A rationale for carboplatin treatment and abdominal hyperthermia in cancers restricted to the peritoneal cavity.

The purpose of this study was to optimize the treatment of cancers restricted to the peritoneal cavity by combining i.p. chemotherapy with abdominal hyperthermia. In vitro experiments demonstrated that the uptake of carboplatin into CC531 tumor cells was increased at temperatures higher than 41.5 degrees C at dose levels of 5 and 50% cell kill. Carboplatin-DNA adduct formation and cytotoxicity, however, were already increased at temperatures of about 40 degrees C, indicating that carboplatin-DNA adduct formation and consequently cytotoxicity could be enhanced by mild hyperthermia (temperatures in the range of 39-41.5 degrees C). CC531 tumor bearing rats were treated i.v. and i.p. with carboplatin (6.15 mg/kg) in combination with regional hyperthermia of the abdomen (41.5 degrees C for 1 h). The mean temperature was 41.5 +/- 0.3 degrees C (SD) in the peritoneal cavity and 40.5 +/- 0.3 degrees C in the esophagus. Enhanced platinum concentrations were found in peritoneal tumors (factor 3) and in kidney, liver, spleen, and lung (a factor 2 average), after the combined i.v. or i.p. carboplatin-hyperthermia treatment. Pharmacokinetic data of i.p. CBDCA combined with hyperthermia demonstrated an increased tumor exposure for total and ultrafiltered platinum in plasma. The areas under the concentration x time curve for total platinum at 37 degrees C and 41.5 degrees C were 69 and 210 microM/h, respectively; for ultrafiltered platinum these values were 47 and 173 microM/h. This may have been due to a slower elimination of platinum from the blood at the higher temperature (t1/2 beta for total platinum 99 and 156 min at 37 and 41.5 degrees C, respectively). The direct exposure of the tumor via the peritoneal fluid appeared to diminish, since the area under the curve for total platinum was lower at 41.5 degrees C than at 37 degrees C (576 microM/h versus 1255 microM/h, respectively). Our results indicate that the advantage of adding hyperthermia is caused by an increased drug exposure of the tumor via the circulation. This was supported by the fact that platinum concentrations in peritoneal tumors after carboplatin treatment at elevated temperatures were similar for the i.p. and i.v. routes.     

The use of oxaliplatin versus cisplatin in intraperitoneal chemotherapy in cancers restricted to the peritoneal cavity in the rat

Pharmacokinetic studies demonstrated the advantage of intraperitoneal oxaliplatin (1-OHP) for cancers restricted to the peritoneal cavity. The area under the concentration X time curve (AUC) in the peritoneal cavity for both total and ultrafiltered drug was almost 2 times higher for 1-OHP than cisplatin (cDDP). The AUC for ultrafiltered 1-OHP in plasma was also a factor 4 higher than cDDP, indicating that peritoneal tumors received a higher exposure from 1-OHP than cDDP directly in the peritoneal cavity and indirectly via the systemic circulation. Total platinum concentrations in peritoneal tumors of rats were determined after i.p. administration of equimolar doses of 1-OHP and cDDP. In spite of the pharmacological advantages, no significant difference in platinum concentration was demonstrated. In addition, no difference in the distribution of platinum within peritoneal tumors was detected after i.p. treatment with equimolar doses, i.e., platinum concentrations were comparable both in the periphery, 29 +/- 4 ppm for cDDP and 22 +/- 8 for 1-OHP and in the center of the tumor, 18 +/- 3 for both drugs. When CC531 tumor cells were incubated in vitro with equimolar concentrations of 1-DHP and cDDP in vitro, 2 to 4 times less platinum was found in cells treated with 1-OHP, indicating that the uptake of 1-OHP differed from that of cDDP. Oxaliplatin was not cross resistant for cDDP in CC531.RL4 tumor cells, a cDDP resistant cell line, which may indicate its value in ovarian cancer patients who did not respond to earlier cDDP treatment.     

Combination chemotherapy with S-1 and carboplatin for head and neck cancers

Chemotherapy plays an important role in the treatment of head and neck cancer (HNC) patients with recurrent and/or metastatic unresectable disease. The standard regimen for HNC has been a combination of cisplatin (CDDP) and 5-fluorouracil (5-FU). We planned to develop a new outpatient regimen that could be carried out safely and had an antitumor activity equivalent to the regimen of CDDP plus 5-FU. For this purpose, we selected a combination of S-1 and carboplatin. The overall response rate of 40.9% in this study was almost equivalent to the study previously reported on 5-FU plus CDDP. This regimen of S-1 plus carboplatin has the possibility of yielding tumor responses equivalent to a conventional regimen of 5-FU combined with CDDP in patients with recurrent and/or metastatic head and neck carcinoma as a second-line palliative chemotherapy.     

吉西他滨联合卡铂治疗晚期鼻咽癌的临床观察

目的观察吉西他滨联合卡铂方案治疗晚期复治鼻咽癌的疗效及毒性反应。方法34例均为一线含顺铂方案化疗失败的晚期鼻咽癌患者,给予吉西他滨与卡铂治疗,吉西他滨1000mg/m^2,静脉滴注,第1、8天;卡铂AUC5,静脉滴注,第2天,21d为1周期,每例患者治疗2周期以上。结果全组完全缓解4例,部分缓解17例,稳定8例,进展5例,总有效率为61.8%。中位生存期8.3个月,1年生存率为43.8%。最常见的毒副反应为骨髓抑制,Ⅲ～Ⅳ度白细胞和血小板下降发生率分别为35.3%和23.6%,其余毒副反应均轻微,可耐受。结论吉西他滨联合卡铂方案对一线含顺铂方案化疗失败的晚期鼻咽癌有较好的疗效,毒性反应可以耐受。     

Combination chemotherapy with carboplatin and docetaxel in the treatment of cancers of the ovary and fallopian tube and primary carcinoma of the peritoneum.

PURPOSE: Standard chemotherapy for advanced ovarian cancer currently includes a platinum agent (usually carboplatin) and paclitaxel. Because docetaxel is an active agent in platinum-resistant ovarian cancer, it is relevant to evaluate both the toxicity and efficacy of the combination of carboplatin and docetaxel in this clinical setting. PATIENTS AND METHODS: The Gynecologic Oncology Program of the Cleveland Clinic Taussig Cancer Center conducted a phase II trial of carboplatin (area under the concentration-versus-time curve of 6) and docetaxel (60 mg/m(2)), delivered every 3 weeks for six courses, in patients with ovarian and fallopian tube cancers and primary carcinoma of the peritoneum who had either received no prior chemotherapy or had experienced a treatment-free interval of greater than 2 years before developing disease recurrence. RESULTS: Fifty patients (median age, 57 years; range, 44 to 81 years) entered the trial (47 had had no prior chemotherapy). Our toxicity findings included the following: grade 4 neutropenia (64% of patients); hypersensitivity reactions (34%, none requiring discontinuation of therapy); peripheral neuropathy (6%). We had objective responses for 32 of 42 (81%) assessable patients. CONCLUSION: The combination of carboplatin and docetaxel is highly active in ovarian cancer, with the major toxicity being bone marrow suppression. Hypersensitivity reactions are frequent but do not prevent continuation of treatment. With the dose and schedule employed in this trial, neurotoxicity is uncommon. Defining a role for this regimen in routine clinical practice will require the conduct of randomized controlled clinical trials.     

以草酸反式环己二胺铂为主的联合化疗治疗晚期胃肠道癌的近期疗效观察

目的评价草酸反式环己二胺铂联合5-FU和CF治疗晚期胃肠道恶性肿瘤的疗效、耐受性及毒副反应.方法 21例晚期胃肠道癌病人应用L-OHP 130mg/m2第1天静点2小时,CF 100mg/m2,第1天～第5天静点,5-FU 400mg/m2,第1天～第5天静点.21天重复,2周期以上评价疗效.结果 OLF方案治疗晚期胃肠道恶性肿瘤21例,总有效率33.3%,完全缓解率14.3%.毒性反应以腹泻常见,胃癌占44.4%,大肠癌占41.7%.其次为恶心、呕吐,口炎,骨髓抑制,静脉炎,但反应轻微,末梢神经炎表现为暂时性外周神经病变,是完全可逆的.未见脱发、过敏、心脏毒性、肾脏毒性.结论 OLF方案治疗晚期胃肠道恶性肿瘤,尤其胃癌,疗效较好,毒副作用轻,可以耐受,值得推广.     

艾素联合卡铂治疗晚期非小细胞肺癌临床研究

目的:观察艾素(国产多西紫杉醇)联合卡铂治疗晚期非小细胞肺癌(NSCLC)的临床疗效与不良反应.方法:80例经手术和病理证实的晚期非小细胞肺癌患者,观察组49例,用艾素联合卡铂化疗;对照组31例,用异长春花碱联合顺铂化疗.观察两组疗效和毒副作用,3周期后评价疗效.结果:两组患者近期总有效率(PR)分别为44.9%(22/49)和41.94%(13/31).主要毒副作用为骨髓抑制,消化道反应和脱发,其发生率无显著性差异(P＞0.05).结论:艾素与卡铂联合给药方案治疗非小细胞肺癌疗效满意,耐受性好,不良反应少,性价比高.     

吉西他滨联合卡铂治疗晚期非小细胞肺癌

目的　观察吉西他滨联合卡铂治疗晚期非小细胞肺癌的疗效及毒副反应。方法　 41例晚期非小细胞肺癌患者给予吉西他滨与卡铂联合治疗 ,吉西他滨 10 0 0mg/m2 ,静脉滴注第 1、8、15天 ,卡铂AUC 5 ,静脉滴注第 1天 ,2 8天为一周期 ,每例患者治疗 2周期以上。结果　全组完全缓解 2例 ,部分缓解 18例 ,稳定15例 ,进展 6例 ,总有效率为 48.8%。初治组有效率为 5 5 .6% ,复治组为 43 .5 % (P >0 .0 5 )。全组中位生存期 11.8月 ,1年生存率为 49%。KPS评分增加者占 70 .7% ( 2 9/4 1)。最常见的毒副反应为骨髓抑制 ,Ⅲ～Ⅳ度白细胞和血小板下降发生率分别为 3 4.1%和 2 9.3 % ,其余毒副反应均轻微 ,可耐受。结论　吉西他滨联合卡铂一线治疗或二线治疗晚期非小细胞肺癌均有较好的疗效 ,毒性可以耐受。     

Evaluation of carboplatin administration into the serous cavity in the treatment of malignant effusion

Carboplatin, a new analogue of cisplatin, was administered into the serous cavity in nine primary lung cancer patients with malignant effusion, consisting of six malignant pleural effusions, two malignant pericardial effusions and one malignant ascites. Clinical effects, toxicities and pharmacokinetics were studied. The doses of carboplatin were 300 mg/m2 in seven patients, 200 mg/m2 in one patient and 1,100 mg/body in one patient. In seven evaluable patients, consisting of four non-small cell lung cancers and three small cell lung cancers, the response rate was 85.7% with 3 CR cases, 3 PR cases and 1 NR case. As toxicities, thrombocytopenia was observed in 57.1%, leukopenia in 57.1%, anemia in 71.4%, anorexia in 42.9%, nausea or vomiting in 28.6%, and low grade fever in 14.3%. However local pain, renal or liver dysfunction were not observed. The pharmacokinetics of free platinum concentration was analyzed with a two-compartment model (t1/2 beta = 18.60 hours) and 14.8% of total platinum remained free in effusion 24 hours after intracavitary administration. A high level of free platinum in effusion was maintained over a long period after carboplatin administration. This method was considered to be effective for the treatment of malignant effusion from the viewpoint of pharmacokinetics and less toxicity.     

Continuous hyperthermic peritoneal perfusion for the treatment of peritoneal dissemination in gastric cancers and subsequent second-look operation

A total of 31 patients with gastric cancer showing peritoneal dissemination received continuous hyperthermic peritoneal perfusion (CHPP) in combination with the administration of cisplatin (CDDP) and mitomycin C (MMC). The authors developed a new special device named the peritoneal cavity expander (PCE) for sufficient perfusion and direct temperature measurement in the peritoneal cavity. As complications of CHPP three patients presented with bone marrow suppressions (leukocytes less than or equal to 3000/mm3 and/or platelets less than or equal to 30,000/mm3): one, leakage of intestinal anastomosis; one, intestinal perforation; and one, acute renal failure. But none of them was lethal. Twelve of 31 patients who had received CHPP during the initial operation underwent second-look operation (SLO) for the assessing the effects of CHPP and for resecting residual or recurrent tumors. Among 12 patients who received SLO complete response (CR) was observed in four patients, partial response (PR) in one, no change (NC) in three, and progressive disease (PD) in four, with the overall response rates (%CR + %PR) standing at 41%. Two-year survival rate of the complete and partial responders was 50%, which was significantly higher than 0% of the other responders (NC + PD). The survival curves of the two groups were significantly different (P less than 0.05, generalized Wilcoxon test). These results supported that CHPP was well tolerated and effective for the treatment of patients with peritoneal dissemination in gastric cancer when combined with anti-cancer drugs having synergism with hyperthermia. Since the outcome of SLO was one of prognostic factors it was important to follow up these patients by SLO.     

Successful treatment of primary peritoneal carcinoma with paclitaxel and carboplatin combination chemotherapy

BACKGROUND: A standard treatment for primary peritoneal carcinoma has not been established to date. We report three patients with primary peritoneal carcinoma who were successfully treated with paclitaxel and carboplatin combination chemotherapy. CASE: Three patients, 66-, 73-, and 71-year-old women who presented with abdominal swelling, were referred to our hospital. Following detailed physical examination, they underwent exploratory laparotomy and were diagnosed with primary peritoneal carcinoma. Postoperatively, the sole treatment was comprised of combination chemotherapy of paclitaxel and carboplatin following which the tumor marker(CA125)levels normalized. Moreover, there was no evidence of tumors on CT scan, and the patients showed good recovery. CONCLUSION: Paclitaxel and carboplatin combination chemotherapy are effective for treatment of primary peritoneal carcinoma and can be considered one of the medical treatment options.     

Pentetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy

Summary Platinum distribution was studied in rat peritoneal tumors after i.p. treatment with equimolar doses of carboplatin and cisplatin. Low platinum concentrations (4 ppm) were detected in the periphery of the tumor after carboplatin treatment, whereas no platinum was detected 0.5 mm in from the periphery. In contrast, after cisplatin treatment, high platinum concentrations (29 ppm) were measured in the periphery of the tumor and moderate concentrations (14 ppm) were measured in the center. Only following increased carboplatin doses were low platinum concentrations detectable in the tumor. The total platinum concentration in the tumors was determined after equimolar administration of both drugs. In all, 7 times more platinum was detected after cisplatin treatment than after carboplatin treatment, and 10 times more carboplatin than cisplatin had to be injected to obtain comparable platinum concentrations in the tumors. When single cells were incubated with equimolar concentrations of carboplatin and cisplatin, 6–7 times more platinum was found in cells treated with cisplatin. However, pharmacokinetic studies favored i.p. administration of carboplatin because the clearance of this compound from the peritoneal cavity, expressed ast _1/2, was lower than that of cisplatin (239 vs 78 min), resulting in an AUC in the peritoneal cavity for both total and ultrafiltered drug that was almost 3 times higher for carboplatin than cisplatin. The AUC for ultrafiltered carboplatin in plasma was 2-fold that for cisplatin (2,801±210 vs 1,334±431 M m). The present study demonstrated that in spite of the pharmacological advantages of carboplatin, its capacity to penetrate into peritoneal tumors and tumor cells is far lower than that of cisplatin.This work was supported by grant NKI 86-5 from the Dutch Cancer Society     

A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers

The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m(-2)) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day(-1) (cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day(-1) (cohort 2b; the erlotinib dose was escalated to 100 mg day(-1) in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100-150 mg day(-1), with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy.     

Combined modality treatment of advanced cancers of the oral cavity and oropharynx

From May 1985 to June 1988, 70 evaluable patients with advanced squamous cell cancers of the oral cavity and the oropharynx were treated with preoperative combined radio-chemotherapy. Treatment consisted of 50 Gy/25 fractions/5 weeks, combined with concomitant administration of mitomycin C on day 1 (15 mg/m2, i.v. bolus) and 5-fluorouracil during the first 5 days of irradiation (750 mg/m2/24 hours, continuous infusion). Surgery was performed 3 to 5 weeks following irradiation. Treatment tolerance was good and local mucosal reaction was increased, but no major systemic side effects were recorded. At surgery, 3-5 weeks following irradiation, 48.6% of the operation specimens did not contain any histologically detectable residual tumor. Overall survival is 61%, being 69% in T2 and T3, while none of the patients with bone invasion has survived. Median survival is 28, 26, and 9 months in T2, T3 and T4 stages, respectively. Loco-regional relapses have been recorded in 33% of the patients, occurring in 27% of T2, 25% of T3, and 88% of T4 stages. Patients have been spared mutilating radical neck dissection because of combined presurgical treatment without impaired survival or loco-regional relapse rate.     

紫杉醇加卡铂方案治疗晚期非小细胞肺癌

目的：探讨紫杉醇加卡铂联合化疗方案对晚期非小细胞肺癌的疗效和毒性反应,方法：78例晚期非小细胞肺癌患者应用国产紫杉醇150mg/m2加卡铂300mg/m2联合方案化疗。结果：58例初治者和20例复治者近期有效率分别为56．9％（33／58）和35％（7／20）,总有效率51．3％（40／78）,有4例（5．1％）获CR。中位生存期9．0个月,1年生存率为33．3％（26／78）,主要不良反应为骨髓抑制及关节或肌肉酸痛。结论：杉醇加卡铂对晚期非小细胞肺癌有较好疗效,不良反应可以耐受。     

Continuous ambulatory peritoneal dialysis: pharmacokinetics and clinical outcome of paclitaxel and carboplatin treatment

PURPOSE: Administration of chemotherapy in patients with renal failure, treated with hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) is still a challenge and literature data is scarce. Here we present a case study of a patient on CAPD, treated with weekly and three-weekly paclitaxel/carboplatin for recurrent ovarian cancer. EXPERIMENTAL: During the first, second and ninth cycle of treatment, blood, urine and CAPD samples were collected for pharmacokinetic analysis of paclitaxel and total and unbound carboplatin-derived platinum. RESULTS: Treatment was well tolerated by the patient. No excessive toxicity was observed and at the end of treatment she was in a complete remission. The plasma pharmacokinetics of paclitaxel were unaltered compared to historical data, with neglectable urinary and CAPD clearance. In contrast, the pharmacokinetics of carboplatin were altered, with doubled half-lives compared to patients with normal renal function. Of the administered carboplatin dose, up to 20% was cleared via the dialysate, while only up to 8% was cleared via the urine. CONCLUSION: Paclitaxel and carboplatin can be safely administered to patients with chronic renal failure on CAPD. For paclitaxel the generally applied dose can be administered, and although for carboplatin dose-adjustment is required due to the diminished renal function, the dose can be calculated using Calvert's formula.     

多西紫杉醇联合顺铂或卡铂治疗晚期非小细胞肺癌

目的：观察多西紫杉醇(泰索帝)联合顺铂或卡铂治疗晚期非小细胞肺癌的疗效及毒副反应。方法：对病理学或细胞学证实的32例晚期非小细胞肺癌患给予泰索帝联合顺铂或卡铂治疗。采用每周疗法，泰索帝25mg／m^2／次，静滴，第1、8、15天三次给药；顺铂75～80mg／m^2静滴，第1～5天或第2、9天分次给予；或卡铂AUC6．0-7．0，静点，第1天或第2、9天分次给予。每28天为一周期，每例患均接受2周期治疗或以上。结果：全组32例中获得完全缓解1例，部分缓解13例，稳定16例，进展2例，总有效率43．7％。临床最常见的毒副反应为骨髓抑制，Ⅲ、Ⅳ度白细胞和血小板下降率分别为15．6％和9．4％，其余无严重毒副反应。结论：泰索帝联合顺铂或卡铂治疗晚期非小细胞肺癌疗效较好，毒副反应较轻，采用每周疗法，病人耐受性较好，针对老年晚期患更加适宜。