The Use of Probenecid as a Chemoprotector Against Cisplatin Nephrotoxicity Charlotte Jacobs, MD,* Sonja Kaubisch, PharmD,+ Joanne Halsey, RN,* Bert L. Lum, PharmD,+ Michael Gosland, PharmD,* C. Norman Coleman, MD,$ and Branimir I. Sikic, MD*

Probenecid inhibits cisplatin (CP) secretion in humans and protects against CP- induced nephrotoxicity in rats. The authors conducted a Phase I trial of escalating doses of CP using probenecid as a chemoprotector. Fifty-four courses of CP at doses ranging from 100 to 160 mg/m* were given by 24-hour infusion to 36 patients. There was no renal impairment at any dose. Ototoxicity, however, became the dose-limiting toxicity; 14 patients experienced a 20 or greater decibel (dB) loss. Seven percent of courses were associated with a leukocyte count of less than 1.5 X lo/pl, and 19% with a platelet count of less than 50 X 103/pl. Only three patients developed neurotoxicity. Correlating pharmacokinetic data and toxicity, the authors found that high cumulative dose, area under the curve (AUC) for unbound platinum, and cumulative AUC were associated with ototoxicity and peripheral neuropathy. It was concluded that probenecid may protect against CP nephrotoxicity and warrants further investigation. Its unique mechanism of action and lack of toxicity make it ideal to combine with other chemoprotectors. Cancer 67:1518-1524,1991.

ISPLATIN (CP) is a highly effective chemotherapeutic C agent with a broad spectrum of activity. Early on, its use was severely limited by renal insufficiency, but this toxicity has been substantially ameliorated by several dif- ferent approaches, including use of mannitol, furosemide, and long-term infusion.'Y2 Standard doses of CP range from 50 to 100 mg/m2, and even at these doses, up to 20% of patients will develop nephrotoxicity, usually de- fined as a serum creatinine greater than 2 mg/d1.3*4 Al- though this amount of renal dysfunction may not be life- threatening, it can limit the ability to deliver subsequent CP chemotherapy and thus eventually compromise out- come. It had been speculated that the nonnephrotoxic analogue, carboplatin, would replace CP, diminishing the clinical significance of the nephrot~xicity.~ Unfortunately, carboplatin is more myelosuppressive, not allowing its

From the *Department of Medicine, Stanford University School of Medicine, Stanford, California; the ?Department of Pharmacy, Palo Alto VA Medical Center, Palo Alto, California; and the $Department of Ra- diation Therapy, Harvard University School of Medicine, Boston, Mas- sachusetts.

Supported by a grant from the Bristol-Myers Company. Address for reprints: Charlotte Jacobs, MD, Stanford University School

Accepted for publication December 12, 1990. of Medicine, Division of Oncology M211, Stanford, CA 94305-5306.

substitution for CP in many chemotherapy combinations, and it is not yet clear whether carboplatin will have the same spectrum of activity.

Nephrotoxicity also diminishes the maximal dose of CP which can be given. For some cancers it may be im- portant to be able to deliver more intensive doses of CP, and a dose-response to CP has been demonstrated in sev- eral malignancies6-' Approaches to prevent renal dys- function at higher CP doses have included hypertonic sa- line infusion," diethyldithiocarbamate (DDTC), I ' sodium thiosulfate," and WR272 1 .' At high doses of CP, however, new dose-limiting neuropathic toxicities have emerged.

Our investigations on the renal disposition of CP sup- port the hypothesis that platinum (Pt) is secreted by the human kidney.13 Furthermore, we could block that se- cretion with probenecid, and we postulated that blockage of secretion may reduce the concentration of Pt in the renal tubule and decrease nephrotoxicity. l 4 In these trials, CP was delivered by 24-hour infusion to achieve a steady state of free Pt necessary for accurate determination of F't clearances. Ross and Gale have shown that administration of probenecid to rats before CP significantly reduced the peak serum creatinine and histologic changes in the kidney but did not decrease therapeutic efficacy. l5 Daley-Yates and McBrien, however, report enhanced nephrotoxicity

1518

No. 6 PROBENECID AGAiNST CISPLATIN NEPHROTOXICITY - Jacobs et a/. 1519

in rats when probenecid was given with an intraperitoneal injection of CP.I6

We present our Phase I dose-escalation trial to deter- mine the maximally tolerated dose of CP with probenecid used as a protector against nephrotoxicity. In addition, the relationship of pharmacokinetic data to toxicity was analyzed.

Materials and Methods Patients were eligible for the study if they had a patho-

logically confirmed cancer which was refractory to stan- dard treatment or for which no effective treatment was available. Eligible patients had a creatinine clearance of greater than 50 ml/minute, a leukocyte count of 3500/p1 or greater, a platelet count of 15O,OOO/p1 or greater, and a Karnofsky performance status of 70 or greater. All pa- tients signed informed consent, as approved by the Hu- man Subjects Committee. Concurrent radiation was al- lowed to limited fields, but could not include solitary sites of measurable disease.

Initial evaluation included complete history and phys- ical examination, complete blood count, liver function tests, creatinine clearance, urine B2 microglobulin, serum magnesium, audiogram, chest radiograph, and appropri- ate computed tomographic scans, bone scans, or magnetic resonance imaging.

Probenecid was given orally at a dose of 1 g every 6 hours beginning 24 hours before CP and continuing 24 hours after completion of the CP infusion, for a total of 12 doses. This dose was based on a study of probenecid’s effects on the disposition of nafcillin,” and studies showing that the plasma half-life of probenecid is dose-dependent. l 8

Before the start of chemotherapy, patients were prehy- drated for 6 hours with 1 1 of dextrose 5% in 0.45% normal saline (USP) (DMNS). The total dose of CP was divided into 6 1 of fluid, alternating 1 1 of D5’/2NS with DSNS, and delivered by continuous infusion over 24 hours. After this infusion, patients received 1 1 DMNS alternating with D5NS every 6 hours for 24 hours. Potassium and mag- nesium were added as needed, and furosemide was ad- ministered only in the case of fluid overload. Antiemetics were given at the discretion of the house officer.

The initial dose of CP was 100 mg/mz. The first esca- lation was by 30 mg/m2 and subsequent steps by 10 mg/ m2. At least three fully evaluable patients were treated at each step, and the dose escalated in the next patient only if the preceding dose was sufficiently nontoxic, defined as less than 50% of the patients experiencing any of the fol- lowing toxicities: creatinine clearance of less than 40 ml/ minute, leukocyte count of less than 15OO/p1, platelet count of less than 20,00O/pl, Grade 3 ototoxicity, or Grade 2 neurotoxicity. Individual patients were retreated at their assigned dose if their tumor had not progressed and tox- icity permitted.

All toxicities were scored according to the Northern California Oncology Group (NCOG) criteria, ranging from 0 to 4 with Grade 4 as life-threatening. For ototox- icity, the following scale was used: Grade 1, 10 decibel (dB) or greater loss; Grade 2,20 dB or greater loss; Grade 3 , 40 dB or greater loss; and Grade 4, 60 dB or greater loss. Patients were evaluated with weekly complete blood counts and serum creatinine. At 3 weeks, patients had repeat creatinine clearance, audiogram, serum magne- sium, appropriate radiographs, and physical examination with special attention to neurologic findings and tumor measurements. The ratio of B2 microglobulin/creatinine was measured in urine before treatment and at 24 hours.”

Patients had free and total plasma Pt levels drawn before chemotherapy, and at 6, 12, 24, and 48 hours after start of the infusion. Blood samples were collected by veni- puncture into an iced syringe, and plasma was immedi- ately obtained for ultrafiltrate preparation. Plasma samples were filtered through Centrifo membrane cones (type CFSOA, Amicon, Danvers, MA) which retain material with a molecular weight of 50,000 or greater for mea- surement of free Pt. A sample of whole plasma was re- tained for measurement of total Pt. These procedures were carried out at 2°C. Plasma Pt values were determined using a flameless atomic absorption spectrophotometer (Perkin-Elmer model 2280; Perkin-Elmer, Nonvalk, CT) with a graphite furnace and programmer (HGA-400).’’

Thirty patients had pharmacokinetic analysis per- formed during 34 courses of CP. The following data was collected cumulative dose, peak plasma concentration (total and free Pt), elimination rate constant, and area under the curve (AUC) at 24 and 48 hours, and estimated cumulative AUC. Patients were characterized as toxic or nontoxic based on the following criteria: neutropenia (na- dir < 2000/pl), thrombocytopenia (nadir < 60,00O/pl), nephrotoxicity (increase in serum creatinine 0.5 mg/dl over baseline and/or decrease in creatinine clearance by 25%), vomiting (Grade 3), diarrhea (Grade 2, 3), ototox- icity (Grade 2-4), and peripheral neuropathy (Grade 1- 4). Painvise analysis between toxic and nontoxic patients was performed using the Wilcoxon rank sum Test.

Although this was a Phase I trial, tumor response for patients with measurable disease was judged as follows: complete response (disappearance of all measurable or evaluable disease, signs, symptoms, and biochemical changes related to the tumor, for at least 4 weeks, during which no new lesions may appear), partial response (when compared with pretreatment measurements, a reduction of at least 50% in the sum of the products of the perpen- dicular diameters of all bidimensionally measurable le- sions lasting at least 4 weeks, during which no new lesions may appear and no existing lesion may enlarge), stable (a less than 50% reduction and less than 25% increase in the sum of the products of two perpendicular diameters of

1520 CANCER March 15 199 1 Vol. 67

all measured lesions, the appearance of no new lesions, and lasting for greater than 8 weeks), or progressive disease (an increase in the product of two perpendicular diameters of any measured lesion by greater than 25% over the size present at entry on study or for patients who respond, the size at the time of maximum regression or the appearance of any new lesions).

Results

Thirty-six patients entered the trial, and all were eval- uable for toxicity and response. There were 22 women and 14 men with a mean age of 52 years (range, 22 to 75). The Karnofsky performance status ranged from 70 to 100 with a mean of 90. The tumor types included head and neck cancers, 14 patients; lung, nine; ovarian, six; sarcoma, three; and unknown primary, four. Twenty-two patients had been treated with prior radiation therapy and three received concurrent radiation to small fields. Prior chemotherapy included regimens without CP in 11 pa- tients and with CP in ten. Three patients received con- current vinblastine.

Fifty-four courses of chemotherapy were delivered at the following doses: 100 mg/m*, 12; 130 mg/m2, 12; 140 mg/m2, 19; 150 mg/m2, eight; and 160 mg/m2, three. In- dividual patients received one to three courses. Disease progression was the most common reason for discontin- uing treatment.

There were no reported side effects from probenecid. Renal function, as measured by serum creatinine and cre- atinine clearance, did not change after treatment with doses up to 160 mg/m2 (Table 1). No patient had a serum creatinine elevation greater than 2 mg/dl. Data for the 48 cycles for which pretreatment and posttreatment serum creatinine and creatinine clearance were available dem- onstrated the following: the mean -t SE pretreatment serum creatinine was 0.9 f 0.4 mg/dl, and the posttreat- ment serum creatinine was 1 .O f 0.5 mg/dl; the pretreat-

ment creatinine clearance was 80 5 3 ml/minute, and the posttreatment creatinine clearance was 76 f 4 ml/minute. The pretreatment creatinine clearance was lower in the group treated at the lowest dose of CP. Early in the study, the ratio of B2 microglobulin/creatinine in the urine was measured as a potentially more sensitive marker of neph- rotoxicity. These ratios were elevated at doses ranging from 100 to 140 mg/m2 (Table 1). Since there was no apparent dose-response relationship of this value to in- creasing CP dose, and since changes in the ratio did not correlate with changes in creatinine clearance, this pa- rameter was not measured at the final dose escalation steps.

Myelosuppression was evaluated by course (Table 2). Significant neutropenia of less than 1500/pl with no as- sociated infections occurred in four courses. Thrombo- cytopenia of less than 50,OOO/pl occurred in ten courses, often requiring platelet transfusions but without associated bleeding. A hemoglobin of less than 10 mg/dl was recorded in 26 courses. All patients had some nausea and vomiting. There appeared to be more Grade 3 vomiting (one to three times daily) at the higher dose levels, but no Grade 4 toxicity. There were two courses associated with Grade 2 and three with Grade 3 diarrhea.

Two patients experienced Grade 2 peripheral neurop- athy, defined as mild paresthesia. One occurred at a cu- mulative dose of 400 mg/m2 in a patient who had also received vinblastine; the other occurred at 440 mg/m2. Five patients experienced hair loss at the 140 to 150 mg/ m2 dose level, and one had transient blurred vision.

The major dose-limiting toxicity was ototoxicity (Table 3). Twenty-eight patients had the required pretreatment and posttreatment audiograms, and 75% had documented hearing loss. Seven experienced Grade 1 ototoxicity (2 10 dB loss), ten developed Grade 2 toxicity (2 20 dB loss), and four experienced Grade 3 toxicity (2 40 dB loss). Hearing loss occurred with the first dose of CP in most patients, and it was only partially reversible. The

TABLE 1. Renal Function After Therapy With Cisplatin Plus Probenecid

Cisplatin dose (mg/mz)

LOO 130 140 I50 160 (n = lo)* (n = 10) (n = 17) (n = 8) (n = 3)

Pretreatment serum creatinine (mg/dl) 1.2 f 0.lt 1.0 f 0.1 0.9 2 0.1 0.7 f 0.1 0.7 2 0.2 1.0 2 0.3

Pretreatment creatinine clearance (ml/min) 64 f 2 79 2 10 79 f 4 98 f 4 95 f 13 Posttreatment creatinine clearance (ml/min) 5 7 f 6 78 f 7 81 f 6 88 f 8 74 f 25 Pretreatment Bz microglobulin/creatinine ratio 8.8 f 5.2 12.1 f 3.9 5.4 2 3.1

Posttreatment B2 microglobulin/creatinine

0.9 2 0.1 Posttreatment serum creatinine (mg/dl) 1.2 f 0.1 1.0 f 0.1 1.0 f 0.1

(n = 5) (n = 8) (n = 12)

ratio 34.4 f 13.3 169.6 2 92.9$ 10.9 f 6.9

* No. of courses. t Mean f SE.

$ High mean and SE accounted for by one value of 784.

No. 6 PROBENECID AGAINST CISPLATIN NEPHROTOXICITY * Jacobs et al. 1521

TABLE 2. Myelosuppression and Gastrointestinal Toxicity of Cisplatin Plus Probenecid

Cisplatin dose (mg/m2)

100 130 140 150 160 (n = 12)* (n = 12) (n = 19) (n = 8) (n = 3)

Toxicity Leukocytes

I 4 2 1

1 2 1

2.1-3 x 1 0 3 / ~ 1 - 1.5-2 x 1 0 ~ / ~ c l 1 1 1 2 1 < I S x 1 0 3 / ~ 1 -

100-150 X 103/pl 1 1 50-99 x 1 0 3 / ~ 1 - - - - <50 x 1 0 3 / ~ 1 - 3 4 2 1

Hemoglobin < 10 g/dl I 8 6 3 2# Vomitingt-Grade 3 - 1 4 5 2 Diarrhea?

Grade 2 - - - - 2 Grade 3 - - - - 3

- Platelets

- - - 3

* No. of courses. t Northern California Oncology Group toxicity scale.

mean age of those who developed this toxicity was 52 years, compared with 53 in those who did not experience this toxicity. Ototoxicity appeared to be more frequent at the higher dose levels: 40% at 100 mg/m2, 67% at 130 mg/m2, 93% at 140 mg/m2, and 100% at 150 and 160 mg/m2.

Pharmacokinetic data of total and free plasma Pt is presented in Table 4. The percent protein binding of plasma Pt increased with time from 70% at 6 hours to almost total binding by 24 hours. The mean peak free Pt was 0.30 & 0.1 pg/dl at 12 hours, and it did not vary with dose. The mean peak total Pt was 2.96 1- 0.9 pg/dl, and AUC for total E't was dose related. There was no difference in the elimination rate constant within the dose range administered.

An analysis of all pharmacokinetic parameters with re- gard to neutropenia and thrombocytopenia failed to demonstrate any correlations. Grade 3 vomiting correlated with the peak total Pt, but not with other factors (Table 5). Five patients developed Grade 2 or 3 diarrhea, and occurrence of this toxicity correlated with the peak free

# Data not available on one patient.

Pt level as well as the AUC for free Pt at 0 to 48 hours. Pharmacokinetic data that significantly correlated with peripheral neuropathy (Grade 1, 2) were AUC of free Pt at 0 to 48 hours and the cumulative AUC. Significant correlations were found between ototoxicity (Grade 2, 3) and AUC for free Pt at 0 to 48 hours, cumulative AUC, and cumulative dose.

Although this was a Phase I dose-escalation trial, all patients were evaluable for response. Three patients had a partial response, 20 had stable disease, and 13 disease progression.

Discussion

Because CP is an active agent for many malignancies, it is important to be able to deliver the drug optimally. This may mean the ability to prescribe repeated standard doses, as for patients with testicular or head and neck cancers, or the ability to use higher doses, as for patients with melanoma or ovarian cancers. Nephrotoxicity- specifically an acute tubular necrosis-has been the major

TABLE 3. Ototoxicity of Cisplatin Plus Probenecid

Cisplatin dose (mg/m2) ~

100 130 140 150 160 (n = 5)* (n = 3) (n = 14) (n = 4) (n = 2)

0 tot o x i c i t y Grade 1 (210 dB loss) 2 - 2 2 1 Grade 2 (220 dB loss)

1 2 1 Grade 3 (240 dB loss) - - Grade 4 (260 dB loss) - - - - -

- - 2 8 -

* No. of patients.

1522 CANCER March 15 1991 Vol. 67

TABLE 4. Pharmacokinetic Data According to Dose

Cisplatin dose (mg/mz)

100 130 140 I50 I60 (n = 5)* (n = 7) (n = 4) (n = 2) (n = 12)

Free plasma Pt ke-(hr-') 0.0597 f 0.0 13f 0.010 k 0.007 0.01 1 f 0.01 0.014 2 0.01 1 0.072 2 0.056 AUC 0-48 hr (pg/ml X hr) 7.03 f 2.13 7.43 k 1.8 6.21 f 2.42 6.31 * 2.15 6.92 f 1.44 Peak level (pglml) 0.37 f 0.12 0.39 k 0.09 0.35 f 0.19 0.38 f 0.08 0.29 f 0.08

AUC 0-48 hr (pg/ml X hr) 85.1 f 16.6 101.6 _+ 11.4 95.0 f 22.6 146.0 f 18.0 121.5 f 24.7 Peak level (uelml) 2.32 rt 0.5 1 2.88 k 0.33 2.62 f 0.52 4.34 k 0.92 4.03 k 1.3

Total plasma Pt

Pt: platinum; AUC: area under the curve. * No. of patients.

dose-limiting toxicity. Despite use of mannitol diuresis, furosemide, or 24-hour infusion, up to one fifth of patients will still experience some renal dysfunction at standard doses.4s21,22 This limits the ability to deliver optimal doses and/or number of courses of drug.

Dose has been shown to be a critical factor in cancer chemotherapy.6 Although the optimal dose of CP for most cancers is yet to be defined, high doses of CP appear to be superior to standard doses for patients with ovarian cancer, lung cancer, and m e l a n ~ m a . ~ - ~ Protective agents which allow delivery of high-dose CP include WR272 1, DDTC, sodium thiosulfate, and hypertonic saline infu- sion.23.?4 In a trial of ovarian cancer patients, CP at 200 mg/m2 was delivered over 5 days with hypertonic saline to decrease levels of the toxic aquated specie^.^ Although

t Mean. f Standard deviation.

32% of patients had a creatinine of greater than 2 mg/dl, there were no cases of renal failure. In a dose-escalation trial of CP and the sulfhydryl agent WR2721, 5% of courses were associated with nephrotoxicity at doses up to 150 mg/m2.* With DDTC, a chelator used to reverse Pt binding to sulfhydryl groups, normal renal function was reported at CP doses of 50 to 120 mg/m2." We have found no nephrotoxicity in escalating CP doses up to 160 mg/m2 with DDTC." Sodium thiosulfate has been suc- cessfully used as a chemoprotector for patients receiving intraperitoneal CP, probably through inhibition of direct binding of CP to the renal tubule.12

In our trial, we have demonstrated prevention of CP- induced renal dysfunction with probenecid. The highest dose of CP was 160 mg/m2, although only three patients

Peripheral neuropathy Grade 1, 2

Ototoxicity Grade 2, 3

TABLE 5 . Relationships Between Pharmacokinetic Variables and Toxicity

Pharmacokinetic Mean in Mean in Toxicity variable nontoxic group toxic group P valuet

Vomiting Grade 3 (n = 20)* (n = 10)

Diarrhea Grade 2, 3 (n = 24) (n = 5)

Peak total Pt (pglml) 2.80 (0.9)$ 3.30 (0.8) 0.04

Free F't (pg/ml) 0.34 (0.1) 0.50 (0.2) 0.05 Free Pt AUC 0-48 hr (pg/ml X hr) 6.33 (2.0) 8.50 (1.9) 0.04

Free Pt AUC

Cumulative dose (mg) 294.00 (179) 467.00 (31) 0.15

(n = 26) (n = 3)

0-48 hr (pg/ml X hr) 6.38 (1.9) 9.55 (0.76) 0.0 1

Cumulative free Pt AUC 35.00 (33) 119.00 (37) 0.0 I

(n = 13) (n = 11) Free Pt AUC 0-48 hr (pg/ml X hr) 6.67 (1.7) 7.07 (2.5) 0.04 Cumulative dose (mg) 302.00 (1 84) 400.00 (162) 0.05 Cumulative free Pt AUC 35.00 (3 1) 68.00 (53) 0.05

W m l X hr)

AUC: area under the curve; Pt: platinum. * No. of patients. t P values are Wilcoxon rank sum pair-wise analysis of toxic versus

nontoxic patient courses (two-tailed values). f Standard deviation.

No. 6 PROBENECID AGAINST CISPLATIN NEPHROTOXICITY . Jacobs et al. 1523

could be treated at this dose due to other toxicities. This protection most likely occurs through partial inhibition of Pt renal secretion and subsequent decrease in Pt con- centration in the renal tubule. One cannot overlook the role of hydration in ameliorating nephrotoxicity. In our prior experience with the 24-hour infusion, however, 50% of the courses given at 120 mg/m2 resulted in a serum creatinine elevation greater than 2 mg/dL2 We did not find the ratio of B2 microglobulin/creatinine to be helpful since an increased ratio did not correlate with changes in creatinine clearance.

In comparison with other chemoprotectors, probenecid is relatively nontoxic, inexpensive, and readily available. Probenecid protection was studied, however, only with CP given by 24-hour infusion. Its potential use with shorter infusion times is untested. In addition, patients only received one to three courses, usually because of dis- ease progression. Probenecid needs to be tested in a pop- ulation of patients with CP-responsive tumors in order to assess its long-term protection. A randomized trial with a hydration-only arm would substantiate the benefits of probenecid, but we believe that such a control arm would be unduly risky to patients treated with high doses of CP.

As one would expect from its local action in the kidney, probenecid did not protect against other toxicities. We found ototoxicity to be the dose-limiting toxicity, and at doses greater than 140 mg/m2, almost every patient had measurable hearing loss. Patients at greatest risk were those who had recently received or were concurrently re- ceiving whole-brain irradiation. In trials of hypertonic sa- line infusion, WR272 1, or DDTC, ototoxicity has oc- curred in the majority of patients as well.7,8,25,26 In our probenecid trial, we did not find substantial peripheral neuropathy, with only two patients reporting mild par- esthesia. This may be a conservative estimate since pe- ripheral neuropathy was determined by clinical exami- nation alone without EMG or other measures of nerve conduction. In addition, the mean cumulative dose was only 260 mg/m2. This is in contrast to the study of Ozols and Young where the median dose of CP was 600 mg/ m2, and 89% experienced peripheral neuropathy leading to ataxia in 37% and wheelchair dependence in 1 l%.7 We observed myelosuppression, particularly thrombocyto- penia, to be greater than one would expect with standard doses of C P 7% of courses were associated with significant neutropenia and 19% with significant thrombocytopenia. Both WR2721 and DDTC may prove to be better pro- tectors against CP-induced myelosuppression than pro- benecid.

In general, the biological activity and toxicity of drugs has been attributed to the free fraction of those drugs. Recent data, however, suggest that protein-bound CP may be able to react with nu~leophiles.~~ Toxicity may also be

enhanced by low levels of free Pt as a result of release from plasma proteins or tissue compartments. Total ex- posure to drug, as defined by AUC, may also be an im- portant determinant of drug effects. Although we found no correlation between AUC of free Pt and dose, the AUC may have been underestimated since Pt was only mea- sured at four time points.

We evaluated possible correlations of pharmacokinetic data and toxicities. In contrast to other reports, we found that neither dose level nor cumulative dose demonstrated significant correlation with myelosuppre~sion.~~~~~ Diar- rhea correlated well with peak free plasma Pt concentra- tion and AUC of free Pt at 48 hours, whereas Grade 3 vomiting correlated with peak total Pt only. Similar to the experience of other investigators, we found peak free plasma Pt to correlate with peripheral neuropathy as well as AUC of free Pt and estimated cumulative AUC, sup- porting the premise that cumulative exposure to concen- trations of unbound Pt over time may be the basis for the development of CP ne~ropa thy .~~ ,~ ' Our data indicate correlation between ototoxicity and cumulative dose, as well as free Pt AUC at 48 hours and cumulative AUC. There was no correlation with individual dose adminis- tered. Although no single pharmacokinetic parameter can be considered predictive for CP toxicities, our data dem- onstrated the importance of AUC of free Pt in ototoxicity as well as peripheral neuropathy. Prospective evaluation of the utility of dose modification based on AUC analysis after the first dose to prevent chronic toxicity may be war- ranted.

A major concern with any protector is that it may in- hibit cytotoxic activity against cancer cells. Probenecid works at the level of the renal tubule, and theoretically would have no impact on antitumor activity of CP. Ross and Gale found that probenecid did not influence the therapeutic action of CP on L1210 leukemia in BDFl mice.15 In our group of heavily pretreated patients, there were three partial responses. A Phase I1 trial would need to be performed to be certain that probenecid does not interfere with CP antitumor activity.

In conclusion, probenecid, an inhibitor of CP secretion in the renal tubule, may prevent nephrotoxicity and war- rants further investigation. It does not protect against other toxicities, and in our trial, ototoxicity became dose-lim- iting. Probenecid may be beneficial in diminishing the risk of renal dysfunction with repeated standard CP doses, and this needs to be studied in a randomized trial. It may also be used to reduce the risk of nephrotoxicity at higher doses, but other toxicities limited dose escalation. Because of the unique mechanism of protection, ease of admin- istration, and lack of toxicity of probenecid, it may be useful in combination with other protectors in future trials.

1524 CANCER March 15 199 1 Vol. 67

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