Pharmacokinetics and metabolism of cyclophosphamide in paediatric patients

Summary The pharmacokinetics and metabolism of cyclophosphamide were studied in nine paediatric patients. Plasma samples were obtained from eight subjects and urine was collected from six children during a 24-h period after drug administration. Cyclophosphamide and its major metabolites phosphoramide mustard (PM), carboxyphosphamide (CX), dechloroethylcyclophosphamide (DCCP) and 4-ketocyclophosphamide (KETO) were determined in plasma and urine using high-performance thin-layer chromatography-photographic densitometry (HPTLC-PD). Cyclophosphamide (CP) was nearly, if not completely, cleared from plasma by 24 h after its administration. The plasma half-life of CP ranged from 2.15 to 8.15 h; it decreased following higher doses and was shorter than that previously reported for adult patients. Both the apparent volume of distribution (0.49±1.4 l/kg) and the total body clearance (2.14±1.4 l m^–2 h^–1) increased with increasing dose. Renal clearance ranged between 0.12 and 0.58 l/h (mean, 0.43±0.19l/h). Between 5.4% and 86.1% of the total delivered dose was recovered as unchanged drug in the urine. The major metabolites identified in plasma and urine were PM and CX. One patient appeared to be deficient in CX formation. This study suggests that there is interpatient variability in the pharmacokinetics and metabolism of CP in paediatric patients. The shorter half-life and higher clearance as compared with adult values indicate faster CP metabolism in children.M.J.T. was supported by a grant from the Fondo de Investigacion Sanitaria, Ministerio de Sanidad y Consumo, Spain. This work was also supported in part by grants from the North of England Cancer Research Campaign, North of England Children's Cancer Research Fund, ASTA Werke Germany, and the Wellcome Trust.     

Pharmacokinetics of trofosfamide and its dechloroethylated metabolites

 To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m² Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUC_Trofo:AUC_Ifo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC_Ifo:AUC_Cyclo 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechloroethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy. Received 21 July 1996 / Accepted: 11 November 1996     

Pharmacokinetic and pharmacodynamic analysis of combined chemotherapy with carboplatin and cyclophosphamide in patients with gynecological cancers

Background. This study was conducted to assess the utility of pharmacokinetic and pharmacodynamic analyses of chemotherapy with carboplatin (CBDCA) and cyclophosphamide (CPA). Methods. The pharmacokinetics (PK) and pharmacodynamics (PD) of chemotherapy with CBDCA and CPA were analyzed in 14 patients (12 with ovarian cancers and 2 with uterine cancers). The PD model based on myelosuppression was assessed in terms of concentrations of free platinum (free-Pt) and total CPA in blood samples. CBDCA (300 mg/m²) was administered intravenously (iv) over 1 h, and CPA (500 mg/m²) over 2 h. Free-Pt and CPA concentrations in blood samples were measured at several time points thereafter. Results. The nadirs of leukocyte and platelet counts were closely correlated with the free-Pt concentration 24 h after infusion (Pt-24), and with the CPA concentration 5 h after infusion (CPA-5). A PD model corresponding to the nadirs of leukocyte and platelet counts was thus generated. Conclusion. This PD model allowed ready prediction, from Pt-24 and CPA-5, of the degree of myelosuppression, a dose-limiting toxicity, for combined CBDCA and CPA chemotherapy. Received: June 19, 1997 / Accepted: July 27, 1998     

DNA damage and repair in patients receiving high-dose cyclophosphamide and radiation

DNA damage and repair were assessed by alkaline sucrose gradients in the nonstimulated circulating mononuclear cells of 7 patients receiving high-dose cyclophosphamide (HDCy) and fractionated whole-body irradiation. Measurable damage produced by HDCy appeared to be repaired in about 60 hours. Damage from a radiation dose of 2 Gy was not completely repaired within 24 hours because DNA molecular weight was found to be decreased by an average of 22%. We attempted to assess the impact of HDCy on radiation damage repair by comparing blood irradiated and incubated in vitro before therapy with in vivo incubation following HDCy administration. Two hours after a radiation dose, repair appeared increased following HDCy. These results suggest the possibility that significant interaction at the DNA level may occur when HDCy and irradiation are administered together.     

Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism

Purpose: The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single 1-h infusion. Based on the concept of bioactivating enzyme saturation with increasing doses, we investigated the influence of fractionated application of HD-CP on dose-dependent changes in metabolism. Patients and methods: Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations of CP and its major metabolites (quantified by [³¹P]-nuclear magnetic resonance spectroscopy; [³¹P]-NMR spectroscopy), were determined in four patients with high-risk primary breast cancer who received adjuvant chemotherapy including both CD-CP (500 mg/m² infused over 1 h) and split HD-CP (50 mg/kg infused over 1 h on each of 2 consecutive days (d): d₁ and d₂. Results: (Data are given as mean values for CD and d₁/d₂ of HD, respectively). Systemic clearance (CL) of CP was similar during CD and d₁ of HD, but significantly increased on d₂ of HD (CL: 83 and 78/115 ml/min; P < 0.01 for d₁ versus d₂). The latter was translated into an increase in formation CL of both active (+16.4 ml/min) and inactive metabolites (+17.6 ml/min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistically significant decrease was observed in the relative contribution of bioactivation CL to overall CL during both days of HD (63% versus 57%/53%). Recovery of intact CP in 24-h urine corresponded to 24%, 29%, 22% of the dose (P < 0.05 for d₁ versus d₂ of HD). Conclusions: Following dose escalation of CP, dividing the high dose over 2 days instead of one single infusion may favorably impact the metabolism of CP in terms of bioactivation. In addition, on day 2 of a split regimen, renal elimination of CP is decreased, which implies that more drug is available for metabolism. Received: 6 February 1998 / Accepted: 17 August 1998     

Pharmacokinetic interaction between ondansetron and cyclophosphamide during high-dose chemotherapy for breast cancer

Purpose: Both ondansetron and cyclophosphamide are thought to be metabolized by hepatic microsomal processes. The purpose of this study was to evaluate the potential pharmacokinetic interactions between ondansetron and high-dose alkylating agent chemotherapy. Methods: A total of 54 breast cancer patients receiving high-dose cyclophosphamide, cisplatin and carmustine were treated prospectively in four sequential cohorts. Cohorts I and II received continuous infusions of both ondansetron and prochlorperazine, and cohorts III and IV received a continuous infusion of ondansetron alone at the same doses. All patients received lorazepam every 4 h. A group of 75 matched historical controls had received a continuous infusion of prochlorperazine with lorazepam. Pharmacokinetic monitoring of each drug used in the high-dose chemotherapy regimen was conducted. Results: Median AUCs of cyclophosphamide in patients receiving ondansetron (73.6 mg/ml · min) were lower than those of the control patients (88.3 mg/ml · min, n = 75, P = 0.0004), but the median cisplatin AUC was approximately 10% higher and no difference in the disposition of carmustine was demonstrated. Patients treated with ondansetron displayed a higher frequency of headaches than the controls. The frequency of achieving complete emetic control was greater in the ondansetron + prochlorperazine groups compared to the ondansetron alone groups and was greater in both these groups than in the prochlorperazine alone group on the first day of therapy only. Conclusion: Ondansetron altered the systemic exposure to cyclophosphamide when these agents were administered concomitantly. Ondansetron did not substantially improve overall emetic control when used alone but may improve control in combination with prochlorperazine. Future randomized studies are needed to delineate the effect of ondansetron on the disposition of the active cyclophosphamide metabolites so that clinical implications can be addressed. Received: 28 October 1997 / Accepted: 9 March 1998     

Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens

Purpose: Cyclophosphamide and thioTEPA are frequently used simultaneously in high-dose chemotherapy regimens. During a pharmacokinetic study of 31 courses in 20 patients of cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide given in the combination cyclophosphamide–thioTEPA–carboplatin, a sharp decrease in 4-hydroxycyclophosphamide concentration was observed immediately after the start of the thioTEPA infusion. A drug-drug interaction was suspected. This putative interaction was investigated in this study. Methods: Possible sequence dependency, due to inhibition of the formation of 4-hydroxycyclophosphamide by thioTEPA, was investigated by altering the sequence of infusion in three patients (four courses) receiving high-dose chemotherapy with cyclophosphamide (1000 or 1500 mg/m² per day), thioTEPA (80 or 120 mg/m² per day) and carboplatin (265 or 400 mg/m² per day) in short infusions for four consecutive days. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were established. Possible inhibition of the metabolism of cyclophosphamide and thioTEPA was investigated in human microsomes. Results: A striking sequence dependency of the pharmacokinetics of 4-hydroxycyclophosphamide was observed. Administration of thioTEPA 1 h prior to cyclophosphamide resulted in decreased C_max (−62%) and AUC (−26%) values of 4-hydroxycyclophosphamide compared to those of thioTEPA administered 1 h after cyclophosphamide. In human microsomes an inhibition of the conversion of cyclophosphamide to 4-hydroxycyclophosphamide by thioTEPA was observed at clinically relevant concentrations with an IC₅₀ of 23 μM. No inhibition of the formation of TEPA by cyclophosphamide was observed. Conclusions: ThioTEPA strongly inhibits the bioactivation of cyclophosphamide and this may decrease both efficacy and toxicity. Our results seriously question the practice of the simultaneous continuous infusion of cyclophosphamide and thioTEPA and suggest that the sequencing and scheduling of these two agents in high-dose chemotherapy regimens may be of critical importance. Received: 31 January 2000 / Accepted: 10 April 2000     

Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism

Background: Patients receiving the highly emetogenic high-dose chemotherapy regimen with cyclophosphamide, thiotepa and carboplatin (CTC) may benefit from the neurokin-1 receptor antagonist aprepitant in addition to standard anti-emetic therapy. As aprepitant has been shown to be a moderate inhibitor of the cytochrome P450 (CYP) 3A4 isoenzyme, its effect on the pharmacokinetics and metabolism of cyclophosphamide and thiotepa was evaluated. Moreover, preliminary results on the clinical efficacy of aprepitant in the CTC regimen are reported. Patients and methods: Six patients were enrolled in a protocol that employed a 4-day course of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg/m²/day), thiotepa (120 mg/m²/day) and carboplatin (AUC 5 mg min/ml/day). Two patients received the tCTC protocol, which comprises two-third of the dose of CTC. In addition to standard anti-emetic therapy, the patients received aprepitant from one day before the start of their course until 3 days after chemotherapy. Blood samples were collected on days one and three of the course and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, thiotepa and its main active metabolite tepa. The influence of aprepitant on the pharmacokinetics of cyclophosphamide and thiotepa was analyzed using a population pharmacokinetic analysis including a reference population of 49 patients receiving the same chemotherapy regimen without aprepitant and sampled under the same conditions. The frequency of nausea and vomiting in the six patients receiving CTC was compared with those of the last 22 consecutive patients receiving CTC chemotherapy without aprepitant. Inhibitory activity of aprepitant on cyclophosphamide and thiotepa metabolism was also tested in human liver microsomes. Results: In our patient population, the rate of autoinduction of cyclophosphamide (P=0.040) and the formation clearance of tepa (P<0.001) were reduced with 23% and 33% when aprepitant was co-administered, respectively. Exposures to the active metabolite 4-hydroxycyclophosphamide and tepa were therefore reduced (5% and 20%, respectively) in the presence of aprepitant. In human liver microsomes, the 50% inhibitory concentrations (IC₅₀) of aprepitant for inhibition of cyclophosphamide (IC₅₀=1.3 g/ml) and thiotepa (IC₅₀=0.27 g/ml) metabolism were within the therapeutic range. Patients receiving aprepitant experienced less frequently CINV both during and after the CTC course compared with the reference population (nausea 3.7 days vs. 5.8 days, P=0.052; vomiting 0.5 days vs. 4.8 days, P<0.001). Conclusion: Aprepitant inhibited both cyclophosphamide and thiotepa metabolism, most probably due to inhibition of the CYP 3A4 and/or 2B6 isoenzymes. The effects of this interaction are, however, small compared to the total variability. Addition of aprepitant may provide superior protection against vomiting in patients receiving the highly emetogenic high-dose CTC chemotherapy.     

Phase II study of second-line treatment with high-dose cyclophosphamide in recurrent metastatic breast cancer

 A total of 78 patients with second recurrence or progression of histologically verified breast cancer were treated with single-agent cyclophosphamide given at 2.5 g/m² by i.v. infusion every 3 weeks along with mesna support. All had previously been treated with epirubicin and cisplatin or epirubicin alone. Toxicity was predominantly hematologic: WHO grade III+IV toxicity was found in 95% of cases. The overall response rate was 26.7% (95% confidence limits, 15.8–41.4%), with 7% of patients achieving a complete response (CR) and 19.7%, a partial response (PR). The median duration of CRs and PRs was 11 and 5 months, respectively. The response rate observed for patients previously treated with epirubicin alone was 30.5% in contrast to the 8.3% recorded for patients previously treated with cisplatin plus epirubicin. Thus, an indication of cross-resistance was absent between cyclophosphamide and epirubicin but possible between cyclophosphamide and cisplatin. Received: 10 January 1995/Accepted: 6 June 1995     

Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma

Background The prognosis of high-grade glioma in children is poor.Purpose Interferon-gamma may increase the immune surveillance of glioma cells. Earlier clinical evidence had shown that low dose cyclophosphamide (CPM) increased immune response.Methods After induction treatment with simultaneous radiation and chemotherapy, patients were treated with individually increasing interferon-gamma (IFN-γ) doses starting from 25 μg/m²/d s.c. increasing up to a maximum of 175 μg/m²/d within 7 weeks. Cyclophosphamide was given at 300 mg/m² i.v. every 21 days. Forty pediatric glioma patients were enrolled (median age: 8.5 year, male: n = 22). Tumor locations included cerebral cortex (n = 8), basal ganglia (n = 4), brainstem (n = 24), cerebellum (n = 3), spinal cord (n = 1). Histologies were GBM (n = 14), AA (n = 14), LGG (n = 2, diffuse intrinsic pontine glioma). There was grade IV toxicity for thrombocytopenia (10%) and leucopenia (2.5%), grade III toxicity for central nervous (2.5%) and hepatic (5%) side effects, no toxic death. The observation time of the six surviving patients was: 1.2, 1.9, 4.2, 4.4, 4.6 and 4.7 years respectively. The median overall survival (1 year) was not significantly different from a historical control group (0.8 years). The survival of pontine gliomas appeared even inferior when compared to the previous protocol (n.s.).Conclusion Maintenance treatment with IFN-γ and low dose CPM has no sufficient beneficial effect for the treatment of high-grade glioma.Joachim Kühl has died 2003     

Phase II trial of simple oral therapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: SWOG S0430

Background.

Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC.

Methods.

The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor–positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1–14, and capecitabine, 1,500 mg twice daily on days 8–21, in 21-day cycles.

Results.

In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7–8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1–22.0 months). The RR was 36% (95% CI, 26%–48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%–48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths.

Conclusions.

PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.     

Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer

Summary A multicenter phase I pharmacokineticstudy of a new triphenylethylene antiestrogen, toremifene, was examined in 70 patients with advanced breast cancer. Patients were randomized to receive single daily oral doses of either 10, 20, 40, 60, 200, or 400 mg for 8 weeks. Plasma toremifene and its major metabolites,N-desmethyltoremifene and 4-hydroxytoremifene, were determined weekly during therapy and at 0, 7, 14, and 21 days after the discontinuation of therapy. The time to reach steady-state plasma concentrations was between 1 and 5 weeks, with steady-state being achieved earlier (1–2 weeks) at daily doses of 200 and 400 mg. The time to peak concentration following oral doses of toremifene ranged from 1.5 to 4.5 h. The terminal half-life of elimination was 5.0, 6.0, and 5.0 days for toremifene, desmethyltoremifene, and 4-hydroxytoremifene, respectively. Plasma concentrations of 4-hydroxytoremifene were detectable only at high doses (200 and 400 mg/day) of toremifene. The results of this phase I pharmacokinetic study show that toremifene has metabolic and kinetic patterns that are similar to those previously reported with tamoxifen.This work was supported by a grant from Adria Laboratories     

Pharmacokinetics and pharmacodynamics of irinotecan and its metabolites from plasma and saliva data in patients with metastatic digestive cancer receiving Folfiri regimen

Purpose: Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic–pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites. Methods: Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks. The irinotecan-administered dose was 180 mg/m²; 17 patients participated in a dose-escalating study. Irinotecan and its metabolites (SN-38, SN-38G, APC, NPC) were quantified in plasma and saliva by high-performance liquid chromatography with fluorescence detection. Results: The mean irinotecan systemic clearance and steady-state volume of distribution values were 14.3 l/h/m² and 211 l/m², respectively. The intrapatient variability (22–28%) was far lower than the interindividual variability (33–88%). Age and weight were the two physiological parameters that influenced drug disposition. For irinotecan, SN-38, APC and NPC, similar pharmacokinetic profiles were observed from plasma and saliva data. The saliva/plasma AUC ratios averaged 1 for irinotecan, 0.3 for SN-38, 0.17 for APC and 0.27 for NPC. Neutropenia, diarrhea and nausea were the main toxicities encountered. From both plasma and saliva data, the percentage decrease in neutrophil count appeared to be related to irinotecan and SN-38 AUCs. Conclusions: All these findings provide a rationale for an individual adaptation of irinotecan dosing. In case of difficult venous access, the titration of irinotecan and of its active metabolite SN-38 in saliva may prove relevant.     

高剂量表阿霉素治疗进展期和晚期乳腺癌

目的评价高剂量表阿霉素（ＨＤ－ＥＰＩ）合并环磷酰胺（ＣＴＸ）、氟脲嘧啶（５－Ｆｕ）治疗进展期和晚期乳腺癌的安全性和有效性。方法对３２例可评价的Ⅲ、Ⅳ期乳腺癌患者静脉给予ＣＴＸ６００ｍｇ／ｍ２、ＥＰＩ９０ｍｇ／ｍ２～１１０ｍｇ／ｍ２、５－Ｆｕ９００ｍｇ／ｍ２,每２１天重复。并与３０例非同期低剂量组比较（ＥＰＩ为５０ｍｇ／ｍ２）。结果高剂量组的总有效率为７１．９％,完全缓解率为１２．５％,明显高于低剂量组（５６．７％和６．７％）;初治的有效率（８０．０％）略高于复治者（６８．２％）。全组中位缓解期７．４个月,中位生存期１２．５个月。白细胞减少为主要的毒副反应,发生率为８９．５％（６８／７６）,Ⅲ、Ⅳ度分别为２７．６％和１８．４％;胃肠道毒性为轻、中度,未见明显的心肝肾毒性。结论ＨＤ－ＥＰＩ＋ＣＴＸ＋５－Ｆｕ方案治疗晚期乳腺癌安全有效,可在临床进一步试用     

Efficacy and safety of fludarabine and cyclophosphamide combined therapy in patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL)-Polish multicentre study

The aim of this study was to investigate the efficacy of a combination of fludarabine (F) and cyclophosphamide (C) in the treatment of patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL). Between November 1999 and December 2001, 63 patients with B-CLL (median age 60 years) received a regimen that consisted of F 25 mg/m² and C 250 mg/m², days 1 - 3, intravenously, every 4 weeks, for a maximum of 6 courses. Response and toxicity were assessed according to current criteria (NCI-WG and WHO). Complete and partial remissions were achieved in 17.5% and 55.6% of patients, respectively; 19% of patients had stable disease and 7.9% of patients showed disease progression. The median follow-up was 16.5 (range 1.5 - 32) months. The median duration of progression-free survival (PFS) has not been reached among patients treated with FC regimen as second-line therapy.The median PFS was 13 (range 8 - 26) months in the 19 responding patients treated with FC regimen as third-line therapy. The most frequent side-effects were neutropenia (45%), thrombocytopenia (42%) and infections (57%). We conclude that the combination of fludarabine and cyclophosphamide demonstrated significant efficacy in pretreated, advanced B-CLL patients, with tolerable toxicity.     

Extremely high exposures in an obese patient receiving high-dose cyclophosphamide,thiotepa and carboplatin

PURPOSE: To evaluate the short-term adverse effects of administration of dolastatin-10 (Dol-10) to dogs with spontaneously occurring malignant tumors. METHODS: A total of 34 tumor-bearing dogs were given Dol-10 as a rapid intravenous bolus every 14 days at starting dosages ranging from 200 to 350 microg/m(2). Acute and short-term adverse effects, antitumor response, and duration of response were characterized. RESULTS: The maximum tolerated dose varied greatly from patient to patient, but a reasonable starting dose for further studies was established at 300 microg/m(2). The median number of treatments per dog was 2 (range 1 to 17). Granulocytopenia was the dose-limiting toxicity. The overall response rate was 3%, consisting of a complete and durable (30 months) response in a dog with high-grade malignant lymphoma that was refractory to standard therapy. Two minor or transient responses were observed, and two dogs experienced disease stabilization for 8 and 16 weeks. CONCLUSIONS: Dol-10 appears to be well tolerated in tumor-bearing dogs at doses approaching those tolerated by humans. The clinical activity observed in dogs with non-Hodgkin's lymphoma warrants further investigation.     

Comparison of conventional dose and double dose carboplatin in patients receiving cyclophosphamide plus carboplatin for advanced ovarian carcinoma: a North Central Cancer Treatment Group Study

Between March 1992 and November 1994, 91 patients with stage III and IV ovarian carcinoma were enrolled in a randomized comparative study of cyclophosphamide 600 mg/m² plus carboplatin 300 mg/m² vs. cyclophosphamide 600 mg/m² plus carboplatin 600 mg/m², each regimen given monthly for six cycles. Patients on the intensive regimen also received 10 μg/kg of granulocyte macrophage colony stimulating factor (GM-CSF) (molgramostim) daily for 14 days following each chemo-therapy treatment. The study was closed prematurely because of very poor case accrual following the preliminary announcement (in May 1993) that paclitaxel appeared superior to cyclophosphamide in the platinum-based treatment of ovarian cancer. More than 4 years after our last case entry, we analyzed the survival results for the 44 eligible patients who received the conventional dose of carboplatin and the 43 eligible patients receiving our intensified dose of carboplatin. More than 90% of the treated patients receiving the conventional dose regimen received at least 75% of the planned doses at each of the six treatment intervals, whereas the percentage of treated patients able to receive at least 75% of the assigned intensive dose regimen had declined from 95% in cycle 2 to 53% by cycle 6. Furthermore, although 32 patients received all six planned cycles of treatment in the conventional regimen group, only 15 received all six cycles of the intensified regimen. Patients receiving the intensive regimen had more fever, dermatitis, lethargy, musculoskeletal pain, and pulmonary complications than did the conventional dose patients. Median survival times for the two treatment groups were very similar (38.5 and 38.1 months, respectively, for the conventional and intensive regimens), and we saw no evidence that the distribution of survival times differed between the treatment regimens (p = 0.95).     

A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel

Purpose: The purpose of this study was to investigate the effect of high-dose progesterone, an inhibitor of P glycoprotein, on the pharmacokinetics and toxicity of paclitaxel. Patients and methods: A total of 29 patients with various tumors were treated with single-agent paclitaxel (125 mg/m² administered over 3 h once every 3 weeks) until progression of disease, at which point high-dose progesterone (3 g administered i.v. over 24 h) was added to the paclitaxel treatment program in 20 patients (13 women, 7 men). Pharmacokinetic studies of paclitaxel administered alone and with progesterone were performed in eight patients. Results: The pharmacokinetic parameters of paclitaxel were highly variable. High-dose progesterone increased the peak plasma levels (3.00 ± 0.94 vs. 4.15 ± 1.63 M; P=0.029; mean ± SD) and the area under the curve (AUC; 14.3 ± 4.75 vs. 17.3 ± 5.59 M × h; P=0.006) of paclitaxel. The absolute neutrophil and platelet nadir counts did not differ significantly between the paclitaxel and the combined treatment cycles. Three of the 20 patients documented to have progressive disease on paclitaxel alone had partial responses when high-dose progesterone was added to the paclitaxel regimen. Conclusion: Progesterone had a statistically significant impact on the pharmacokinetics of paclitaxel. The addition of high-dose progesterone to paclitaxel is feasible, but the small number of patients prevents conclusions being drawn about the clinical efficacy of combined progesterone and paclitaxel. Received: 11 September 1998 / Accepted: 15 February 1999     

The addition of mesna to hyperhydration does not decrease the incidence of hemorrhagic cystitis in patients receiving high-dose cyclophosphamide

To assess the efficacy of hyperhydration Versus hyperhydration plus mesna in preventing cyclophosphamide induced hemorrhagic cystitis a retrospective analysis was conducted of 110 patients who received hyperhydration alone (baseline intravenous intake of at least 3.6 1/m(2)/day) and 107 patients who received hyperhydration plus mesna (120% of daily cyclophosphamide dose) while receiving cyclophosphamide (total dose 150-200 mg/kg) as part of a dose intensive regimen. Macroscopic hematuria was noted in 17 (16%) and 9 (8%) patients who received hyperhydration with or without mesna, respectively (p=0.08). This analysis failed to demonstrate a benefit in adding mesna to hyperhydration alone in preventing cyclophosphamide induced hemorrhagic cystitis.