Absolute and relative activities of platinum-complexes on human tumors as evaluated by an antimetabolic in vitro assay

An in vitro assay, which evaluates drug effect on ³H-thymidine incorporation, was used to investigate the absolute and relative activities of cisplatin (DDP), carboplatin (CBDCA) and iproplatin (CHIP) on 317 specimens from untreated tumors, including breast and ovarian cancers and malignant melanomas. Similar activities were generally observed for DDP and CHIP, whereas CBDCA exhibited a lower, although not significantly different cytotoxicity on breast and ovarian cancers. The relative activities of Platinum analogues were analyzed on 239 two-way drug sensitivity comparisons. The overall agreement rates ranged from 80.2 to 83.9% for the different comparisons. High coresistance, from 61.1 to 93.8%, was observed for all the comparisons, regardless of the tumor type. Cosensitivity rates were poor for breast and ovarian cancers, from 0 to 37.5%, whereas for melanomas an association in sensitivity was observed in 80% of the cases.     

干扰素单独或与卡铂联合应用对卵巢癌的抑制作用

目的研究干扰素-αⅡb(IFN-αⅡb)单独以及与卡铂联合应用时,在体外对卵巢上皮癌细胞株OVCAR-3和HO-8910增殖的抑制作用.方法应用四唑蓝显色法(MTT法),检测IFN-αⅡb以及联合应用卡铂作用后OVCAR-3和HO-8910细胞的增殖变化.结果(1)当IFN-αⅡb的浓度≥103IU/ml时,对OVCAR-3和HO-8910细胞的增殖均具有一定的抑制作用,而且抑制作用与浓度呈正相关(P＜0.01).(2)各浓度的IFN-αⅡb和卡铂联合应用时,未见协同作用.结论干扰素具有抗卵巢上皮癌增殖作用.     

Kidney Function after Treatment for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study

BackgroundSurvivors of childhood cancer may be at increased risk for treatment-related kidney dysfunction. Although associations with acute kidney toxicity are well described, evidence informing late kidney sequelae is less robust.MethodsTo define the prevalence of and risk factors for impaired kidney function among adult survivors of childhood cancer who had been diagnosed ≥10 years earlier, we evaluated kidney function (eGFR and proteinuria). We abstracted information from medical records about exposure to chemotherapeutic agents, surgery, and radiation treatment and evaluated the latter as the percentage of the total kidney volume treated with ≥5 Gy (V5), ≥10 Gy (V10), ≥15 Gy (V15), and ≥20 Gy (V20). We also used multivariable logistic regression models to assess demographic and clinical factors associated with impaired kidney function and Elastic Net to perform model selection for outcomes of kidney function.ResultsOf the 2753 survivors, 51.3% were men, and 82.5% were non-Hispanic White. Median age at diagnosis was 7.3 years (interquartile range [IQR], 3.3–13.2), and mean age was 31.4 years (IQR, 25.8–37.8) at evaluation. Time from diagnosis was 23.2 years (IQR, 17.6–29.7). Approximately 2.1% had stages 3–5 CKD. Older age at evaluation; grade ≥2 hypertension; increasing cumulative dose of ifosfamide, cisplatin, or carboplatin; treatment ever with a calcineurin inhibitor; and volume of kidney irradiated to ≥5 or ≥10 Gy increased the odds for stages 3–5 CKD. Nephrectomy was significantly associated with stages 3–5 CKD in models for V15 or V20.ConclusionsWe found that 2.1% of our cohort of childhood cancer survivors had stages 3–5 CKD. These data may inform screening guidelines and new protocol development.     

A phase II study of carboplatin and paclitaxel in esophageal cancer.

BACKGROUND: This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with esophageal cancer. MATERIALS AND METHODS: Thirty-five patients were enrolled. Patients were treated with paclitaxel 200 mg/m(2) intravenously (i.v.) over 3 h and carboplatin i.v. at an AUC of 5 mg/h/ml. Thirty-three patients were assessable for toxicity and objective response. RESULTS: A total of 166 treatment courses were administered with a median of five courses per patient. The objective response rate was 43% [90% confidence interval (CI) 0.3-0.58] by the intention-to-treat analysis. The median response duration was 2.8 months (90% CI 2.1-5.4). The median survival time was 9 months (90% CI 7-13.8) and the 1-year survival rate was 43% (90% CI 0.29-0.57). The major grade 3-4 toxicity observed was neutropenia, occurring in 17 patients (52%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is an moderately active and tolerable regimen in advanced esophageal cancer.     

腹腔灌注联合射频透热治疗28例晚期卵巢癌

[目的]探讨晚期卵巢癌腹腔转移的治疗方法。[方法]以顺铂 卡铂 依托泊甙为主的联合方案行腹腔持续热灌注化疗并腹腔射频透热治疗28例晚期卵巢上皮癌，观察其疗效及毒副反应。[结果]完全缓解(CR)5例，部分缓解(PR)16例，稳定（NC）5例，进展（PD）2例，总有效率75.0%。主要毒副反应为骨髓抑制。[结论]双铂联合依托泊甙腹腔热灌注并射频透热治疗对中晚期卵巢癌疗效较好，毒副反应少。     

Phase I study of combined radiation, hyperthermia and intra-arterial carboplatin for local recurrence of cervical cancer.

BACKGROUND: Patients with cervical cancer who develop pelvic recurrence after primary surgery are usually treated with radiation-based therapy. However, their prognoses are dismal. We conducted a phase I study of combined radiation, hyperthermia and intra-arterial (IA) carboplatin for local recurrence of cervical cancer. PATIENTS AND METHODS: Patients with local recurrence of cervical cancer without extrapelvic recurrence were included in this study. Carboplatin was given as a 5-min IA infusion without hydration just before pelvic radiation every day. External pelvic irradiation (1.8 Gy/day for 28 days) was performed according to local standard schedules. After 20 Gy had been administered, hyperthermia was performed once a week with a radio frequency heating system for four cycles. RESULTS: Fifteen patients were entered through the four dose levels of carboplatin. The maximum tolerated dose was determined to be 25 mg/m(2 )and the dose-limiting toxicities were leukocytopenia, neutrocytopenia and diarrhea. Grade 3/4 leukocytopenia and diarrhea were observed in nine (60%) and three (20%) of 15 patients. Tumor responses included five complete responses and nine partial responses, and the overall response rate was 93.3% (14 of 15) (95% confidence interval 59.4% to 100%). Tumor reductions were observed only at 20 Gy in 10 cases of 14 responders (71.4%). CONCLUSION: The combination therapy of radiation, hyperthermia and IA carboplatin is safe and well-tolerated for locally recurrent cervical cancer.     

Phase I/II investigation of paclitaxel, ifosfamide and carboplatin for advanced non-small-cell lung cancer.

BACKGROUND: The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. PATIENTS AND METHODS: Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m(2) as a 1-h infusion on day 1 with carboplatin at an area under the concentration-time curve (AUC) of 6 mg.min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m(2) on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m(2) on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg.ml/min. Therapy for dose levels I and III included filgrastim support (5 micro g/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/ micro l. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen's activity and tolerability. RESULTS: Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered in the initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. CONCLUSIONS: The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.     

Steroids decrease uptake of carboplatin in rat gliomas – Uptake improved by intracarotid infusion of bradykinin analog, RMP-7

A blood-tumor barrier (BTB) limits delivery of antitumoragents to brain tumors. This study sought todetermine whether dexamethasone (DXN) treatment of rats withintracranial gliomas would 1) further impair delivery ofcarboplatin to brain tumors, and 2) whether intracarotidinfusion of the bradykinin analog, RMP-7, would improvedelivery during concurrent DXN treatment. Wistar rats withRG2 gliomas were utilized and a unidirectional transport,Ki, of radiolabeled [¹⁴C] carboplatin was determined usingquantitative autoradiography. In DXN pretreatment animals, 3 mg/kg/dayof DXN was administered intraperitoneally for 3 daysprior to Ki determinations. At 10 days aftertumor implantation, Ki of [¹⁴C] carboplatin into DXN-treatedtumors and brain surrounding tumor (BST) was significantlylower compared to non-DXN treated tumors and BST(3.30 ± 0.91 vs. 4.47 ± 1.80, p< 0.05, and 0.94 ± 0.84 vs. 2.18± 0.79, p < 0.05, respectively). Intracarotid infusionof RMP-7 (0.1 mg/kg/min) significantly increased the Kifor carboplatin in DXN-treated tumors (6.35 ± 3.10vs. 3.30 ± 0.91, p < 0.01), however, RMP-7increased Ki to a greater extent in tumorsnot pretreated with DXN (12.07 ± 3.60 vs.4.47 ± 1.80, p < 0.0001). Our studiesshow that dexamethasone decreases transport of carboplatin intobrain tumors. Intracarotid infusion of RMP-7 selectively increasescarboplatin transport to tumors.     

A limited-sampling method for evaluation of the area under the curve of ultrafilterable carboplatin in children

Carboplatin is a widely used cytotoxic agent in numerous solid tumors of children. Since there is a large degree of interpatient variability in the area under the curve of free carboplatin for a given dose of the drug, the current tendency is to adjust the carboplatin dose so as to reach a target area under the curve rather than to determine a carboplatin dose on the basis of the body surface area. A limited-sampling method was developed for estimation of the ultrafilterable carboplatin area under the curve and for adjustment of the carboplatin dose on subsequent treatments. Population parameters were obtained from 16 children (reference group). We used the maximum a posteriori (MAP) Bayesian approach on 15 children with complete carboplatin pharmacokinetic data (test group). Two blood samples were sufficient to obtain reliable prediction of the area under the curve. The best sampling times were: (a) 30 min after the end of the infusion and (b) 5 h after the end of the infusion. On the basis of these data it is possible to prescribe prospectively a target area under the curve for free carboplatin given in a fractionated daily infusion and to adapt the carboplatin dose directly to ultrafilterable carboplatin measurements. Received: 8 June 1997 / Accepted: 9 January 1998     

Intra-arterial administration of carboplatin and the blood brain barrier permeabilizing agent,RMP-7: A toxicologic evaluation in swine

RMP-7 is a bradykinin B2 receptor agonist shown to permeabilize the blood-brain barrier, especially that associated with brain tumors, when administered via both intracarotid and intravenous routes. Both routes of administration are currently being tested in human trials in combination with the chemotherapeutic agent carboplatin as therapy for gliomas. As an essential prerequisite to the initial intracarotid clinical trials, the potential neurotoxicity of intra-arterial administration of RMP-7 (at a high or low dose), alone and in combination with carboplatin, was assessed in anesthetized Red Duroc swine. Five treatment groups were evaluated with each pig receiving a series of alternating, intra-arterial infusions of RMP-7 (or saline) followed by carboplatin (or saline), as follows: (1) vehicle control: saline/saline; (2) carboplatin only control: saline/carboplatin (50 mg total); (3) RMP-7 only control: RMP-7 (750 ng/kg)/saline; (4) low dose combination: RMP-7 (75 ng/kg)/carboplatin (50 mg total); and (5) high dose combination: RMP-7 (750 ng/kg)/carboplatin (50 mg total). For each subject, one of the alternating dosing sequences (above) was repeated four times during a single dosing session which lasted approximately 40 minutes. Assessments during the in-life phase of the study in the pre- and post-treatment periods consisted of heart rate, arterial blood pressure (systolic, diastolic, and mean), blood gases, body weight, general clinical observations (including evaluation for neurological deficit) and clinical pathology (including a comprehensive battery of standard blood coagulation, hematological and serum chemistry tests). In addition, during the time of treatment, heart rate and arterial blood pressure were monitored. The animals were terminated two weeks after dosing and the brain and rete mirabile (distal to site of infusion) were evaluated for gross and histopathological abnormalities. The histopathology analysis included a reader-blinded analysis using low and high power light microscopic examination of both H&E and Kluver-Berrera stained sections through several key cortical and subcortical brain regions. Transient decreases in arterial blood pressure (mean of 10–25 mmHg) were observed in both groups receiving the high dose of RMP-7 (i.e., 750 ng/kg). No other side effects attributable to RMP-7 and/or carboplatin were observed, and clinical observations revealed no evidence of neurologic deficits. Post-mortem examination revealed no evidence of CNS or cerebral vascular pathology attributable to carboplatin and RMP-7. This study demonstrates that intracarotid administration of the maximum tolerated dose of RMP-7 (750 ng/kg) alone, or in combination with carboplatin (50 mg) is not accompanied by any serious adverse effect, apparent cerebrovascular abnormality or neuropathologic consequence and offers further evidence for the safety of this novel therapeutic approach for enhancing delivery of chemotherapeutics to brain tumors.