Effect of repeated intraperitoneal chemotherapy with epirubicin on the hepatic transport of bile acids and their enterohepatic circulation

The effect of repeated intraperitoneal perfusion with epirubicin on the clearance of 14C-taurocholate by the liver and the enterohepatic circulation of the synthetic bile acid 75-SeHCAT were investigated using a rat model. After six treatments there was no significant difference in the transport rate constants (plasma to liver, liver to bile and liver to plasma) between and within the saline and epirubicin groups. Similarly, there were no differences detected between the groups for the parameters derived from these transport rate constants. Thus the initial plasma clearance after six perfusions was 39 +/- 9, and 36 +/- 11 ml/min/kg in the epirubicin and saline groups respectively. The excretory efficiency of the liver at this stage was identical: 67 +/- 10% in the epirubicin treated animals and 67 +/- 6% in the saline controls. A deterioration in the SeHCAT retention was observed after repeated intraperitoneal perfusion in both groups. This was significant only in the cytotoxic group, between the first and sixth epirubicin perfusion: 59 +/- 9% vs 48 +/- 9% at 24 h (P = 0.03), 31 +/- 8% vs 22 +/- 5% at 48 h (P = 0.019) and was not cumulative beyond this stage. These findings indicate that repeated intraperitoneal perfusion chemotherapy with epirubicin does not impair bile acid clearance by the hepatocyte. The decrease in the retention of SeHCAT is unlikely to be the result of epirubicin-induced ileal mucosal damage since the reduction was not cumulative beyond 48 h of administration of the compound.     

胃癌术后早期表阿霉素腹腔内化疗的药代动力学变化

对１２例进展期胃癌患者根治术后用表阿霉素灌注，观察腹腔液和血中表阿霉素的浓度变化。方法术后第１天用表阿霉素１０ｍｇ（０．２ｍｇ／ｋｇ）加入１０００ｍｌ（２０ｍｌ／ｋｇ）乳酸钠林格氏液行腹腔保留灌注。用高效液相色谱法测定腹腔液和外周静脉血中表阿霉素在２４小时内的浓度变化。结果表阿霉素在术后早期腹腔内化疗时腹腔液峰值浓度比外周静脉高２２８倍，且持续时间长；腹腔液总平均浓度比外周静脉高１６７倍。结论进展期胃癌术后早期表阿霉素腹腔内化疗对防治术后腹腔复发，具有药代动力学优势和合理性。     

Effects of ICRF-187 on the cardiac and renal toxicity of epirubicin in spontaneously hypertensive rats

Summary A study was made of the protective effect of ICRF-187 against the cardiotoxicity and nephrotoxicity produced by epirubicin in spontaneously hypertensive rats (SHR). A total of 20 SHR were divided into 4 groups of 5 animals; the first group received i.v. injections of 1.5 mg/kg epirubicin; the second was treated with i.p. injections of 50 mg/kg ICRF-187 30 min before receiving 1.5 mg/kg epirubicin; the two remaining groups received ICRF-187 and saline, respectively, and served as controls. The experiment was terminated after 12 weekly injections (total cumulative dose of epirubicin, 18 mg/kg). Morphologic studies showed that severe cardiomyopathy manifested by myofibrillar loss and dilatation of the sarcoplasmic reticulum and nephropathy characterized by tubular dilatation and atrophy, protein casts in the lumina of renal tubules, and glomerular vacuolization occurred in SHR given epirubicin alone. Animals receiving the combination of ICRF-187 and epirubicin showed a marked reduction in the severity of cardiomyopathy and a moderate reduction in nephropathy. These changes, and their modification by ICRF-187, were similar to those we have previously observed in SHR treated with total cumulative doses of 12 mg/kg doxorubicin. Such pathologic changes were absent in animals receiving ICRF-187 or saline alone. The findings of this study suggest that ICRF-187 can be used clinically to prevent the cardiotoxicity of epirubicin, particularly in situations in which this drug may have to be given either in large doses or to patients at high risk of developing anthracycline cardiotoxicity.     

Pharmacologic study of intraperitoneal docetaxel in gastric cancer patients with peritoneal dissemination

This study was designed to evaluate the pharmacokinetics and toxicity of docetaxel administered via an intraperitoneal (i.p.) route for patients with gastric cancer. Eleven patients with peritoneal dissemination were entered into this trial. Patients were treated with 45 mg/m2 of i.p. docetaxel administration in 1 l of saline. Peak peritoneal concentration was 40.0 +/- 14.5 micrograms/ml and peritoneal concentration at 24 hours after drug administration was 4.3 +/- 3.9 micrograms/ml. The median pharmacokinetic advantage (AUC peritoneal/AUC plasma) was 515 (range 22-1, 770). Grade 2 and 3 toxicities included 5 episodes of diarrhea; 3 of abdominal pain; 3 of ascites; 2 of alopecia; and 1 of neutropenia. We conclude that intraperitoneal docetaxel administration is well tolerated and provides a peritoneal pharmacokinetic advantage for the treatment of peritoneal dissemination.     

Docetaxel and epirubicin as first-line treatment for patients with metastatic breast cancer: a Minnie Pearl Cancer Research Network Phase II trial

BACKGROUND: Taxanes and anthracyclines are the two most active classes of cytotoxic agents in the treatment of patients with metastatic breast cancer. Epirubicin, a doxorubicin analog, has shown modest toxicity advantages when compared to the parent compound. In this Phase II trial, we evaluated the activity and toxicity of a docetaxel/epirubicin combination. METHODS: Thirty patients with previously untreated metastatic breast cancer were treated with docetaxel 60 mg/m2 one-hour IV infusion and epirubicin 90 mg/m2 IV bolus; both drugs were repeated at 21-day intervals. Patients were evaluated for response after 2 courses of treatment; responding and stable patients continued treatment for a total of 6 courses. RESULTS: Fifteen patients (50 percent) had objective response to treatment; an additional 20 percent of patients had stable disease of more then 6 months duration. The median and 2-year progression-free survivals were 12 months and 34 percent, respectively. Median and 2-year overall survivals were 18 months and 42 percent, respectively. Myelosuppression was the most common Grade 3/4 toxicity, and 2 patients in this trial (6 percent) had treatment-related mortality associated with severe sepsis. CONCLUSION: The results of this Phase II trial confirm previous observations regarding the efficacy and toxicity profile of the docetaxel/epirubicin combination. This combination has activity similar to other taxane/anthracycline combinations used in the first-line treatment of metastatic breast cancer.     

Pharmacokinetics and toxicity of intraperitoneal cisplatin combined with regional hyperthermia

Hyperthermia (HT) potentiates in vitro cytotoxicity of cisplatin, providing a rationale for HT enhancement of cisplatin effect in vivo. In this study, regional abdominal HT was combined with intraperitoneal (IP) cisplatin in canines to characterize temperature distributions, as well as pharmacokinetics and toxicity of IP cisplatin with and without HT. Cisplatin (65 mg/m2) in normal saline was administered IP with a two-hour dwell time in ten Beagle dogs. Five of the ten dogs were randomly selected to receive concurrent regional microwave-producing HT at approximately 41.5 degrees C (IP) for a 60-minute period. Systemic temperatures in heated animals ranged from 37 degrees C to 40 degrees C; IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP cisplatin concentrations were ten to 22 times greater than serum levels; the IP drug half-lives were 133 +/- 9 minutes and 68 +/- 15 minutes in heated and unheated dogs, respectively (P less than .001). Total concentrations of serum and urine cisplatin did not differ between the heated and unheated controls. The area under the concentration v time curve for free, ultrafilterable cisplatin in serum in units of percent minutes was 40 +/- 8 in heated and 60 +/- 7 in unheated controls (P = .006). Except for transient nausea and vomiting, no evidence of serious toxicity was observed in serum chemistries or histopathologic sections at 21 days post-treatment. Experiments involving in vitro incubation of cisplatin in normal saline were performed as a function of saline temperature; these showed that the amount of reactive cisplatin metabolites formed increased linearly with temperature by approximately 30% from 38 degrees C to 44 degrees C. This study supports the hypothesis that, with IP temperature elevation, there is an increased rate of generation and retention of reactive metabolites of cisplatin in the peritoneal cavity relative to unheated controls. In spite of these differences in pharmacokinetics, no significant toxicity was encountered. This study provides a model for treatment of IP malignancy such as ovarian carcinoma with IP cisplatin and regional HT.     

Effect of yttrium-90-labeled anti-carcinoembryonic antigen monoclonal antibody on the morphology and phenotype of human tumors grown as peritoneal carcinomatosis in athymic mice

Grossly visible peritoneal carcinomatosis resembling that seen in man was produced in athymic mice 7 days after intraperitoneal injection of 8 x 10(5) cells of the carcinoembryonic antigen (CEA)-producing human colon carcinoma cell line LS174T. The mice received intraperitoneal injections of 40 to 160 microCi of yttrium-90 (90Y)-labeled anti-CEA monoclonal antibody (MAb). When the mice were killed 12 days after injection, a significant inhibition of tumor growth, ranging from 40% to 95%, was observed in the treated animals when compared to the growth of tumors in the untreated animals (P less than 0.001). No mortality secondary to the therapy was seen. The bone marrow was depleted significantly at the higher doses of labeled MAb, but total recovery was observed 4 weeks after treatment. Histologically, the treated tumors showed extensive radiation effects early in the posttherapy period and massive necrosis at later times. Minute foci of viable tumor remained in the periphery. New tumor outgrowths with histologic features similar to those in the untreated controls began to appear 3 weeks after therapy. The CEA expression of the treated tumors was similar to that of the untreated controls during the early posttreatment period, diminishing progressively as the tumors became necrotic. Newly grown tumor nodules in the treated animals lacked significant CEA expression both initially and at later times. Our studies suggest that therapy with 90Y-anti-CEA MAb therapy results in selection of tumor clones lacking CEA, and that a single large dose of 90Y-MAb should be more effective than multiple fractions of smaller doses.     

Docetaxel: pharmacokinetics and tissue levels after intraperitoneal and intravenous administration in a rat model

PURPOSE: Docetaxel (Taxotere) has been shown to possess a broad spectrum of antitumor activity against various malignancies such as breast and lung cancers, but also against intraabdominal malignancies such as mesothelioma and ovarian cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the prolonged high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue distribution of intraperitoneal versus intravenous docetaxel. METHODS: The study animals were comprised of 15 Sprague Dawley rats. They were randomized into three groups according to dose and route of administration (15 mg/kg intravenously, 15 mg/kg intraperitoneally, or 150 mg/kg intraperitoneally) and then given a single dose of docetaxel. Blood and peritoneal fluid were sampled using a standardized protocol for 90 min. At the end of the procedure the rats were killed and docetaxel concentrations in peritoneal fluid, plasma and selected tissue samples were determined by high-performance liquid chromatography (HPLC). RESULTS: When docetaxel was delivered at 15 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (110.6 microg/ml.min) as compared to intravenous administration (0.043 microg/ml.min; P=0.0079). This represents more than a 2500-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. Conversely, at the same dose the AUC of the plasma was significantly lower with intraperitoneal administration (0.11 microg/ml.min) as compared to intravenous administration (4.25 microg/ml.min; P=0.0079). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 976 for intraperitoneal administration as opposed to 0.01 for intravenous delivery. The AUC ratio for intraperitoneal docetaxel at 150 mg/kg was 3004. There were significantly different concentrations in the heart and the abdominal wall ( P=0.0079) and in the stomach and colon ( P=0.0159) when intraperitoneal versus intravenous docetaxel were compared. CONCLUSIONS: The exposure of the peritoneal surface to docetaxel is significantly increased and the systemic exposure decreased with intraperitoneal docetaxel administration. Also, high concentrations of drug were observed in the abdominal wall and in the colon after intraperitoneal delivery. This experiment suggests the need for clinical studies to evaluate intraperitoneal administration of docetaxel in humans.     

腹腔灌注顺铂射频热疗联合EF方案治疗晚期胃癌临床观察

目的:观察腹腔灌注顺铂(DDP)射频热疗联合静脉注射表阿霉素(EPI)、5氟尿嘧啶(5FU)治疗晚期胃癌的疗效及安全性。方法:共入组晚期胃癌56例,其中管状腺癌5例,低分化腺癌26例,黏液腺癌16例,印戒细胞癌9例,治疗方案为DDP40mg/m2加入44℃生理盐水1500～2000mL中,行腹腔灌注。然后腹腔射频热疗1.5h,温度42℃～43℃,d1、d8;EPI50mg/m2,静脉冲入,d1;5FU500mg/m2,静脉滴入6～8h,d1～d5。21d为1个周期,至少应用4～6个周期。结果:可评价疗效51例中,CR4例,PR25例,SD16例,PD6例,总有效率为56.9%(29/51),中位肿瘤进展时间5.3个月,中位生存期12.4个月,主要不良反应为骨髓抑制、恶心、呕吐。结论:腹腔灌注DDP射频热疗联合静脉注射EPI、5FU治疗晚期胃癌疗效较好,毒性可耐受。     

Pharmacologic study of intraperitoneal paclitaxel in gastric cancer patients with peritoneal dissemination

This study was designed to evaluate the pharmacokinetics and toxicity of paclitaxel administered via an intraperitoneal (i.p.) route for patients with gastric cancer. Fourteen patients with peritoneal dissemination were entered in the trial. Three distinct dose levels from 120 to 180 mg/body were studied. A major pharmacokinetic advantage (550-2,000 fold) for peritoneal cavity exposure compared with the systemic compartment was seen following intraperitoneal delivery of paclitaxel. The dose-limiting toxicity was found to be abdominal pain at 180 mg/body. Grade 2 toxicity included 1 episode of neutropenia and grade 1 toxicities included 1 case of finger-numbness and 2 of alopecia. We conclude that intraperitoneal paclitaxel administration is well tolerated and provides a peritoneal pharmacokinetic advantage for the treatment of peritoneal dissemination.     

顺铂和氟尿嘧啶交替腹腔灌注并ECF方案治疗原发性腹膜癌疗效观察

目的观察顺铂（DDP）、氟尿嘧啶（5-Fu）交替腹腔灌注并ECF（表阿霉素、顺铂、5-氟尿嘧啶）方案治疗原发性腹膜癌腹水控制效果及近期临床疗效、不良反应。方法DDP、5-Fu交替腹腔灌注并ECF方案静脉化疗,21天为一周期,共6~8周期,至少4周期评定疗效。结果15例患者,腹水控制率86.6%;总有效率（RR）86.6%,其中完全缓解（CR）26.6%,部分缓解（PR）60%;主要不良反应为Ⅱ~Ⅲ度骨髓抑制。结论顺铂、氟尿嘧啶交替腹腔灌注并ECF方案治疗原发性腹膜癌腹水控制效果好,近期疗效好,不良反应轻,治疗费用低,可作为原发性腹膜癌的一线治疗方案推广。     

Treatment of aggressive non-Hodgkin's lymphoma with dose-intensified epirubicin in combination of cyclophosphamide, vincristine, and prednisone (CEOP-100): a phase II study.

Epirubicin is an agent with a lower incidence of cardiotoxicity and myelotoxicity compared with doxorubicin; and it is active in patients with non-Hodgkin's lymphoma (NHL). Our aim was to define the therapeutic efficacy and toxicity of dose-intensified epirubicin in combination with cyclophosphamide, vincristine, and prednisone (CEOP) in patients with diffuse large-cell NHL. Previously untreated patients aged between 15 and 75 years, with at least one measurable lesion, adequate liver, renal, cardiac functions, and no central nervous system involvement were included in the study. The planned chemotherapy regimen CEOP consisted of cyclophosphamide 750 mg/m2, epirubicin 100 mg/m2, and vincristine 1.4 mg/m2 intravenously on day 1 and 100 mg prednisone taken orally on days 1 to 5. Courses were repeated every 21 days. Patients with stage I and II received four cycles of chemotherapy followed by involved-field radiotherapy, and patients with stage III and IV received six cycles of chemotherapy followed by radiotherapy to bulky lymph node sites. Seventy-five patients were enrolled in the study. The complete response rate was 83.8%, and 72 patients were assessable for toxicity. The most common toxicity was myelosuppression; 13.9% of the patients had grade III-IV neutropenia. Severe mucositis, diarrhea, and emesis were uncommon (<10%). At a median follow-up period of 41 months, the 5-year progression-free survival and overall survival rates were 63.5% and 65.3%, respectively. Increasing the dose intensity of epirubicin can yield a similar complete response rate compared with the regimens used in NHL without significantly increasing the toxicity rate associated with chemotherapy. The role of dose-intensive epirubicin should be investigated further in future randomized trials.     

The effect of chronic ethanol consumption on the tumorigenicity of N-nitrosopyrrolidine in male Syrian golden hamsters

The effect of oral administration of ethanol on the tumorigenicity of N-nitrosopyrrolidine (NPYR) in chow-fed male Syrian golden hamsters has been investigated. Groups of hamsters were given tap water, 7.4% ethanol or 18.5% ethanol-water mixtures 4 weeks prior to and throughout the carcinogen administration period. A total dose of 1 mmol NPYR was administered by intraperitoneal injection to both tap water and ethanol-consuming animals over a 25-week period. Twenty-four hours after the last injection, ethanol-consuming animals were returned to tap water. In control animals treated with NPYR we observed 3/26 animals with tracheal papillomas, and 6/26 animals with hepatic neoplastic nodules. In animals receiving 7.4% ethanol-water mixtures, we observed 6/26 tracheal papillomas, and 17/26 hepatic neoplastic nodules. Similar results were observed in animals receiving 18.5% ethanol. These data indicate that chronic administration of ethanol to chow-fed hamsters increases the incidence of hepatic neoplastic nodules although no differences in the two levels of ethanol were observed.     

Effect of intraperitoneal chemotherapy and fibrinolytic therapy on tumor implantation in wound sites

Failure of surgical treatment for gastrointestinal cancers is often caused by recurrence of the tumor in traumatized peritoneal surfaces. This study examined the effect of intraperitoneal administration of doxorubicin and recombinant tissue plasminogen activator (rt-PA), a fibrinolytic agent, on incidence and volume of postoperative tumor implants in peritoneal wounds. Prior to randomization, a surgical wound was created on the right parietal peritoneum of 110 BDIX rats and 6 × 10⁵ DHD/K12 colon cancer cells were inoculated intraperitoneally (ip). The control group was given an intraperitoneal injection of saline. Five groups received 1 mg/kg of ip doxorubicin at different times postoperatively: at the end of surgery (DO), 3 hr after surgery (D + 3), postoperative day 1 (Dl), postoperative day 3 (D3), and postoperative day 7(D7). In a second set of experiments, five groups of rats received, in addition to postoperative doxorubicin, 5 mg/kg of intraoperative ip rt-PA. Incidence and volume of tumor implants in peritoneal wounds were assessed for each group 20 days after the tumor inoculation. All rats of the control group (incidence = 100%) developed tumor implants in peritoneal wounds. Mean (SD) volume was 16.2 (4.7) mm³. When administered at DO, D + 3, and Dl intraperitoneal doxorubicin reduced significantly the incidence and volume of tumor implants in wounds. Postoperative administration of doxorubicin at D3 and D7 did not affect significantly the incidence and the volume of tumor implants in peritoneal wounds. When rt-PA was administered intraoperatively, ip injection of doxorubicin at any postoperative timing decreased significantly the incidence and volume of tumor implants. In conclusion, ip doxorubicin administered before postoperative D3 may act on tumor cell implanted in peritoneal wounds. Delayed (D3, D7) ip administration of doxorubicin does not prevent the development of tumor implants in peritoneal wounds. Intraoperative administration of rt-PA may significantly increase the efficacy of delayed ip chemotherapy. © 1996 Wiley-Liss, Inc.     

A pilot study of intraperitoneal cisplatin in the management of gastric cancer

BACKGROUND: This phase II trial was designed to evaluate the feasibility,toxicity, relapse pattern and survival following adjuvant intraperitonealcisplatin in patients with gastric cancer at high risk of relapse. PATIENTS AND METHODS: Patients who had undergone complete surgical resection of adenocarcinomaof the stomach and who had positive serosa and/or regional lymphnodes and/or peritoneal washings has insertion of either a Tenckhoffcatheter or temporary peritoneal dialysis catheter and weretreated with cisplatin 60 mg/m² intraperitoneally every 21 daysfor 4–6 courses. Peritoneal lavage or cytology was donebefore each treatment. RESULTS: Eighteen patients were studied. Seventeen patients had serosalinvolvement, 11 had regional lymph node involvement and 2 hadpositive peritoneal washings before treatment. The median numberof courses of chemotherapy was 4 (range 2–6). Radioisotopetracer studies (6 patients) showed good distribution throughoutthe peritoneal cavity. No WHO grade 3/4 toxicity was seen. Twelvepatients (67%) have relapsed, 6 (33%) intra-abdominally, 4 (22%)with hepatic metastases and 2 (11%) outside the abdominal cavity.The median survival was 17 months. CONCLUSIONS: Cisplatin can be administered safely as adjuvant therapy topatients with gastric cancer, however, as single agent therapythe pattern of relapse and subsequent death was similar to thatexpected. The occurrence of distant metastases may argue forsystemic rather than local adjuvant treatment. gastric cancer, intraperitoneal cisplatin     

多西紫杉醇联合氟尿嘧啶腹腔灌注治疗晚期胃癌

 目的 观察多西紫杉醇联合氟尿嘧啶腹腔化疗治疗晚期胃癌的临床疗效及副作用。 方法 多西紫杉醇75mg/m2,静滴,第1天和第8天,氟尿嘧啶1.0g,腹腔灌注,第2天,21天为一周期,共2~4周期。 结果 总有效率为43.24％（16/37）,中位疾病进展时间为5.3月,临床受益反应评价有效者占78.38％（29/37）。主要副作用为血液毒性反应,白细胞下降发生率72.97％。 结论 多西紫杉醇联合氟尿嘧啶腹腔化疗治疗晚期胃癌疗效好,毒性低。     

TRL型体腔循环灌注热化疗系统安全性评估的动物实验

目的:探讨在不同温度下进行体腔恒温循环热灌注化疗(Coelom Continued Circulatory HyperthermiaPerfusion,CCCHP)对实验动物生命体征和腹腔各脏器的影响,以寻求治疗的最适温度和有效控温的途径。方法:应用TRL型体腔循环灌注热化疗系统建立CCCHP动物模型,选用健康杂种家犬16只分别用41℃(分为单纯生理盐水组和顺铂组),42℃(生理盐水组),43℃(生理盐水组)腹腔温度对每组动物CCCHP 3次(临床治疗一个疗程),每次1h,间隔2d。记录犬的生命体征和治疗的各项参数。在每次CCCHP前及最后一次CCCHP 24h后抽取外周血备检肝肾功。CCCHP3次24h后及2周后时每组分别处死2只犬,开腹观察内脏器官的形态学改变,并切取肝、肾等脏器进行病理检查。结果:41℃腹腔温度下3次CCCHP对犬的生命体征及肝肾功无明显影响,肝、肾、脾和肠组织损伤轻微;41℃腹腔温度联合顺铂3次CCCHP也未对犬的正常生理功能造成明显影响;42℃,43℃腹腔温度行3次CCCHP后均对犬的生命体征及肝肾功有不同程度的影响,肝、肾、脾及肠组织均有不同程度的损伤,损伤程度随温度上升而加重。结论:41℃腹腔温度CCCHP 3次,每次1.0h是安全可行的,可以作为CCCHP联合化疗的安全治疗温度。     

Intraoperative hyperthermic versus postoperative normothermic intraperitoneal chemotherapy for colonic peritoneal carcinomatosis: a case–control study

BackgroundCytoreductive surgery and intraperitoneal chemotherapy has improved prognosis in patients with peritoneal carcinomatosis. The main modes of intraperitoneal chemotherapy treatment are peroperative hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic sequential postoperative intraperitoneal chemotherapy (SPIC). The aim of this study was to compare HIPEC and SPIC with respect to overall survival, disease-free survival, morbidity, and mortality in patients with peritoneal carcinomatosis from colon cancer.Patients and methodsA matched case–control study was conducted in patients with surgical macroscopic complete removal of carcinomatosis; matching was according to the peritoneal cancer index score. Thirty-two patients were included, 16 in each group (HIPEC and SPIC). Overall survival, disease-free survival, morbidity, mortality, and clinicopathological parameters were compared.ResultsMedian overall survival was 36.5 months in the HIPEC group and 23.9 months in the SPIC group (P = 0.01). Median disease-free survival for these groups was 22.8 (HIPEC) and 13.0 months (SPIC; P = 0.02). Morbidity was not statistically different, 19% in SPIC and 37% in HIPEC. Postoperative mortality was observed in one patient in each group.ConclusionHIPEC was associated with improved overall survival and disease-free survival compared with SPIC at similar morbidity and mortality, suggesting that HIPEC is the treatment of choice in colonic peritoneal carcinomatosis.     

Doubling epirubicin dose intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rates. An international randomised phase III study in metastatic breast cancer

Purpose: A phase III study was performed in patients with metastaticbreast cancer (MBC) to evaluate the effect on response rate and survival ofa doubling of the epirubicin dose intensity.Patients and methods: Four hundred fifty-six patients were randomisedto receive either epirubicin 100 mg/m² or 50mg/m² in combination with 5-FU (500 mg/m²) andcyclophosphamide (500 mg/m²) (FEC 100 vs. FEC 50) i.v., every21 days for a maximum of six cycles (eight in case of CR).Results: Of 456 patients, 390 were evaluable for efficacy. Objectiveresponse (CR + PR) was seen in 57% (FEC 100) vs. 41% (FEC 50)of the evaluable patients (P = 0.003). The CR rate was higher in the FEC100 arm (12% vs. 7%, P = 0.07). FEC 100 producedsignificantly higher response rates in patients with visceral localisation(50% vs. 34%, P = 0.011) and in patients with more thantwo metastatic organ sites (64% vs. 37%, P = 0.001).Median time to progression (7.6 vs. 7 months) and overall survival (18 monthsvs. 17 months) were similar. Myelosuppression was the principal toxic effect,with grade IV neutropenia observed in 57% of the patients treated withFEC 100 vs. 9% of those on FEC 50. Grade IV infection or febrileneutropenia were observed in 8% (FEC 100) vs. 0.4% (FEC 50), butthe incidence of septic death was the same in the two arms (two patientseach). Cardiac toxicity was similar in the two treatment groups, with5% vs. 3% of the patients taken off study due to cardiac events,primarily due to a decline in LVEF. Only three patients (two in FEC 100)experienced congestive heart failure.Conclusion: This trial shows that FEC with epirubicin at 100mg/m² can be administered for repeated cycles without bonemarrow support with increased, though acceptable, toxicity and with asignificant increase of antitumor effect (especially in visceral and/orhigh-burden disease), but no increased survival.     

The relative toxicity of intravenous and intraperitoneal doses of epirubicin

Summary The toxicity of single doses of the anthracycline epirubicin was compared in the rat after either the intravenous (i.v.: 2–6 mg/kg) or intraperitoneal (i.p.; 4–8 mg/kg) administration of the drug. These doses produced comparable acute toxicity that was characterised by a dose-dependent, transient reduction in body weight (<15%) in the first 2 weeks after drug administration. Sequential measurements of cardiac output in animals that received i.v. doses of epirubicin showed that the time-related changes in cardiac function were biphasic. There was an initial decline in cardiac output in the first 12 weeks, which was followed by a phase of persistent depression in cardiac output between 12 weeks and 20 weeks. The time-related changes in cardiac function after i.p. doses of the drug were more variable, although the trend of changes, as after i.v. administration, appeared to be dose-dependent. Recovery of cardiac function occurred at 20 weeks after an i.p. dose of 4 mg/kg; however, after 6 mg/kg, cardiac function was significantly depressed after 16 weeks. For both routes of administration, the likelihood of late cardiac complications was dependent on the level of the reduction in cardiac output at 12 weeks. A study of the impairment of cardiac output and the incidence of cardiac-related mortality demonstrated that epirubicin was more cardiotoxic after i.v. administration. Equivalent cardiotoxic doses of epirubicin after i.v. and i.p. administration were highly linearly correlated (r=0.998), although there appeared to be a threshold dose of 3.33 mg/kg after i.p. administration of the drug. Thus, the relative cardiotoxicity between the two routes of administration was found to be dependent on the drug dose and, hence, the level of effect. The difference in the effect was less for high drug doses. The LD₅₀ for deaths due to cardiotoxicity at 20 weeks was 4.42±0.42 mg/kg after i.v. administration, which was significantly lower than the value of 6.28±0.41 mg/kg obtained after i.p. administration of the drug (P<0.01). There was no qualitative difference in the histological lesions induced in the myocardium after the i.v. vs i.p. administration of epirubicin.