Comparison of N-acetylcysteine and mesna as uroprotectors with ifosfamide combination chemotherapy in refractory germ cell tumors

From January 1983 through August 1988, 318 consecutive patients with refractory germ cell neoplasms were treated with ifosfamide-containing combination chemotherapy. The patients received ifosfamide at 1.2 gm/m² day with cis-platin 20 mg/m² day for 5 days and etoposide 75 mg/m² day for 5 days or vinblastine 0.11 mg/kg on days 1 and 2 for each cycle. Of 277 evaluable patients, NAC was used as an uroprotector in the initial 86 patients while the latter 191 consecutive patients received mesna to reduce urothelial toxicity. Dosages of NAC was 2.0 gm po q 6 hr and for mesna 120 mg/m² IV push prior to ifosfamide and then 1200 mg/m²/day as continuous infusion of 5 consecutive days. All patients received 3.0 liters of normal saline per day. The number of courses of chemotherapy given in the two groups were similar. Twenty-four of the 86 patients (27.9%) receiving NAC developed hematuria (13 patients — grade 1, 4 patients — grade 2, and 7 patients — grade 3 toxicity). While 8 out of 191 (4.2%) mesna patients developed hematuria (6 — grade 1 and 2 — grade 3) (p<0.0001). The incidence of severity of renal toxicity was similar in the two groups. Ifosfamide dosage was reduced solely for urothelial toxicity in 11 patients receiving NAC compared with none of the patients receiving mesna (p<0.0001). Chemotherapy response was similar in the two groups. In conclusion, mesna provides better urothelial protection from ifosfamide-induced toxicity than NAC and allows better maintenance of the drug dosage.     

Determination of cis-diamminedichloroplatinum (II) in plasma proteins and hemoglobin of cancer patients

A study was conducted to determine the levels of cis-diamminedichloroplatinum (II) (cisplatin) in plasma proteins and hemoglobin of cancer patients after cisplatin chemotherapy. Thirty-seven cancer patients with different type of cancers (lung, esophageal, urinary tract, and testicular cancer, melanoma, osteosarcoma etc) received cisplatin 32–110 mg/m² either as a single intravenous infusion or as infusions given on 5 consecutive days. Blood samples were classified according to time from previous cisplatin infusion. They included a total of 103 samples taken before the cisplatin infusion, immediately after infusion, 1, 2 or 3–5 days after infusion or 2–3, 4, or 5–7 weeks after infusion. Platinum (Pt) concentration in plasma proteins and hemoglobin was measured by atomic absorption spectroscopy (AAS). The data showed a correlation between the dose of cisplatin and the concentrations of Pt in plasma proteins and hemoglobin of cancer patients. Plasma proteins bound more cisplatin than hemoglobin, the respective maxima in the patients receiving > 50 mg/m² being 27.7 and 1.6 ng/mg protein in samples drawn immediately after treatment. The kinetics of disappearance of Pt from plasma proteins showed several components; the initial half-life was about 5–7 days. The disappearance of Pt from hemoglobin showed a single component of a half-life of 12–14 days.     

Effect of methotrexate on the pharmacokinetics and renal excretion of cisplatin

Summary The kinetics of platinum in plasma and erythrocytes, and its renal excretion, have been examined in five patients with non-small cell carcinoma of the lung, after treatment with cisplatin 50 mg/m² (Platidiame) and, three weeks later, a combination of 50 mg/m² cisplatin and 40 mg/m² methotrexate. The patients were given 0.9% saline 11 l h prior to drug application.Plasma platinum elimination was biphasic with a short initial phase (t_1/2a 10–31 min) and a long-phase (t_1/2 65–91 h). With the exception of increased AUC values in all five patients 0–8 h after the injection, no significant change in the kinetics of platinum in plasma was found after coadministration of methotrexate.In four of the five patients renal platinum excretion was reduced in the first 6 h after administration of methotrexate. The renal clearance of platinum was 50% lower in those four patients 0–3 h after the injection.With the exception of one patient, no signs of nephrotoxicity were observed after combined drug administration. Other toxic effects were mild and showed no increase after the initial administration of methotrexate.     

Phase II study of MTX-HSA in combination with Cisplatin as first line treatment in patients with advanced or metastatic transitional cell carcinoma

Summary Purpose: To assess the efficacy, tolerability and safety of MTX-HSA (methotrexate (MTX) covalently linked to human serum albumin (HSA)) combined with cisplatin as first line therapy for advanced bladder cancer. Methods: Patients (pat) were treated with a loading dose of 110 mg/m² of MTX-HSA followed by a weekly dose of 40 mg/m² starting on day 8. Cisplatin was given on day 2 of each 28 day cycle at a dose of 75 mg/m². Results: Tumor response evaluation was possible in 7 patients. Complete response (CR) and partial response (PR) was observed in 1 patient each (overall response rate: 29%). Key toxicities included CTC Grade (G) 3/4 stomatitis in 6 patients, vomiting G3 in 1 patient, fatigue G3 in 1 patient and thrombocytopenia G3 in 3 patients. Conclusion: The combination of MTX-HSA with cisplatin is feasible and shows antitumor activity against urothelial carcinomas combined with an acceptable toxicity profile. None of the authors of this article declares any conflict of interest that could have inappropriately influenced their work.     

Phase II trial of docetaxel in patients with recurrent malignant glioma: a study of the National Cancer Institute of Canada Clinical Trials Group

Summary Background. We conducted a phase II study to determine the response to, and toxicity of, docetaxel (Taxotere; Rhône Poulenc Rorer Pharmaceuticals, Inc) in patients with recurrent malignant glioma. Patients and methods. Eighteen patients with recurrent malignant glioma were treated with 100 mg/m² (no prior chemotherapy) or 75 mg/m² (prior adjuvant chemotherapy) of docetaxel intravenously over 1 hour, every 3 weeks. Premedication with dexamethasone, diphenhydramine and ranitidine or cimetidine was given to all patients. Five (28%) had gioblastoma multiforme (GBM) and the rest other malignant gliomas. Eleven (61%) had an ECOG performance status of 0 or 1, and 13 (72%) were on corticosteroids at the start of treatment. Rigorous response criteria were used. All were eligible and évaluable for response. Results. No complete or partial responses were observed; the objective response rate was 0% (95% confidence interval: 0–15.3%). Patients received a median of 2 cycles (range, 1–6). Grade 3 or 4 neutropenia occurred in 17 (94%) patients and was associated with fever that required intravenous antibiotics in 4 (22%) patients. An additional patient received intravenous antibiotics for an infection not associated with neutropenia. Six (33%) patients had mild hypersensitivity reactions. Onychodystrophy, peripheral edema and peripheral neuropathy were uncommon and mild. Conclusions. Docetaxel has no significant activity in patients with recurrent malignant glioma.     

Pharmacokinetics of high-dose methotrexate treatment in children

Summary The pharmacokinetics of intravenous high-dose methotrexate were studied in two groups of children being treated for malignant diseases, mostly acute lymphatic leukemia. The peak serum level of methotrexate of 2.32·10^–5 mol/l was found in children given 500 mg methotrexate/m² by a 24 h infusion, and another group given 2790 mg/m² during a 6 h infusion had serum levels as high as 2.16·10^–4 mol/l. The decay of serum concentration of methotrexate after completion of the infusion followed a diphasic curve, with an initial serum half-life of 4.8 h, followed by a second half-life of 34.4 h at distribution equilibrium. The apparent volume of distribution was 56.8 litres/m². Significant levels of methotrexate were found in cerebrospinal fluid, but penetration into cerebrospinal fluid was slow. Urinary excretion of methotrexate was considerable. Four to five days after commencement of the infusion, urinary concentrations of methotrexate still exceeded the serum levels.     

Neoadjuvant chemotherapy with gemcitabine and cisplatin in stage IIIA/B non-small cell lung cancer

Purpose. We studied cisplatin plusgemcitabine as induction (neoadjuvant)therapy in patients with stage IIInon-small cell lung cancer (NSCLC) toassess its objective remission rate,resectability, survival, and toxicity. Patients and methods. Patients with stageIII NSCLC received 2 cycles of gemcitabine1250 mg/m² on days 1, 8, and 15,plus cisplatin 100 mg/m² on day 2.Subsequently, patients were assigned tolocal therapy – surgery or radiotherapy. Results. Twenty-nine eligiblepatients (male/female: 21/8) with a medianage of 59 years (range, 43–71 years) wereenrolled between October 1996 and February1999. A total of 80 cycles were given,with a median of 3 per patient (range, 1–4cycles). Overall, toxicities were mild;only one patient had febrile neutropenia,and there were no grade 4 non-hematologicaltoxicities. There was one toxic deathfollowing afebrile grade 4 neutropenia.Overall clinical response rate (2 completeresponses [CRs] + 16 partial responses[PRs]) was 62% (95% CI, 45%–79%);10 patients had stable disease and noneprogressed; one patient was not evaluable.Eight of the 18 operated patients hadpathological response: 1 CR and 7downstagings to N(–); 14 patients wereresected. Median survival was 17 months(95% CI, 13–21 months), with 1-year and2-year actuarial survival rates of 61%and 29%, respectively. Conclusions. Gemcitabine pluscisplatin is a very active andwell-tolerated induction regimen in stageIII NSCLC. Comparative studies with otherstandard regimens are warranted.     

Gemcitabine and mitoxantrone in metastatic breast cancer: A phase-I-study

Background: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. Patients and methods: Patients with metastatic breast cancer were treated with gemcitabine (1000–1400 mg/m²) on days 1, 8 and 15 and mitoxantrone (10–14 mg/m²) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. Results: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m² gemcitabine and 14 mg/m² mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m² based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. Conclusion: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m².     

A phase II study of mitoxantrone in advanced gastric cancer

Summary Sixteen patients with advanced adenocarcinoma of the stomach were entered into a phase II study of mitoxantrone at a dosage of either 12 mg/m² or 14 mg/m² given at 3 weekly intervals. Nine patients had received prior chemotherapy including doxorubicin. No patients achieved either a complete or partial response, five patients had stable disease and the remainder disease progression. Moderate to severe leukopenia occurred in 10 patients with one septic death. Median survival for all patients was eight weeks (range 1–49 weeks). It is concluded that mitoxantrone has no worthwhile activity in gastric cancer at the described doses.     

Trimetrexate in advanced carcinoma of the esophagus

Summary Twenty-four patients with advanced epidermoid carcinoma of the esophagus were treated with trimetrexate (TMTX), a lipid soluble non-classical antifol. Patients were given TMTX 8 mg/m² intravenously day 1–5 every 28 days. In nine of these patients the dose was escalated to 12 mg/m² day 1–5 every 28 days. Three patients had a partial response (95% confidence limit 3–32%) with a median response duration of 14 weeks. No hematologic toxicity was documented. Two patients developed moderate stomatitis and only 3 patients experienced any nausea or vomiting. The median survival of all patients is 12 weeks. It is concluded that a higher dose of TMTX should be studied in patients with esophageal cancer in order to assess the true therapeutic value of the agent at a dose closer to the median tolerated dose. A phase II ECOG study using TMTX 12 mg/m² intravenously day 1–5 every 21 days is currently being conducted.     

Phase II evaluation of bisantrene hydrochloride in refractory malignant melanoma

Patients with a pathologically proven diagnosis of malignant melanoma were entered into a phase II trial of bisantrene. Eligibility criteria included: measurable, metastatic disease; performance status 0–2 SWOG; and adriamycin total cumulative dose of < 400 mg/m². The initial bisantrene dosing schedule was 260 mg/m² every three weeks for good risk patients. Due to the absence of an objective response and the lack of severe toxicity in the first 25 bisantrene treated patients, the starting dose was increased to 300 mg/m² for good risk patients. Fifty-one patients received a median of two bisantrene courses (range 1–11 courses). Leukopenia was the major toxicity. Fifteen (68%) of the 22 good risk, intermediate dose patients (260 mg/m²), and 8 (80%) of the 10 good risk, high dose patients (300 mg/m²) evaluable for toxicity experienced mild-severe leukopenia. None of the 51 patients experienced a complete or partial response to bisantrene. Median survival was 3.3 months. We conclude that bisantrene is ineffective in the treatment of metastatic melanoma. Address for offprints: Southwest Oncology Group (SWOG-8118), Operations Office, 5430 Fredericksburg Road, Suite #618, San Antonio, TX 78229, USA     

Mitoxantrone in the treatment of acute leukemia

Summary Forty-six patients with acute leukemia were treated with mitoxantrone as a single agent. Twenty-nine patients had relapsed and/or refractory acute leukemia. Seventeen patients with acute non-lymphatic leukemia had received no prior treatment. Twelve mg/m² of mitoxantrone was given intravenous on five consecutive days. Treatment related side effects included bone marrow suppression, mucositis, alopecia, nausea, vomiting and infection. Cardiotoxicity was documented in 7 patients. This study reconfirms that mitoxantrone is an active agent in acute leukemia with complete response documented in 10 of 29 patients with relapsed and/or refractory acute leukemia (34% response rate, 95% confidence limits 18–53%) and complete response documented in 11 of 17 patients (65% response rate, 95% confidence limits 38–87%) with previously untreated acute non-lymphatic leukemia.     

Phase I study of liposomal daunorubicin in patients with acute leukemia

The dose of anthracyclines used during induction has been identified as a significant prognostic factor in acute leukemias. Liposomal encapsulation of anthracyclines has been proposed as a way of decreasing toxicity and probably increasing efficacy of these agents, therefore allowing the exploration of high-dose anthracycline therapy in acute leukemias. We conducted a phase I study of liposomal daunorubicin (Daunoxome® DNX) in patients with refractory or relapsed acute leukemias. Patients received three daily doses of DNX at 75, 100, 150 or 200 mg/m² on each cycle, to a total dose of 225, 300, 450, and 600 mg/m², respectively. At least three patients were included at each dose level before escalating to the next level, and patients could receive more than one course at the next dose level. Twenty-four patients were included and 23 are evaluable. Fifteen patients received one course, seven received two courses, and one received three courses of DNX. Seventeen patients had previously received anthracyclines. The dose-limiting toxicity was mucositis which occurred (grade 3–4) in 3 of 5 patients treated at 200 mg/m², 2 of 9 treated at 150 mg/m² and 1 of 6 at 100 mg/m². Other non-hematologic toxicity was mild and infrequent. There was no change in post-LVEF among 9 patients with available data and no significant cardiac events were documented. Two patients had a complete response: one patient with chronic myeloid leukemia in refractory blast phase went back to chronic phase, and one patient with second relapse acute promyelocytic leukemia achieved a third complete remission. We conclude that the maximally tolerated dose of DNX in this schedule is 150 mg/m² and has significant anti-leukemia activity.     

Phase II trial of ICRF-187 in patients with acquired immune deficiency related Kaposi's Sarcoma (AIDS-KS)

Summary Thirteen patients with AIDS related Kaposi's Sarcoma were entered on a phase II trial of ICRF-187, 1000 mg/m² IV daily for 3 days every 3 weeks. Eight patients had received prior chemotherapy for AIDS-KS. Six patients had prior opportunistic infection. There were no complete responses; one partial response lasting six months was seen. Toxicity was significant, and of the first 5 patients treated, 3 out of 5 had grade III or IV neutropenia. Because of this, subsequent patients received 800 mg/m² IV days 1–3 if previously untreated or 600 mg/m² if previously treated. Overall 4 of 13 patients had Grade IV neutropenia and 5 of 13 had Grade III neutropenia. One patient had Grade IV thrombocytopenia. ICRF-187 at a daily × 3 schedule has some efficacy in the treatment of AIDS related KS, future trials should evaluate lower doses or alternate schedules of administration.     

Phase I trial of motexafin gadolinium and doxorubicin in the treatment of advanced malignancies

Purpose To assess the safety, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT), of motexafin gadolinium (MGd), given in combination with doxorubicin, in patients with advanced solid tumors. Study Design The combination of MGd and doxorubicin was administered every 28 days (cycle 1) and then every 21 days (subsequent cycles). The dose of MGd, given daily for 3 days, was escalated from 1.0 mg/kg/d to 3.3 mg/kg/d, while the dose of doxorubicin was held at 30 mg/m². Results Fifteen patients received 37 cycles of treatment, for a median of 2 cycles per patient (range 0–6 cycles). Three patients (20%) completed 6 cycles of therapy. The MTD was identified as MGd, 2 mg/kg/day and doxorubicin, 30 mg/m². Dose limiting toxicities included grade 3 hypertension, pneumonia, bacteremia, and elevated GGT. Serious adverse events also included pulmonary embolism and urinary tract infection requiring hospitalization. There was no exacerbation of cardiac toxicity. No patients attained a response to treatment. Six patients (54%) had stable disease. The median time to disease progression, or to last assessment, was 49 days (range 8–195 days). Conclusions The combination of MGd and doxorubicin was fairly well tolerated. However, due to emerging preclinical data suggesting that MGd inhibits ribonucleotide reductase, further development of the combination of MGd plus doxorubicin is not recommended.     

Dose dependent methotrexate elimination following bolus intravenous injection

Summary The pharmacokinetics of methotrexate have been assessed at two dose levels in six patients recciving the drug for treatment of malignant disease. Each patient received bolus intravenous doses of 25 mg and 100 mg given at least one week apart, the order of administration being random. Blood and urine were collected until 48 h for methotrexate analysis by radioimmunoassay and data analysed by a model-independent pharmacokinetic approach. In each patient area under the methotrexate serum concentration-time curve (o to ) increased out of proportion to the increase in methotrexate dose. This was reflected in a mean clearance value after the 100 mg dose of 31±16 (SD) ml · min^–1 compared with a mean clearance of 62±19 ml · min^–1 following injection of 25 mg methotrexate. Renal clearance of methotrexate was markedly lower following the 100 mg dose (18±6 ml · min^–1) than after 25 mg (53±19 ml · min^–1). Saturation of the proximal tubular organic acid transport system is the likely cause of methotrexate's capacity limited elimination.     

Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma

Summary Purpose: The purpose of this single-center phase II study was to determine the activity of pemetrexed administered as second-line therapy in patients with advanced urothelial carcinoma. Methods: Patients with advanced urothelial carcinoma that had relapsed after receiving perioperative chemotherapy, or progressed on first-line chemotherapy for metastatic disease, were eligible for enrollment. Patients received pemetrexed 500 mg/m² every 21 days along with folic acid and vitamin B12 supplementation. Results: A total of 13 patients were enrolled. An objective response was achieved in 1/12 evaluable patients for an overall response rate of 8% (90% upper limit 29%). This level of activity did not meet criteria for expansion based on the pre-defined optimal 2-stage Simon design and the trial was concluded. Treatment was generally well tolerated, however, 2/13 patients developed febrile neutropenia. Non-hematologic grade ≥ 3 toxicity was rare. Conclusions: Pemetrexed as second-line therapy in advanced urothelial carcinoma is associated with modest activity. The role of this novel antifolate in chemotherapy-na?ve patients warrants further investigation.     

A Phase I Trial of Cisplatin Plus Decitabine, a New DNA-Hypomethylating Agent, in Patients with Advanced Solid Tumors and a Follow-Up Early Phase II Evaluation in Patients with Inoperable Non-Small Cell Lung Cancer

The authors describe a phase I trial of cisplatin plusdecitabine, a novel DNA-hypomethylating agent, in patients withadvanced solid tumors, which was followed by an early phase IIevaluation of the combination in patients with inoperablenon-small cell lung cancer (NSCLC). In the phase I trial,cisplatin was studied at a fixed dose of 33 mg/m²,while decitabine was escalated in four (I–IV) doseescalation levels (45, 67, 90 to 120 mg/m²,respectively) in consecutive groups of at least 3 patients perdose level. Decitabine was administered to the patients as atwo-hour intravenous infusion, while cisplatin was givenintravenously immediately after the end of decitabine infusion.Both agents were given on days 1–3 every 21 days.Twenty-one patients were included in the phase trial. Dose levelIV (120 mg/m² decitabine) was considered the maximumtolerated dose (MTD), while the dose-limiting toxicities wereneutropenia, thrombocytopenia and mucositis. The recommendeddoses for phase II trials in good- and poor-risk patients were90 (level III) and 67 mg/m² (level II), respectively.One short-lasting partial response was observed in a patient withcervical cancer, while two minor regression were documented ina patients with NSCLC and cervical cancer, respectively. Doselevel II was selected for the phase II trial in patients withinoperable NSCLC. Fourteen consecutive patients were included inthis part of the study. The median age of the patients was 57years (range, 39–75), male/female ratio of –11/3 anda median WHO performance status 1 (0–2). The stage ofdisease were IIIB (5) and IV (9). Prior irradiation to the chestwas given in one case. A total of 30 treatment courses wereevaluable for toxicity and response, with a median of 2 coursesper patient (1–4). Grade 3–4 neutropenia andthrombocytopenia were observed in about half of the cases.Mucositis, diarrhea, nausea and vomiting, and skin rash were alsoobserved in some patients. Three minor responses were documented,which lasted for 4, 16 and 36 weeks. Median survival of patientswas 15 weeks (4–38). In conclusion, the cisplatin plusdecitabine combination did not exhibit significant antitumoractivity in patients with NSCLC at the dose and schedule appliedin this trial to justify its further evaluation in this patientpopulation.     

5-Fluorouracil and Folinic Acid: a Phase I–II trial in gastrointestinal malignancy

Summary Fifty-one patients with metastatic adenocarcinoma received Folinic Acid (FA) combined with 5-Fluorouracil (5FU) in a Phase I–II clinical trial. Two different schedules were used: (a) bolus infusion — 5FU 7 –12 mg/kg/d I.V. d1–5, FA 1.6 mg/kg/d I.V. d1–5; (b) continuous infusion — 5FU 600–1200 mg/m²/d I.V. d1–4, FA 60 mg/m²/d I.V. d1–4. Mucositis and myelosuppression were dose-limiting, with recommended dose levels of 5FU for further trials being 10 mg/kg/d I.V. d1–5 and 1000 mg/m²/d I.V. d1–4 on the bolus and continuous infusion schedules, respectively. Forty-one evaluable patients with measurable disease were treated. Thirty-six had metastatic colorectal carcinoma, and 14/36 patients responded (CR-1, PR-13), including responses in three patients who had previously failed 5FU treatment alone. In the two patients with unknown primary sites and three with gastric cancer, no response were seen. 5FU and FA have activity equivalent to 5FU alone, and the responses in patients receiving prior 5FU suggest it may be superior. The possibility that toxicity may be enhanced does exist. Further trials of these two agents are warranted.     

Pharmacokinetics of Platinum in Cancer Patients Treated with Carboplatin in Combination with High-Dose Methotrexate

The pharmacokinetics of platinum was investigated in 10 cancer patients treated with a 1-hr infusion of 300 mg/m² of carboplatin which was given 2–4 days after the administration of 100 mg/kg (20-mg/kg bolus and 80-mg/kg intravenous infusion) of methotrexate. Platinum was analyzed in the samples by flameless atomic absorption spectrophotometry. The concentration vs time data for total platinum in plasma followed a two-compartment model and the mean (and SE) values for , TBC, V _c, and RC were 0.0827 (0.22) hr^–1, 2.355 (0.252) liters/hr · m², 10.74 (0.62) liters/m², and 2.405 (0.228) liters/hr · m², respectively. There was no significant change in the creatinine clearance or TBC with repeated treatment. The ultrafilterable platinum which was measured in the plasma of two patients constituted 82 and 11.3% of the total platinum at 1 and 24 hr, respectively, and the data conformed to the one-compartment model. The mean (SE) values for t , TBC, and V _d for free platinum were 1.844 (0.208) hr, 4.583 (1.059) liters/hr · m², and 11.88 (1.45) liters/m², respectively. The above data are in good agreement with those reported earlier for platinum following the administration of carboplatin as a single agent. These results suggest that high-dose methotrexate therapy, when administered 2–4 days before carboplatin, does not affect the pharmacokinetics of platinum in the plasma.