[CANCER RESEARCH 48, 3869-3874. July 1, 1988]

Pharmacokinetic and Toxicity Evaluation of Five-Day Continuous Infusion versusIntermittent Bolus m-Diamminedichloroplatinum(II) in Head and Neck CancerPatients1

Arlene A. Forastiere,2 James F. Belliveau, Marshall P. Goren, Walter C. Vogel, Marshall R. Posner, andGerard P. O'Leary, Jr.

Department of Medicine, Hematology-Oncology Division, University of Michigan Hospital and Veterans Administration Medical Center, Ann Arbor, Michigan 48105[A. A. F., W. C. y.]; Departments of Biology and Chemistry, Providence College, Providence, Rhode Island 02918 [J. F. B., G. P. O.J; Department of Pathology andLaboratory Medicine, St. Jude Children 's Research Hospital, Memphis, Tennessee 38101 [M. P. G.]; and Department of Medicine, Brown University and Roger Williams

General Hospital, Providence, Rhode Island 02908 [M. R. P.]

ABSTRACT

We administered cis-diamminedichloroplatinum(II), 30 my/iir/day for5 days by continuous infusion to six patients with head and neck cancer,and compared the total and filterable plasma concentrations of platinum,and toxic effects, with those observed in five additional patients whoreceived the same dose and schedule of cij-diamminedichloroplatinum(II)by intermittent bolus. In the continuous infusion group, the total 5-dayexposure to filterable platinum, determined from the area under theconcentration-time curve, was 1.5 to 2-fold higher (P < 0.01) than thatobserved in the intermittent bolus group although the maximum filterableplatinum concentration achieved was 8-fold lower (P < 0.01). Thesedifferences were not reflected by total platinum levels. Subclinical neph-rotoxicity, as judged by monitoring the urinary excretion of the renalenzymes yV-acetyl-0-D-glucosaininidase and alanine aminopeptidase, aswell as ototoxicity, and the incidence and severity of nausea and vomitingwere similar in both groups. In contrast, myelosuppression, and hypo-magnesemia were more frequent in the continuous-infusion patients,suggesting that the total exposure to free platinum contributes more tothese toxicities than peak levels achieved. Considering the clinicallyacceptable toxicity observed after administration by continuous infusion,we recommend larger therapeutic trials to define the efficacy of increasedtumor exposure to filterable platinum.

INTRODUCTION

Cisplatin3 is one of the most active agents available for the

treatment of solid tumors, in particular, head and neck (1),testicular, and ovarian cancers (2). In clinical trials the commonmethod of administration is either a large single bolus or dailybolus dosing. The dose-limiting toxicity is acute renal tubulardamage which is reduced by using hydration and forced diuresis(3) or a vehicle with high chloride ion concentration (4, 5).These maneuvers however, offer no protection against neuro-toxicity, ototoxicity, myelosuppression, and nausea and vomiting. In a previous trial conducted at the University of Michigan, we administered cisplatin in a dose of 50 mg/m2/day for4 days or 40 mg/m2/day for 5 days as a bolus to advanced head

and neck cancer patients. We observed a 73% response rate,double that expected from single-agent cisplatin. However,cumulative toxicities limited treatment to two or three coursesin the majority of patients (6).

Received 7/6/87; revised 12/28/87, 3/31/88; accepted 4/5/88.The costs of publication of this article were defrayed in pan by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1Supported in part by USPHS Grant 5M01-RR-00042, National CancerInstitute Grants CA-13943-14, and CA-20892-11, and Providence College Fundto Aid Faculty Research.

2To whom requests for reprints should be addressed, at University of Michigan

Medical Center, Department of Internal Medicine, Division of Hematology/Oncology, 3119 Taubman Center, P. O. Box 0374, Ann Arbor, MI 48109.

3The abbreviations and trivial name used are: cisplatin, <r/s-diamminedichlo-

roplatinum(II); AUC, area under the curve; CI, continuous infusion; IB, intermittent bolus; CV, coefficient of variation; NAG, iV-acetyl-/3-D-glucosaminidase;AAP, alanine aminopeptidase.

The active platinum species is nonprotein-bound or filterableplatinum (7). In vitro data suggest that prolonged low doseexposure may be advantageous for increasing cell kill andreducing toxicity (8). Since our data and that of others supporta dose-response effect for cisplatin (4, 6, 9), an importantquestion is whether the therapeutic index can be improved byusing an alternate method of administration. Therefore, weconducted a trial directly comparing the pharmacokinetics ofbolus and continuous infusion cisplatin in the treatment of aresponsive tumor, head and neck cancer. The specific objectiveswere to determine the exposure to filterable cisplatin for eachmethod of drug administration as measured by the product ofdrug concentration x time (AUC) and to determine the toxiceffects.

MATERIALS AND METHODS

Patients

All patients had a histologically confirmed diagnosis of squamouscell carcinoma of the head and neck, either recurrent disease or newlydiagnosed Stage IV cancer. Patients with prior exposure to cisplatinwere excluded; however, they may have had other chemotherapy orradiation therapy not less than 4 weeks prior to study entry. All patientshad bidimensionally measurable disease, a Karnofsky performance status of at least 60%, a life expectancy of at least 12 weeks, adequatebone marrow reserve (WBC > 3500 cells/Ml, platelets > 100,000 cells/ml), adequate renal function (creatinine clearance > 60 ml/min, serumcreatinine < 2 mg/dl), normal sensorimotor neurological exam, andaudiometry. If a hearing loss was present, this could not exceed 30 dBat 500, 1000, and 2000 Hz. There was no age limitation. However,patients over 70 were required to have a performance status of at least70% and a creatinine clearance of at least 80 ml/min. All patients gaveinformed consent in accordance with institutional guidelines.

Patients were alternately assigned to treatment with either CI or IBcisplatin in a dose of 30 mg/m2/day for 5 days. There was no attempt

to balance the two treatment groups with regard to prior treatment orextent of disease. Pre- and posttreatment hydration were identical forboth groups. This consisted of 500 ml of normal saline over 2 h priorto the start of cisplatin on Day 1 and 500 ml of normal saline with 20meq KC1 over 2 h followed by 500 ml D5W with 4 g MgSO«over 2 hat the completion of cisplatin on Day 5. CI cisplatin was started at 7:00a.m. on Day 1. The total daily dose of 30 mg/m2 was divided in 3 litersof normal saline and infused at 125 ml/h over each 24-h period for 5days. IB cisplatin was administered as 30 mg/m2 in 150 ml normal

saline over 20 min, from 4:40 p.m. to 5:00 p.m., daily for 5 days.Between cisplatin doses normal saline was infused at 125 ml/h. Nodiuretics were administered to either group unless patients showedsigns of fluid overload. Antiemetics were not given prophylactically.Thiethylperazine maléate(Torecan) was administered for nausea onlyand metoclopramide for nausea and vomiting.

Courses were repeated every 29 days or when the WBC count wasgreater than 3500 cells/^1 and platelets were greater than 100,000 cells/n\. Prior to each course, patients underwent a complete physical examination which included an audiogram, sensorimotor testing, and

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assessment of measurable disease parameters. Laboratory studies included 24-h civ,amine clearance, serum electrolytes, BUN, creatinine,complete blood count and platelet count. During treatment patientswere monitored with daily electrolytes, BUN, and creatinine determinations. Between treatments complete blood count and differential,platelet count, serum electrolytes, creatinine, and magnesium weredetermined weekly. Dose adjustments were based on the nadir countsof the preceding course. A 75% dose was given if the nadir WBC countwas less than 1500 cells/Ml or the nadir platelet count was less than50,000 cells/VI. Patients were removed from study if the creatinineclearance decreased to less than 60 ml/min, grade 2 or greater neuropathy occurred (absent deep tendon reflexes, motor weakness, and peripheral nerve pain), a symptomatic high frequency hearing loss or anyhearing loss in the speaking range occurred, or progressive disease wasdocumented. Standard response criteria were used (10).

Pharmacokinetic Determinations

nation phase, representing the turnover of protein bound platinum,were below the limits of detection of our analytical method and thusnot directly measured. However, to determine the potential effect ofthe secondary elimination phase on filterable platinum exposure, themaximum contribution that could be added during the 5-day period oftreatment was estimated using a steady state level of 0.020 mg Pt/literfrom the time that the primary elimination curve decreased to this level(approximately 4 h post-IB infusion) to the next IB infusion. The useof this level, 0.020 mg Pt/liter, is supported by the literature (13) andis twice the standard deviation of our filterable blank. Total platinumAUC for the 5-day IB period was calculated by summing the measuredAUCs for Days 1, 3, and 5 and multiplying the sum by 1.67 to accountfor Day 2 and 4 AUCs. Pharmacokinetic parameters were comparedbetween CI and IB cisplatin using the t test for significance betweenunpaired variâtes.

Tubular Nephrotoxicity Evaluation

Sample Collection/Preparation. Blood samples for the pharmacoki- Urine specimens were obtained before and daily for 2 weeks withnetic evaluation of CI cisplatin were drawn in heparinized tubes at each course of cisplatin. Urinary concentrations of NAG, AAP, andtimes 0, 3, 24, 48, 72. 96, and 120 h during infusion and 15, 30, 45, total urinary protein were determined by automated spectrophotometric60, and 120 min after the infusion was stopped. For the IB cisplatin methods (14, 15). Enzyme and protein concentrations were expressedgroup, samples were drawn on Days 1, 3, and 5 at 0, 15, 30, 45, 60, relative to the concentration of urinary creatinine to account for varia-120, and 240 min, where time 0 represented the end of the 20-minbolus infusion.

24-h urines were collected and monitored for platinum excretion foreach 24-h period during the 5-day continuous infusion and the 5-day

intermittent bolus administration.For analysis of the filterable (i.e., nonprotein-bound) platinum con

centrations in plasma, all samples were immediately centrifuged andduplicate 2-ml portions of the resultant plasma were removed andcentrifuged at 1000 x g for 1 h in CF50A Centriflow membrane cones(Amicon Corporation, Danvers, MA) to obtain filterable platinum.Total platinum was analyzed by using an aliquot of unfiltered plasma.Samples were stored at —20°Cuntil analyzed, usually a time period of

a few weeks.Plasma Analyses. Unfiltered plasma samples were diluted fourfold

with 10% HCI (v/v) and these were analyzed directly at 306.4 nm in aSpectraspan III (Applied Research Laboratories, Sunland, ÇA),a conventional d-c argon plasma emission spectrometer. Calibration standards (0.0, 0.5, and 1.0 mg/liter) were made up in plasma from hospitalpatients not on cisplatin therapy and these standards were also dilutedfourfold with 10% HCI (v/v). The lower detection limit for platinum inunfiltered plasma, defined as three times the standard deviation of theplatinum blank (11, 12), is 0. i O mg/liter (CV = 33% at detection limit;CV = 3.3%at 1.0 mg/liter).

Filtrate portions, because of their low volumes (0.7 ml) and lowplatinum concentrations (down to 0.030 mg/liter), were analyzed without dilution and by taking the amplified emission signal directly fromthe instrument to a recorder, thus avoiding time delays which arepresent when the microprocessor operates on the signal. A singleanalysis using full instrumental sensitivity and a sample volume as lowas 0.5 ml is accommodated with this technique. [Pt]nnerabiewas analyzedat 306.4 nm and calibration standards (0.00, 0.10, and 0.20 mg/liter)were prepared by standard addition of the appropriate amount of a 100mg/liter platinum stock solution to filtrate samples from hospitalpatients not on platinum therapy.

Urine samples were analyzed at 306.4 nm and calibration standards(0.50-5.00 mg/liter) were prepared by standard addition of a 1000 mg/liter platinum stock solution to urine samples from hospital patientsnot on platinum therapy. The lower detection limit for platinum inurine and filtered plasma samples is 0.03 mg/liter (CV = 33% atdetection limit; CV = 10% at 0.1 mg/liter).

Data Evaluation. The natural logarithm of 11'I ¡,,!,,,,,M.versus time datafrom the postinfusion phase were fitted to a single-kinetic eliminationterm using a linear least-squares routine. This procedure gave estimatesof the elimination rate constant (k), the half-life of elimination (¿1/2)and the plasma concentration (C..,.,j at the beginning of the postinfusionphase. The area under the [Pt]niuraMe-timecurve (AUC) was calculatedusing the trapezoidal rule during infusion and Cm*K/k¿for the postin-fusion phase. IB filterable platinum levels during the secondary elimi-

tions in urine output (16).For each course, the average AAP, NAG, and total protein concen

trations were calculated for the 14-day period during and after drugadministration. Increases over the pretreatment levels (average markerconcentrations minus the pretreatment concentration) were used forcomparisons of enzyme and protein excretion. Values for courses ofcisplatin administered by continuous infusion were compared to thoseadministered by intermittent bolus by the Mann-Whitney test (two-sided).

RESULTS

Pharmacology. The pharmacokinetic parameters determinedfor both patient groups are summarized in Table 1. The maximum total platinum was similar for CI and IB; however, maximum filterable platinum was approximately eight times higherfor IB (P < 0.01). The filterable platinum exposure for the 5days as measured by area under the concentration-time curve(AUC) was increased approximately 1.5-fold by CI administration, 9.2 ±2.5 mg h/liter compared to 6.5 ±0.9 mg h/liter forIB, P < 0.01. This represents the minimum difference in exposures and likely underestimates the actual increase in AUCresulting from CI. This is due to the maximum steady statelevel of 0.02 mg Pt/liter used in the estimation of the secondaryelimination phase occurring beyond the 4-h period in whichplasma specimens were obtained. Without an estimation ofsecondary elimination, the filterable platinum exposure for IBbecomes 4.4 ±0.9 mg h/Hter (range, 3.0-5.8) which results ina 2-fold increase in exposure for CI administration. Thus theminimum increase in exposure using CI compared to IB is 1.5-fold and the maximum 2.0-fold. In using only a single-kineticelimination term in the data evaluation, half-lives for filterable

Table 1 Summary of plasma pharmacokinetic parameters

No. ofpatientsNo.ofcoursesMaximum

|1M|..„,.Maximum

|Pt]r,i«,.wt[Ptjnitcnbic

exposureHalf-life

[Pt]r,i,„.bi«Continuous

infusion6111.9

±0.3°mg/liter(1.5-2.5)0.10

±0.03mg/liter(0.06-0.15)9.2

±2.5 mgh/liter(6.1-12.8)122

±74min(32-289)Intermittent

bolus592.1

±0.6 mg/liter P=0.05(1.1-3.0)0.85

±0.19 mg/literP<0.0\(0.50-1.15)6.5

±0.9 mg h/liter/><0.01(5.1-7.8)36

±6 minP<0.0\(23-47)

' Mean ±standard deviation. Numbers in parentheses, range.

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platinum elimination were significantly longer for the CI schedule.

The mean plasma concentrations of total and filterable platinum for the 11 courses administered by CI are illustrated inFig. 1. Samples were obtained over the 120 h of infusion andfor 2 h after the infusion ended. There was a significant lineartrend using a repeated measures analysis of variance for increasein total platinum over time, P = 0.001, and for increase infilterable platinum, P = 0.001 during the continuous infusion.These data indicate an accumulation in plasma of filterableplatinum. In addition a prolonged half-life of filterable platinum, 122 ±74 min was observed. Since the maximum filterableplatinum levels with CI are significantly lower than those withIB, the decrease of the cisplatin complex with its 30-min half-life is not the unique major process as is observed with biphasicIB elimination. A pharmacokinetic evaluation using a single-elimination term results in a longer half-life due to the important contribution of the slower tissue redistribution/eliminationprocesses. A biphasic or multiphasic analysis was not appliedbecause of the limited postinfusion data which were close tothe analytical detection limit. In comparison, Fig. 2 illustratesthe mean plasma concentrations of total and filterable platinumover 240 min after bolus administration. The data are derivedfrom 27 bolus doses. The half-life of filterable platinum was 36±6 min. Filterable platinum decreased more rapidly than totalplatinum indicating a high degree of protein binding associatedwith early rapid renal excretion of filterable platinum. Thisrapid decrease in filterable platinum would in part account forthe lower total exposure over the 5 days of treatment comparedto CI. Pharmacokinetic parameters were obtained for Days 1,3, and 5 of the IB group (Table 2). There was a significantincrease in the maximum total platinum measured over these Sdays (P = 0.02); however, maximum filterable platinum, half-life of filterable platinum, and exposure did not vary significantly. The percentages of platinum excreted in the urine forthe 5-day period was 24 ±8% for CI and 14 ±6% for IB, P<0.01. This increase in the percentage of platinum excreted inthe urine in the CI patients is consistent with the increase infilterable plasma platinum concentration over time (AUC) sinceonly nonprotein-bound platinum species are filtered by the

enE

co

••—•

coL.

O)oCoÜ

end of 120 hr infusion

0.0120 40 60 100 120 121 122

Time after beginning of infusion (hours)Fig. 1. Semilogarithmic graph of mean platinum concentrations versus time

for continuous infusion cisplatin. The data are derived from 11 5-day courses ofcisplatin; vertical bars, range of value; •,total Pt; O, filterable Pt.

O)

E

o•*—'edL_•+—

C<DUCOÜ

0.01-20 O 30 60 90 120 150 180 210 240

Time (min.)Fig. 2. Semilogarithmic graph of mean platinum concentrations versus time

for intermittent bolus cisplatin. The data are derived from 27 bolus administrations; vertical bars, range of values; •,total Pt; O, filterable Pt.

kidney. Intercycle platinum excretion did not change betweencycles 1 and 2 for IB patients (15% excreted for the 5-dayperiod), however the platinum excretion decreased from 27 ±7% for cycle 1 to 21 ±7% for cycle 2 for CI patients (P = 0.3).

Response and Toxicity. In this series of 11 patients, eightwere newly diagnosed and three had recurrent disease, only oneof which had received prior chemotherapy. Six patients received15 courses of CI cisplatin (three patients, two courses; threepatients, three courses) and five received 11 courses of IBcisplatin (four patients, two courses; one patient, three courses).Recurrent disease patients were treated until progressive diseasewas documented. Newly diagnosed patients received definitivelocal treatment with surgery and/or radiation therapy afterthree courses if complete or partial regression of disease occurred or after two courses and disease stabilization only.Responses were observed in four (one complete, three partial)or six treated by CI and there were two partial responders offive treated by IB. Although there was a trend for more responses in the CI group, the numbers of patients were too smallfor a meaningful statistical analysis.

Toxicities are detailed in Table 3. Leukopenia occurred morefrequently in CI patients. Prolonged myelosuppression resultedin treatment delays in four CI patients compared to none of theIB patients. Three patients (one IB, two CI) had dose reductionsdue to low nadir counts. This resulted in 75% dose administeredfor two IB courses and two CI courses. Gastrointestinal toxic-ities, nausea, vomiting, and diarrhea were a maximum of Grade2 (Southwest Oncology Group criteria) and similar for bothpatient groups. Neuropathy was limited to paresthesias only,even after a cumulative dose of 450 mg/m2 in two CI patients.

No patient required diuretics for fluid overload. Acute renaltubular toxicity was assessed by measurements of urinary AAP,NAG, and total protein. As shown in Fig. 3, the pattern ofurinary enzyme and total protein excretion was qualitativelysimilar for the IB and CI groups. While enzyme excretionpeaked on Day 6, total protein peaked between Days 6 and 9.The increases in enzyme and total protein excretion, whenaveraged over the 14-day period of observation, did not differsignificantly between the two treatment groups. The average

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Table 2 Pharmacokinetic parameters of intermittent bolus administration

Day1Maximum[Pt]„„i 1.6 ±0.5°mg/liter

(1.1-2.6)Maximum [Pt]f,i,„.bh: 0.87 ±0.19 mg/liter

(0.58-1.14)[Pt|mi,r.bi,exposure 0.81 ±0.18 mg/h/liter

(0.49-1.06)Half-life [Pt]r,ilmbi. 32 ±7 min

(23-47)°Mean ±standard deviation. Numbers in parentheses,range.*Significant / test result. Day 3 versus Day 5, P =0.02.Table

3 ToxicityContinuous

IntermittentinfusionbolusNo.

of patients 6 5No. of courses 1511No.

of patients No. ofpatientsMyelosuppression

Nadir WBC(cells/^1)2-3000301-200020<100001Nadir

platelets (cells/Ml)50- 100.000 22<50,000

10Nausea/vomiting

4 5Diarrhea 22Hypomagnesemia

5°2*Paresthesias

31Highfrequency hearing loss 31"

Ten of 15 courses.* Three of 11courses.•5;

6-c

55Q_

J4<

b<_31

23

|Q~

/~ ~\/

\ /—--// V/ \ ,AXs/

/ ^~~~~~~~~^'^''¿Z^?~^1

i 1 1 1 1 1 1 1 11ÃœJCc

5OS4Z"3o1

2100.7c

g°'6Q)"05'S

£ r,Aol

2c.n3m"•t;

oío2o^i- s o.iQA/A/'

/ \ —v¿_/

^—^v^*>^lililí1~/***^\/

'X'NSNX\''l'Xy^\/

JNN^V-_~__¿_/x^»_lililí

i234567 8 9 10 II 12 1314Time

(days)Fig.

3. Daily median concentrations of urinary AAP, NAG, and totalproteinduringand after 10 courses of cisplatin (Days 1-5) administered by i.v. bolus

(wliil line) and 12 courses administered by continuous infusion (dashed line).The upper limits of the reference range for AAP and NAG are 3.0 and 1.1U/mmol

creatinine, and for total protein, 0.15 g/gcreatinine.creatinine

clearance prior to treatment was 84 ml/min forCIand94 ml/min for IB. At the time patients left the study,theseaverages

were 69 ml/min for CI and 85 ml/min for IBpatients,notsignificantly different. One patient in each group had aDay

3 Day52.0±0.5 mg/liter 2.6 ±0.4* mg/liter

(1.1-2.5) (1.8-3.0)0.77 ±0. 18 mg/liter 0.90 ±0. 19 mg/liter

(0.50-0.99) (0.62-1.15)0.83 ±0.19 mg/h/liter 0.98 ±0.22 mg/h/liter

(0.58-1.15) (0.70-1.31)38 ±7 min 38 ±3 min

(24-43)(33-44)decrease

in creatinine clearance to less than 60 ml/minandtreatmentwas stopped. The maximum serum creatinine re

corded was 1.8 mg/dl. Despite similar acute renaltubularinjury,hypomagnesemia occurred in 67% of CI courses com

pared to 27% of IB courses (P < 0.05). This supports theideathaturinary magnesium loss may be mediated by aspecificmembrane

or transport system defect(17).DISCUSSIONOur

results show pharmacokinetic differences which are dependent on the method of administration of the identicaldoseof

cisplatin. Filterable platinum exposure (AUC) was 1.5 to2-foldgreater and the half-life nearly four times longer with5-dayCI compared to a 5-day IB schedule. All differenceswerehighly

significant, P< 0.01. These differences were not aresultofsignificant intercycle variability in a small number ofpatients.There

were no statistically significant differences forintercycledatafor AUC, half-life, and concentration parameterswitheitherIB or CI groups. To our knowledge this is the firsttrialto

directly compare the pharmacokinetics of continuous infusion with a high dose intermittent bolusschedule.In

the 1970s, initial Phase I clinical trials wereconductedusingIB dosing. DeConti et al. reported a biexponential elim

ination for bolus doses with an initial filterable platinumhalf-lifeof 25-49 min and a secondary phase of 58-73 h. Ninety%of

platinum was protein bound within 4 h. Urine excretionwasincomplete,27-45% in the first days (18). Our data andotherrecent

studies evaluating the pharmacokinetics of bolusandbriefinfusions of less than 1 h duration are in agreementwiththeseresults (19,20-22).Interest

in the administration of cisplatin by prolonged infusion in order to improve the therapeutic index stemmedfromthe

work of Derwinko et al. (8). Using cultured humanlym-phomacells, these investigators showed that low dose contin

uous exposure to cisplatin resulted in cell kill equivalenttoshortterm high dose exposure. This concept was testedinseveral

Phase I and II clinical trials evaluating the toxicityof24-120-hcontinuous infusion cisplatin (23-26). Jacobs etal.administered

50-130 mg/m2 (average, 80 mg/m2) over 24 hto18

patients with advanced head and neck cancer andconcludedthatthe response rate was equivalent to larger bolus doseswhiletoxicity

was greatly reduced (24). Three otherinvestigatorsevaluated5-day continuous infusions ranging from 20-40mg/m2/day

(23, 25, 26). They observed a change in thetoxicityprofile,

myelosuppression being the primary toxicity, whilenephrotoxicity and gastrointestinal toxicities were mild.Lokich(23)

and Posner (26) found 25-30 mg/m2/day to be the maxi

mum tolerabledose.Inour pharmacokinetic trial, toxicity from CI and IB cispla

tin was similar with the exception of myelosuppressionandmagnesiumwasting. Thrombocytopenia and/or leukopenia oc

curred in all six CI patients but in only two of five IB patients3872

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(P = 0.06). Prolonged marrow suppression was also responsiblefor treatment delays occurring only in CI patients. This toxicitypattern suggests that myelotoxicity is dependent on exposurerather than peak plasma levels.

Monoexponential pharmacokinetics of prolonged cisplatininfusions (greater than 20 h) have been observed by severalinvestigators (19, 21, 27). However, direct comparisons of 5-day CI and IB filterable platinum exposures analyzed by thesame laboratory have not been reported. Filterable platinumcontains unbound platinum and platinum which is bound tolow molecular weight nucleophiles (sulfhydryl-containing molecules) such as amino acids or small peptide chains. The therapeutic activity of the latter is unknown. The increased exposureto filterable platinum that we observed with CI may be explained by two factors. The plasma concentration of filterableplatinum increases over the duration of the 120-h constantinfusion (Fig. 1) due to the continual release of protein boundplatinum from tissues into the plasma compartment and itsslow elimination. The elimination half-life of the cisplatin complex after termination of the infusion is similar to the rate ofelimination of platinum from tissues. In addition, changes inrenal reabsorption of filterable platinum may contribute to theexposure difference observed between IB and CI cisplatin. Renalclearance of platinum involves tubular secretion and reabsorp-tion (28). Reece (29) has shown that in patients receiving boluscisplatin, tubular reabsorption is saturated immediately afterdrug is infused, when plasma and urinary platinum levels arehigh. As these levels decline, proportionally more reabsorptionoccurs with a reduction in renal clearance. Thus CI of cisplatinmay avoid saturation of this transport leading to increasedreabsorption of potentially active platinum species and prolonged plasma levels of filterable platinum.

In contrast, a biphasic decrease in filterable platinum occursafter IB cisplatin. The initial rapid elimination phase has a half-life of approximately 30 min and is due to the elimination ofthe cisplatin coordination complex or the active, nonprotein-bound platinum. The second much longer phase is due to theturnover of protein-bound platinum from tissues. When only asingle-kinetic elimination term was used in the data evaluation,the half-lives for filterable platinum eliminations were significantly longer for the CI schedule. Our observations are consistent with pharmacokinetic models established by Farris et al.(30).

Our increase in AUC with CI stands in contrast to that ofVermorken et al. (31), who reported similar AUCs for 100 mg/m2 dosages as 8-min, 3-h, and 24-h infusions. This literature

data was for only one course of therapy with each infusionprotocol as compared to multiple patients and courses with ourstudy. Moreover, the dose-rate (mg/h) for CI in our study wassubstantially lower than that reported by Vermorken. The observed increase in AUC with extended infusions has been previously reported (21).

In summary, we found that a total dose of 150 mg/m2 of

cisplatin administered in divided dose over 5 days by CI or IBwas tolerable. Gastrointestinal toxicity, ototoxicity, and neuropathy were mild and not treatment limiting. The exposure tofilterable platinum was significantly increased by CI. Althoughthe actual amount of free platinum or active drug is unknown,a therapeutic advantage may result from a continuous infusionof cisplatin. The spectrum of toxicity appears different with CIas suggested by the increase in myelosuppression in this seriesof patients. One may speculate that there is a continuumbetween the nephrotoxicity associated with maximum peakplasma levels and the non remi I toxicities of maximum-filterable

platinum exposure. Based on the increase in AUC, our resultssuggest that single agent cisplatin in a dose of 150 mg/m2administered as a 5-day CI may approach an optimal therapeutic index producing acceptable toxicity. The response rate ofthis regimen remains to be defined in larger numbers of patients.However, results of Phase II trials suggest that bolus cisplatinin doses of up to 200 mg/m2 produce higher response ratesthan conventional doses of 80-120 mg/m2 (4, 6, 9) although

cumulative toxicities limit treatment. While various hydrationschemes have been developed to minimize the risk of nephrotoxicity, in our experience, the daily administration of low totaldoses, either by bolus or continuous infusion does not requireexcessive hydration, forced diuresis, and multidrug prophylacticantiemetic regimens. Our results provide a pharmacokineticrationale for further testing of CI cisplatin in larger numbers ofpatients to determine if a therapeutic advantage does exist.

ACKNOWLEDGMENTS

The following students at Providence College assisted in the platinumanalyses: Paula Joly and Eric Ingersoll. The authors thank Hank Griffinand the personnel at the Chemistry and Materials Laboratories atTexas Instruments, Inc., Attleboro, MA, for granting permission to usetheir two plasma emission spectrometers and for their invaluable technical assistance. We acknowledge Barbara Blair for technical assistancewith the renal enzyme studies. We wish to thank Wilma Savitski forexpert secretarial assistance.

REFERENCES

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3. Hayes, D. M., Cvitkovic, E., Golbey, R. B., Scheiner, E., Helson, L., andKrakoff, I. H. High dose c/i-platinum diammine dichloride: amelioration ofrenal toxicity by mannitol diuresis. Cancer (Phila.), 39: 1372-1381. 1977.

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1988;48:3869-3874. Cancer Res   Arlene A. Forastiere, James F. Belliveau, Marshall P. Goren, et al.   Patients-Diamminedichloroplatinum(II) in Head and Neck Cancer

cis Intermittent Bolus versusContinuous Infusion Pharmacokinetic and Toxicity Evaluation of Five-Day

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