consisted of continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, infusion of CDDP or NDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. Plasma concentrations of 5-FU were determined by high performance liquid chromatography at 5 PM on days 3, 10, 38 and 45, and at 5 AM on days 4, 11, 39 and 46. The circadian rhythm in plasma concentrations of 5-FU observed in the case of CDDP was altered when NDP was used instead. The clinical response can be predicted by monitoring plasma concentrations of 5-FU in the CDDP group, but not in the NDP group.

Low‐intensity ultrasound and microbubbles enhance the antitumor effect of cisplatin

Cell permeabilization using microbubbles (MB) and low-intensity ultrasound (US) have the potential for delivering molecules into the cytoplasm. The collapsing MB and cavitation bubbles created by this collapse generate impulsive pressures that cause transient membrane permeability, allowing exogenous molecules to enter the cells. To evaluate this methodology in vitro and in vivo, we investigated the effects of low-intensity 1-MHz pulsed US and MB combined with cis-diamminedichloroplatinum (II) (CDDP) on two cell lines (Colon 26 murine colon carcinoma and EMT6 murine mammary carcinoma) in vitro and in vivo on severe combined immunodeficient mice inoculated with HT29-luc human colon carcinoma. To investigate in vitro the efficiency of molecular delivery by the US and MB method, calcein molecules with a molecular weight in the same range as that of CDDP were used as fluorescent markers. Fluorescence measurement revealed that approximately 10(6)-10(7) calcein molecules per cell were internalized. US-MB-mediated delivery of CDDP in Colon 26 and EMT6 cells increased cytotoxicity in a dose-dependent manner and induced apoptosis (nuclear condensation and fragmentation, and increase in caspase-3 activity). In vivo experiments with xenografts (HT29-luc) revealed a very significant reduction in tumor volume in mice treated with CDDP + US + MB compared with those in the US + CDDP groups for two different concentrations of CDDP. This finding suggests that the US-MB method combined with chemotherapy has clinical potential in cancer therapy.

Protective Effect of Geranylgeranylacetone on Cisplatin Ototoxicity

Background: Geranylgeranylacetone (GGA) has the ability to induce heat shock proteins and to protect cells from apoptotic insults. This study aims to investigate whether GGA has a protective effect on cisplatin (CDDP) ototoxicity. Methods: The auditory threshold was assessed using the auditory brainstem response test. Hsp70 and C-reactive protein expressions were investigated by Western blot analysis. The amount of hair cells was counted under scanning electron microscopy. Results: The auditory threshold and the percentage of missing outer hair cells in the CDDP group were significantly higher than in the GGA + CDDP group. C-reactive protein expression was less in the GGA + CDDP group compared with the CDDP group. Hsp70 expression showed an adverse result. Conclusion: It was suggested that GGA had a protective effect on CDDP ototoxicity.

Efficacy of Unresectable or Recurred Gastric Cancer Treated with TS-1 Chemotherapy or TS-1/CDDP Combination Chemotherapy

Purpose：Although several chemotherapy regimens used against advanced and recurred gastric cancer have been studied extensively in an attempt to further improve the prognosis of patients, no standard chemotherapeutic regimens have been established. The aim of this study was to determine the anti-tumor efficacy and safety of TS-1 or TS-1 plus cisplatin (CDDP). Materials and Methods：From December 2004 to June 2007, we treated 43 patients with unresectable or recurred gastric cancer either with 80 mg/m2 of TS-1 for 28 days, which was followed by a 2-week rest, or with 80 mg/m2 of TS-1 for 28 days and 60 mg/m2 of CDDP on day 3 every 6 weeks. Results：Tumor response rates in the primary chemotherapy group and in the recurrent group were 46.7% and 21.4%, respectively. The median survival rates in the primary and the recurrent group were 14 months and 8 months, and it was not significantly different. But the one-year survival rates according to the kinds of regimens (TS-1 or TS-1/CDDP group) were significantly different (P=0.0014). The incidences of grade 3 or 4 adverse effects were 18%, respectively. Conclusion：The anti-tumor efficacy and safety of TS-1 and TS-1 plus CDDP in unresectable or recurred gastric cancer patients seemed to be high with modest adverse effects, thus suggesting the possible use of this regimen for unresectable or recurred gastric cancer patients.

Adenovirus carrying TIMP-3: A potential tool for cervical cancer treatment

Objective. Previous studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in cervical cancer progression. Tissue inhibitor of metalloproteinases-3 (TIMP-3) can inhibit all of MMPs, and its overexpression can retard many kinds of tumor growth. Especially, a potent bystander effect would make it to be more advisable for treating cervical cancer whose primary growth pattern is to invade adjacent structures. These characters prompted the authors to explore its further applicability in human cervical cancer. Methods. We constructed a replication deficient adenoviral vector carrying TIMP-3 (Ad-TIMP-3). It was transferred into different cervical cancer cell lines in vitro and was injected into the tumor xenografts of nude mice in vivo. Results. Overexpression of TIMP-3 by adenovirus vector arrested cervical cancer cells in G 2/M phase. It also promoted growth inhibition of cancer cells by bystander effects. Ad-TIMP-3 infection produced a more potent cell killing effect than Ad-p53 ( P < 0.05). A synergic effect was observed when Ad-TIMP-3 and cisplatin (cDDP) were used in combination ( D < 1). In vivo, Ad-TIMP-3 could inhibit cervical cancer xenografts growth. Compared with Ad-TIMP-3 and cDDP groups, tumor growth in Ad-TIMP-3 combined with cDDP group was inhibited more significantly ( P < 0.05). Conclusion. These findings indicated that Ad-TIMP-3 bear a therapeutic potential for cervical cancer.

6500 ORAL Randomized phase II trial using concomitant chemoradiation plus induction (I) or consolidation (C) chemotherapy (CT) for unresectable stage III non-small cell lung cancer (NSCLC) patients (pts). Mature results of the SLCG 0008 study

To analyse the results achieved with radio-chemotherapy (RTCT) or radiotherapy alone (RT) in elderly patients (pts) affected with squamous cell anal cancer.From 1990 to 2002, 62 pts aged ≥70 years were treated with RT (14) or RTCT (48). There were 9 stage I, 29 stage II, 11 stage IIIa and 13 stage IIIb. MMC + 5FU was given concomitantly with RT in an early period, later replaced by Cddp + 5FU. In the RTCT group, 36 Gy were delivered to pelvic + inguinal lymph nodes, with a tumor boost (18 Gy).Stage II fared significantly better than stage III in terms of locoregional control (LRC) but not overall survival (OS). Pts treated with RTCT had improved LRC, but not OS. LRC was 81% at 3 and 5 years for the RTCT group; the RT group had a LRC of 61% at 3 years. There were more locoregional relapses in the MMC group (29%) versus the Cddp group (19%) and in pts treated with a split (32%) versus no split (19%). No G3 acute toxicity was observed in the RT group; in the RTCT group 15 pts (31%) developed a G3+ acute toxicity. G3+ late damage occurred in 2 pts in the RT only group and in 3 pts in the RTCT group.Elderly people considered fit for RTCT should undergo the same schedules used for younger people. MMC or Cddp + 5FU are feasible in the elderly, even without a planned split.

Relationship between Expression of Vascular Endothelial Growth Factor in Tumor Tissue from Gastric Cancers and Chemotherapy Effects: Comparison between S-1 alone and the Combination of S-1 plus CDDP

We have reported that vascular endothelial growth factor (VEGF) expression in gastric cancers might be a selective marker between 5-fluorouracil (5-FU) and a combination of 5-FU plus cisplatin (CDDP). In this study, the relationship between VEGF expression and effects of S-1 with and without CDDP is investigated. The subjects were 44 patients treated with S-1 (40 mg/m2, twice daily, days 1-28, repeated every 6 weeks) and 24 patients treated with S-1 plus CDDP (S-1 40 mg/m2, twice daily, days 1-21, CDDP, 60 or 70 mg/m2, day 8, repeated every 5 weeks). VEGF expression in pretreatment endoscopic biopsy samples was assessed immunohistochemically. Median survival times (MST) of the patients treated with S-1 and S-1 plus CDDP were 344 and 388 days. Among evaluable patients, the response rates of patients with VEGF (+) and (-) tumors to S-1 were 40% (6/15) and 54% (13/24), and to S-1 plus CDDP, 79% (15/19) and 80% (4/5). While the survival of patients with VEGF (-) tumors was slightly longer than those with VEGF (+) tumors in the S-1 group (MST, 425 versus 308 days, P = 0.42), patients with VEGF (+) tumors survived remarkably longer than those with VEGF (-) tumors in the S-1 plus CDDP group (MST, 570 versus 333 days, P = 0.19). Similarly to our previous study, it is suggested that the effects of adding CDDP to S-1 might be more remarkable in gastric cancer patients with VEGF (+) tumors than in those with VEGF (-) tumors. These results should be confirmed in a large phase III study.

抗がん剤投与に伴う栄養指標への影響

CDDP(Cisplatin) and CBDCA(Carboplatin) are likely to cause nausea and vomiting,which are considered to be factors lowering QOL for patients undergoing chemotherapy.In the present study,our Nutrition Support Team(NST) investigated the influence of cancer chemotherapy regimens using CDDP or CBDCA on ALB(serum albumin value) and TP(serum total protein).All measurements indicated that ALB and TP levels were significantly decreased after chemotherapy(ALB :CDDP p<0.001 CBDCA : p=0.002 TP : CDDP p<0.001 CBDCA p<0.001).Decreases were greater in the CDDP group than in the CBDCA group.ALB decreased by approximately 15% in the CDDP group compared to a decrease of about 6% in the CBDCA group.Decreases of TP were approximately 14% and 5%,respectively.Though we cannot conclude that decreases in ALB and TP levels are definitely due to platinum drugs,we considered that there is a strong relationship between them and the decreases and that CDDP is more likely to cause vomiting and nausea than CBDCA.These findings convince us that the NST needs to continuously monitor the nutritional needs of patients undergoing chemotherapy with platinum drugs even if their nutritional condition was good before chemotherapy.

Silymarin Modulates Cisplatin-Induced Oxidative Stress and Hepatotoxicity in Rats

Cisplatin (CDDP) is a widely used anticancer drug, but at high dose, it can produce undesirable side effects such as hepatotoxicity. Because silymrin has been used to treat liver disorders, the protective effect of silymarin on CDDP-induced hepatotoxicity was evaluated in rats. Hepatotoxicity was determined by changes in serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST], nitric oxide [NO] levels, albumin and calcium levels, and superoxide dismutase [SOD], glutathione peroxidase [GSHPx] activities, glutathione content, malondialdehyde [MDA] and nitric oxide [NO] levels in liver tissue of rats. Male albino rats were divided into four groups, 10 rats in each. In the control group, rats were injected i.p. with 0.2 ml of propylene glycol in saline 75/25 (v/v) for 5 consecutive days [Silymarin was dissolved in 0.2 ml of propylene glycol in saline 75/25 v/v]. The second group were injected with CDDP (7.5 mg /kg, I.P.), whereas animals in the third group were i.p. injected with silymarin at a dose of 100 mg/kg/day for 5 consecutive days. The Fourth group received a daily i.p. injection of silymarin (100 mg/kg/day for 5 days) 1 hr before a single i.p. injection of CDDP (7.5 mg/kg). CDDP hepatotoxicity was manifested biochemically by an increase in serum ALT and AST, elevation of MDA and NO in liver tissues as well as a decrease in GSH and the activities of antioxidant enzymes, including SOD, GSHPx in liver tissues. In addition, marked decrease in serum NO, albumin and calcium levels were observed. Serum ALT, AST, liver NO level, MDA was found to decreased in the combination group in comparison with the CDDP group. The activities of SOD, GSHPx, GSH and serum NO were lower in CDDP group than both the control and CDDP pretreated with silymarin groups. The results obtained suggested that silymarin significantly attenuated the hepatotoxicity as an indirect target of CDDP in an animal model of CDDP-induced nephrotoxicity.

THE EFFECT OF ANTIOXIDANT CAFFEIC ACID PHENETHYL ESTER (CAPE) ON SOME ENZYME ACTIVITIES IN CISPLATIN-INDUCED NEUROTOXICITY IN RATS

Aim: Neurotoxicity is the next common side effect of cisplatin (CDDP)-based chemotherapeutics following nephrotoxicity. We investigated the effect of CDDP on some brain metabolic enzyme activities such as hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PD), lactate dehydrogenase (LDH), and malate dehydrogenase (MDH) in an experimental model of CDDP toxicity, and examined the protective role of Caffeic acid phenethyl ester (CAPE), a phenolic antioxidant derived from the honeybee propolis, on the enzyme activities mentioned above. Methods: Female Wistar albino rats were divided into three groups: sham operation group (n:6), CDDP group (n:9), and CAPE + CDDP group (n:8). All the chemicals used were applied intraperitoneally. HK, G6PD, LDH, and MDH activities were determined spectrophotometrically in the brain supernatant at the end of the surgical procedures. Results: There were decreased G6PD activities and increased MDH activities in CDDP group compared to control group (p<0.05, p<0.05). LDH activities were increased in CAPE+CDDP group compared to CDDP group (p<0.001). Conclusion: These results provide a new point of view on the glucose metabolizing enzymes of brain tissue affected from CDDP and the protective effects of CAPE on these enzymes.

Modified intrapleural cisplatin treatment for lung cancer with positive pleural lavage cytology or malignant effusion

We evaluate the efficacy and safety of the modified intrapleural cisplatin treatment for lung cancer patients with positive pleural lavage cytology or malignant effusion. The treatment was performed for seven patients with malignant effusion and 18 patents with positive pleural lavage cytology. After pulmonary resection, the pleural cavity was filled with cisplatin with a normal saline solution for 30 min. Complications and survival of the patients were evaluated. The chest tube duration were significantly prolonged in the treatment (CDDP) group (5.7 +/- 3.6 vs. 2.8 +/- 2.6 days). We had one operative death that developed a bronchial fistula; however, the other complications were not severe. The mortality rate was 4% and the morbidity rate was 60%. We experienced two carcinomatous pleuritis in the CDDP group. The median survival time of the CDDP group was 47.0 +/- 11.1 months and the 3- and 5-year survival rate was 52.6% and 11.3%, respectively. We were able to perform this treatment for these advanced lung cancer patients, which had the preventive effect of carcinomatous pleuritis. This therapy shows the possibility of a treatment that might lead to an improvement in the prognosis of these patients, without causing severe complications.

Efficacy and Safety Profile of TS-1 or TS-1/CDDP in Patients with Advanced Gastric Cancer

Purpose: Although several chemotherapy regimens used against advanced gastric cancer (AGC) have been studied extensively in an attempt to further improve the prognosis of patients, to date, no standard chemo-therapeutic regimens have been established. The aim of this study was to determine the anti-tumor efficacy and safety of TS-1 or TS-1 plus cisplatin (CDDP). Material and Methods: We treated 78 patients with AGC either with of TS-1 for 28 days, which was followed by a 2-week rest, or with of TS-1 for 21 days and of CDDP on day 8 every 5 weeks. Results: Tumor response rates in the neoadjuvant chemotherapy group and in the recurrent or post-palliative surgery group were 87.5% and 32.4%, respectively, and they were 28.6% and 48.4%, respectively, in the TS-1 group and the TS-1 plus CDDP group. The survival rates in the recurrent and the post-palliative surgery group were significantly different according to the degree of tumor response (P=0.0016), but the one-year survival rates according to the kinds of regimens (TS-1 or TS-1/CDDP group) were not significantly different. The incidences of grade 3 or 4 adverse effects in the TS-1 and the TS-1/CDDP groups were 14.3% and 36.8%, respectively. Conclusion: The anti-tumor efficacy and safety of TS-1 and TS-1 plus CDDP in Korean patients with AGC seemed to be high with modest adverse effects, thus suggesting the possible use of this regimen as a standard chemotherapy for gastric cancer.

Evaluation of the Observed Cisplatin Nephrotoxicity in Adult Cancer Inpatients: A Historical Cohort Study by Using Clinical Data Warehouse

Objectives: To evaluate the observed cisplatin (CDDP) nephrotoxicity in adult cancer inpatients by using Clinical Data Warehouse (CDW). Methods: A historical cohort study was conducted in Osaka University Hospital. Adult cancer inpatients (2000/1/1-2004/12/31) whose sCr level on admission < 1.2 mg/dl were divided into three groups based on the exposure of CDDP, non-exposure of CDDP but with (Non-CDDP group) or without (Control group) other anticancer agents. Patients whose sCr ≥ 1.2 mg/dl at least once during hospitalization were considered as those having the occurrence of the nephrotoxicity and their sCr < 1.2 mg/dl on discharge as having recovered from the nephrotoxicity. After matching patients' characteristics through stratification and randomization, the rates of nephrotoxicity and the rates of recovery among the three groups were compared. Logistic regression was performed to investigate the CDDP doses — nephrotoxicity associations. Results: The rate of observed nephrotoxicity was 28.0% (127/454) in the CDDP group, 19.6% (89/454) in the Non-CDDP group and 19.4% (88/454) in the Control group, respectively (p = 0.002). The risk ratio (RR) was 1.43 (95%CI: 1.13-1.81), 1.44 (95%CI: 1.14-1.83) and 1.01 (95%CI: 0.78-1.41) between CDDP vs. Non-CDDP, CDDP vs. the control and Non-CDDP vs. the Control group. The recovery rate was 69.3% (88/127), 61.8% (55/89) and 69.3% (61/88) in the three groups, respectively (p = 0.903). The observed CDDP nephrotoxicity was dose associated (p = 0.037) but not total accumulated doses associated (p = 0.144). Conclusions: CDDP is a risk factor to the observed nephrotoxicity in our adult cancer inpatients. The observed nephrotoxicity was CDDP dose related and is considered to be reversible.

Radiation therapy combined with cis-diammine-glycolatoplatinum (nedaplatin) and 5-fluorouracil for Japanese stage Ii–Iv esophageal cancer compared with cisplatin plus 5-fluorouracil regimen: a retrospective study

To evaluate the treatment outcome of radiotherapy combined with cis-diammine-glycolatoplatinum (nedaplatin) plus 5-fluorouracil (5-FU) for esophageal cancer. From January 2000 to December 2004, a total of 12 esophageal cancer patients with locally advanced and metastatic esophageal cancer (stages II-IVB) were treated with radiation therapy (50.4 Gy) combined with nedaplatin (80 mg/m(2), bolus infusion) and 5-FU (800 mg/m(2)/24 h, continuous infusion for 4 days) (NDP group). We compared the data with those of patients during the same period receiving a different chemotherapy regimen consisting of cisplatin (75 mg/m(2), bolus infusion) and 5-FU (1000 mg/m(2)/24 h, continuous infusion for 4 days) (n = 29, CDDP group) combined with the same radiation therapy. The median survival period was 11.5 months in the NDP group and 13.1 months in the CDDP group. The overall survival rates at 1-, 2-, and 3-years were 40%, 13%, and 13% in the NDP group and 56%, 42%, and 8% in the CDDP group (P = 0.2472), respectively. Grade III and IV leukocytopenia was observed in six (50%) and none of the patients in the NDP group and 14 (48%) and seven (24%) in the CDDP group, respectively. Grade III thrombocytopenia was observed in three (25%) in the NDP group and four (14%) in the CDDP group. Radiation combined with nedaplatin and 5-FU is a safe and effective method for treating esophageal cancer. We recommend that NDP should be used rather than dose-reduction of CDDP combined with 5-FU in patients with impaired renal function as indicated by low creatinine clearance value (40-60 mL/min).

Long-term outcome of S-1 and cisplatin combination therapy in patients with advanced or recurrent gastric cancer

Although combination therapy of S-1 and cisplatin (CDDP) has excellent efficacy against gastric cancer, the effect of the treatment on survival has been unclear. The aim of this study was to evaluate the long-term outcome of this combination therapy. Sixty-three patients with advanced or recurrent gastric cancer were treated with S-1, with or without CDDP, as first-line chemotherapy, and the clinical results were compared retrospectively. S-1 was administered orally at a standard dose of 80 mg/m(2). In the treatment of the S-1 group, S-1 was given for 28 consecutive days, followed by a 14-day rest. In the treatment of the S-1/CDDP group, S-1 was given for 21 consecutive days, followed by a 14-day rest, and CDDP, at 60 mg/m(2), was infused on day 8. The incidence of adverse reactions of more than grade 3 was 22.5% in the S-1 group and 43.5% in the S-1/CDDP group, and the treatment compliance was better in the S-1 group. The overall response rate was 25.9% in the S-1 group, and 36.8% in the S-1/CDDP group. The combination of S-1 with CDDP had better effects on the primary lesion and on differentiated-type carcinoma than S-1 alone. However, there was no difference in survival between the two patient groups. The median survival time after the initiation of treatment in the S-1 group was 322 days, and that in the S-1/CDDP group was 319 days. Our results suggest that the combination of CDDP with S-1 does not improve the long-term outcome of S-1 therapy.

Antitumor effect of Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with cytotoxic agent on murine hepatocellular carcinoma

To investigate the inhibitory effect of gefitinib combined with cytotoxic agent cisplatin (CDDP) on hepatocellular carcinoma (HCC). Female Kunming mice and H22 hepatocarcinoma cells were used. Gefitinib at daily dose of 100 mg/kg body weight (BW) or lecithin liquid was given by gastrogavage once a day for 5 or 10 successive days. CDDP or normal saline (NS) was administered intraperitoneally (i.p.) once a day for 5 successive days. Mice were randomly divided into control group (lecithin, or NS, i.p.), CDDP group (daily dose, 1.2 mg/kg BW; d1-5, or d6-10), Gefitinib (d1-5, or d6-10, or d1-10), and Gefitinib combined with CDDP groups. The inhibitory rate (IR) of tumor, net BW, spleen index (SI), thymus index (TI) and the amount of peripheral blood cells of mice were detected on the 12th experiment day. The growth of HCC in mice was inhibited by Gefitinib alone (IR: 41% in d1-10 group and 30% in d1-5 group, respectively) or CDDP alone (IR: 32-54% in d1-5 group or d6-10 group). The highest inhibitory effect (IR: 56%) on HCC growth was observed in Gefitinib (d1-10) combined with CDDP (d1-5) group. Higher inhibition was also observed in CDDP (d1-5) followed by Gefitinib (d6-10) group than that in Gefitinib (d1-5) followed by CDDP (d6-10) group (IR: 61% vs 36%, P < 0.01) in the independent study. Net BW, SI, TI and the amount of blood cells of mice in Gefitinib alone group were not significantly different from those in control groups. Gefitinib can significantly inhibit the growth of murine H22 hepatocellular carcinoma. If Gefitinib is used after CDDP treatment in animal experiments, the inhibitory effect could be enhanced.

Which is more recommendable as the second line chemotherapy to S-1 for advanced gastric cancer; combination of CPT-11 plus CDDP or weekly paclitaxel?

4136 Background: Since S-1 has the highest response rate as a single-agent for advanced gastric cancer (AGC) is usually used as the first line chemotherapy in Japan. Imamura et al. reported that combination of CPT-11 plus CDDP treatment for AGC showed a good response rate (52%) and its adverse reactions were mild (ASCO 2002; 622 abstr.). On the other hand Arai et al. reported that Paclitaxel was active in AGC with a good safety profile, feasibility and activity as salvage treatment (ASCO 2003; 1040 abstr.). The aim of this study is to evaluate which is recommendable as a subsequent second line chemotherapy to S-1;depends on document reviewcombination of CPT-11 plus CDDP (group A) ordepends on document reviewPaclitaxel (group B). Methods: The eligibility criteria included microscopically proven advanced and/or recurrent gastric cancer with measurable metastatic lesions; adequate organ functions; oral intake is possible; ECOG PS of 0, 1 or 2; an age of <= 75; no prior chemotherapy; and provision of written informed consent. S-1 was administered orally 40mg/m2 twice a day for 28 consecutive days followed by a 14-day rest period. When tumor progression is observed, the second line treatment followed after 2 weeks rest. The treatment regimen consisting of CPT-11 (60mg/m2) on days 1 and 15 and CDDP (10mg/m2) on days 1, 2, 3, 15, 16, and 17 (group A; 14 patients) or Paclitaxel (70mg/m2) by on days 1, 8, 15 (group B; 11 patients) was repeated every 4 weeks. Results: The overall response rate (RR) of S-1 as the first line chemotherapy was 36% (2 CRs, 7 PRs, 10 SDs and 6 PDs). Neither grade 4 hematological toxicities nor grade 3 or 4 febrile neutropenia occurred. RRs of second line therapy in group A and B were 36% (5 PRs, 6 SDs and 3 PDs) and 36% (1 CR, 3 PRs, 4 SDs and 3 PDs), respectively (P=0.6784). There were no treatment-related deaths. After median follow up periods from the first line chemotherapy of 875 (488–1171) and 319 (163–1027) days, 1-year survival rats were 30% (MST; 355 days) and 89% in group A and B, respectively (P=0.026). Conclusion: Both regimens showed similar RR and Paclitaxel as the second line showed a better one-year survival rate than a combination of CPT-11 plus CDDP. No significant financial relationships to disclose.