Nephroprotection by Theophylline in Patients with Cisplatin Chemotherapy: a Randomized, Single-Blinded, Placebo-Controlled Trial

JASN Express. Published on December 8, 2004 as doi: 10.1681/ASN.2004030225

Nephroprotection by Theophylline in Patients with Cisplatin Chemotherapy: A Randomized, Single-Blinded, Placebo-Controlled Trial

Peter Benoehr,* Patricia Krueth,† Carsten Bokemeyer,† Almut Grenz,‡ Hartmut Osswald,‡ and Jorg T. Hartmann† *Department of Nephrology and Rheumatology, University of Go¨ttingen, Go¨ttingen, Germany; and †Medical Center II, Department of Hematology and Oncology, Immunology, Rheumatology and Pneumonology and ‡Department of Pharmacology and Toxicology, Eberhard-Karls University of Tu¨bingen, Tu¨bingen, Germany

The aim of the present study was to assess the possible prevention of cisplatin-induced impairment of GFR by theophylline in patients with various malignancies. The trial design was parallel, randomized, single blinded, and placebo controlled. Patients received cisplatin at a dosage of 50 mg/m2 either combined with etoposide, ifosfamide, and epirubicin or with paclitaxel and 5-fluorouracil/folinic acid with the usual precautions, including a standard hydration scheme before application of cisplatin in both arms. In the control arm, placebo was administered; in the verum arm, patients received theophylline in a loading dose of 4 mg/kg intravenously over 30 min before cisplatin, followed by 0.4 mg/kg per min over a minimum of 6 h, and then 350 mg three times daily orally for 4 consecutive days after completion of chemotherapy. GFR of each patient was assessed by renal clearance of inulin within 3 d before and at day 5 after cisplatin chemotherapy. Despite usual precautions, patients in the placebo group had a 21% decrease (range, 11 to 31%) of inulin clearance after a single cycle of cisplatin- containing chemotherapy (92.9 ؎ 3.4 versus 71.8 ؎ 3.5 ml/min; P < 0.01). Patients who received theophylline had no deterioration of GFR (91.5 ؎ 3.7 versus 90.0 ؎ 3.8 ml/min; P > 0.05). No adverse effects have been observed during theophylline application. Conventional precautions such as hydration and osmotic diuresis cannot prevent a significant decrease of GFR after a single cycle of cisplatin-containing chemotherapy. The prophylactic application of theophylline as an intravenous loading dose and oral maintenance regimen may preserve kidney function in terms of GFR. J Am Soc Nephrol 16: ???-???, 2005. doi: 10.1681/ASN.2004030225

isplatin is a potent antineoplastic drug that is usually Adenosine is involved in the regulation of renal hemody- combined with other chemotherapeutic agents in the namics, tubular function, and hormone release. In contrast to C treatment of various cancer types. Its clinical use is other vascular beds, adenosine induces vasoconstriction in kid- limited by relevant organ toxicities such as nephrotoxicity, ney vessels, thereby coupling renal perfusion to the metabolic ototoxicity, gastrointestinal toxicity, myelosuppression, and al- rate of the organ (4,5). To limit renal energy expenditure, affer- lergic reactions (1,2). A decrease of GFR up to 30% was ob- ent arteriolar tone and glomerular perfusion are regulated by a served after two cycles of cisplatin-based chemotherapy despite negative feedback mechanism (tubuloglomerular feedback), precautions such as hydration and the use of diuretics (2,3). In dependent on the tubular load with fluid and solutes (6,7). addition, cisplatin leads to tubular enzymuria and electrolyte Substantial experimental evidence exists that adenosine is in- disturbances. This renal damage may be associated with several volved in signal transmission and serves as a principal media- patterns of histologic changes, including acute focal necrosis of tor of tubuloglomerular feedback response (4,8,9). The renal the distal convoluted tubules and the collecting ducts. In rats, actions of adenosine are primarily mediated via activation of cisplatin-induced nephrotoxicity has its maximum on days 3 to the membrane-bound adenosine receptor subtype and suscep- 5 with several structural and ultrastructural changes (e.g., focal tible to antagonism by theophylline (10,11). Various experimen- loss of brush border, cellular swelling, cytoplasmic vacuoliza- tal investigations have demonstrated elevated tissue adenosine tion, condensation of nuclear chromatin). concentrations after increased metabolic load (12), renal ischemia (11), or drug-induced nephrotoxicity (13) consecutively causing a decrease of GFR. In rats, continuously applied aminophylline treatment was Received March 23, 2004. Accepted October 19, 2004. able to prevent the reduction of GFR induced by cisplatin (14). Published online ahead of print. Publication date available at www.jasn.org. Therefore, this study examined the potential nephroprotective Address correspondence to: Dr. Peter Beno¨hr, Department of Nephrology and effect of theophylline at established pharmacologic doses dur- Rheumatology, Georg-August-University, Robert-Koch Strasse 40, 37075 Go¨ttingen, Germany. Phone: ϩ49-551-39-8509; Fax: ϩ49-551-39-8507; E-mail ing cisplatin-based chemotherapy in cancer patients with nor- [email protected] mal kidney function.

Materials and Methods and folinic acid (500 mg/m2; T-PLF). In addition, each patient received Eligibility 3000 ml of isotonic electrolyte solution, including 60 mmol of magne- The trial design was parallel, prospective, randomized, placebo con- sium and 6.9 mmol of calcium per 24 h and mannitol, 250 ml (20%), trolled, and single blinded. It was performed after the approval of the immediately before and after application of cisplatin in the control arm local institutional ethic committee review board of the Eberhard-Karls and in the verum arm. University of Tu¨bingen. Written informed consent was given by each patient before study inclusion. The study followed the Declaration of Collection of Samples and Clearance Investigations Helsinki and good clinical practice guidelines. Before the start of treatment GFR (measured by inulin clearance), Patients who had various types of cancer and were allocated to clinical parameters, and proteinuria were determined. GFR was as- cisplatin-based combination chemotherapy and had normal renal func- sessed by renal clearance of inulin. Indwelling catheters were inserted tion (measured by creatinine clearance Ͼ60 ml/min) were eligible for into a vein of both forearms for infusion and contralateral blood sam- the trial. Other eligibility criteria included age Ն18 yr, predicted life pling. Patients received a priming dose of 113 mg of inulin (InU test; expectancy Ͼ2 mo, Karnofsky status Ն60%, and adequate baseline Fresenius Pharma Austria, Linz, Austria) expressed per kilogram of organ functions. body weight dissolved in sodium chloride solution (250 ml, 0.9%) Patients were excluded when they had received previous treatment infused within 30 min. Thereafter, inulin was continuously infused at a with aminophylline derivatives immediately before study entry; had an rate of 313 mg/kg body wt, dissolved in sodium chloride solution (500 uncontrolled coronary heart disease, angina pectoris, arrhythmia, hy- ml, 0.9%) at a rate of 80 ml/h. After the equilibration period of 1 h, four perthyroidism, acute infection, bilateral loss of hearing Ͼ°II according 30-min baseline clearance periods were performed, during which uri- to World Health Organization criteria, sensory peripheral neuropathy, nary fluid losses were substituted orally by medicinal water (total time known adverse events in association with theophylline; or were preg- period 180 min). Urine was collected by spontaneous voiding, and nant and lactating or noncompliant. blood samples were drawn at the midpoint of each urine collection period. Study Medication On day 5, a second inulin clearance, clinical parameters, and protein- The intravenous study medication (Bronchoparat, Klinge, Germany) uria were assessed. Concentrations of inulin in plasma and urine were was prepared in the Chemistry department of the University of Tu¨- determined by a colorimetric assay (15), plasma levels of theophylline bingen under sterile conditions and distributed in a blinded manner. and clinical parameters using standard methods in the laboratory of the Study medication was infused using an initial dosage of 4 mg/kg body University of Tu¨bingen, and urinary protein excretion with a nephelo- wt intravenously within 30 min before cisplatin, then the infusion rate metric assay. was reduced to 0.4 mg/kg body wt intravenously for a minimum duration of 6 h. After intravenous application, a peroral medication Statistical Analyses (350 mg three times daily; Theophylline retard ratiopharm, Ratio- After inclusion, patients were randomly allocated to receive either pharm, Germany) was started for 4 consecutive days until assessment placebo or study medication. A computer-based randomization proce- on day 5 (see Figure 1 for details). dure was used. A sample size of 40 patients was planned. Patients were stratified according to chemotherapeutic pretreatment. Statistical dif- Chemotherapy Regimens and Precautions ferences between groups were evaluated by t test for paired and un- Cisplatin was applied at a dosage of 50 mg/m2 at day 1 combined paired samples. All values are expressed as the mean Ϯ SEM. P values with etoposide (500 mg/m2), ifosfamide (4 g/m2), and epirubicin (50 were determined by a two-sided calculation. Results were considered mg/m2; VIP-E) or with paclitaxel (80 mg/m2), 5-fluorouracil (2 g/m2), to be statistically significant at P Ͻ 0.05.

Figure 1. Details on theophylline application. J Am Soc Nephrol 16: ???-???, 2005 Nephroprotection by Theophylline in Patients with Cisplatin Chemotherapy 3

Results Twenty-six percent of patients (n ϭ 5) who were treated with Patients chemotherapy plus placebo had a GFR Ͻ60 ml/min at day 5 Forty-one patients entered the study at the Medical Center II, after treatment compared with 6% of patients in the verum arm Department of Oncology and Hematology, University of Tu¨- (Table 1). Seven patients in the placebo arm had a Ͼ20% de- bingen, Germany. Five patients were ineligible (n ϭ 2 fulminant crease of GFR compared with baseline, whereas this occurred in tumor progression, n ϭ 2 withdraw of consent, n ϭ 1 exacer- none of the patients who were treated with chemotherapy plus bated depression). In total, 17 patients received theophylline theophylline. and 19 patients received placebo and completed all study ex- aminations. There were no statistical differences in the baseline Effects on Serum Parameters patients’ characteristics, e.g., in terms of age distribution, gen- Neither differences among both treatment groups nor signif- der, type of malignancy, pretreatment, previously applied cu- icant changes within the two treatment arms from pre- to mulative cisplatin dose, serum creatinine and serum magne- postchemotherapy measurements in terms of serum magnesium values, creatinine clearance, and proteinuria before start sium or creatinine values were observed. of treatment (P Ͼ 0.05; Table 1). Patient characteristics are listed Effects on Urinary Protein Excretion in Table 2. In total, 16 patients were treated with VIP-E chemo- In the theophylline group, baseline protein excretion was therapy (eight patients in the verum and eight patients in the slightly higher compared with the placebo arm (128 Ϯ 35 versus placebo arm), and 20 patients were treated with T-PLF chemo- 71 Ϯ 10 mg/g creatinine). On day 5 after therapy, urinary therapy (nine patients in the verum arm and 11 patients in the protein excretion increased significantly in the verum group to placebo arm). All 36 patients were evaluated for serum creati- 317 Ϯ 69 mg/g creatinine and to a somewhat smaller extent in nine, inulin clearance, magnesium serum values, and urinary the placebo group (145 Ϯ 30 mg/g creatinine). In total, urinary marker excretion analysis. Patients in both arms had received protein excretion was elevated approximately two- to threefold the same volume load of electrolytes solution as well as the after chemotherapy in both groups at day 5 (Table 3). There same diuretic regimen, e.g., mannitol. were no signs of any pre- or postrenal causes for these changes, e.g., hemorrhagic cystitis. Effects on GFR High urine volumes were observed in both groups during Adverse Effects of Study Medication Ϫ Ϯ the clearance investigations on day 3 and day 5 (10.3 0.71 All patients had received chemotherapy, study medication, Ϯ ml/min for placebo and 10.7 0.75 ml/min for verum on day or placebo on a phase I study ward. Online monitoring for BP Ϫ Ϯ Ϯ 3; 9.4 0.71 ml/min for placebo and 9.3 0.65 ml/min for and pulse rate were performed, and no toxicity related to study verum on day 5). After a single cycle of cisplatin-based combi- medication was observed (Table 4). All patients had taken the nation chemotherapy, the median GFR values decreased by full oral dose of theophylline on 4 consecutive days after com- Ϯ 21% (range, 11 to 31%) from 90.0 ml/min ( 3.8) at baseline to pletion of treatment and discharge from the ward. 71.8 ml/min (Ϯ3.5) at day 5 in control patients (P Ͻ 0.01). In contrast, in the theophylline arm, the GFR was completely Theophylline Serum Concentrations preserved with 91.5 ml/min (Ϯ3.7) before and 92.9 ml/min For all patients in the verum arm, blood samples revealed a (Ϯ3.4) after application of chemotherapy (Figures 2 through 4). theophylline serum level in the therapeutic range of 5 to 15

Table 1. Serum parameters of renal toxicity

Verum Arm (Mean Ϯ SEM) Placebo Arm (Mean Ϯ SEM) P

GFRa day Ϫ3 91.5 Ϯ 3.7 90.0 Ϯ 3.8 NS day 5 92.9 Ϯ 3.4 71.8 Ϯ 3.5 P Ͻ 0.001 P NS P Ͻ 0.001 % of patients with subnormal values 1 (6%)/1 (6%) 1 (5%)/5 (26%) % of patients with Ͼ20% decrease — 7 (37%) Serum magnesium (mmol/L) day Ϫ3 0.80 Ϯ 0.06 0.80 Ϯ 0.10 NS day 5 0.82 Ϯ 0.07 0.79 Ϯ 0.10 NS P NS NS Serum creatinine (mg/dl) day Ϫ3 0.67 Ϯ 0.20 0.76 Ϯ 0.13 NS day 5 0.69 Ϯ 0.20 0.76 Ϯ 0.19 NS P NS NS

aMeasured by inulin clearance (ml/min). 4 Journal of the American Society of Nephrology J Am Soc Nephrol 16: ???-???, 2005

Table 2. Patient characteristicsa

Verum Arm Placebo Arm

N (patients)b randomized 20 21 assessable 17 19 Genderb male 10 14 female 7 5 Median age (yr ͓range͔)b 49 (25–63) 54 (29–70) Primary tumor (n patients)b gastric cancer 8 12 NHL 7 4 Hodgkin’s 1 1 larynx cancer 1 — cancer of unknown primary — 1 testicular cancer — 1 Previous chemotherapy (n patients)b 13 (76%) 15 (79%) Cisplatin-containing (n patients)b 6 (35%) 12 (63%) Median cisplatin dose (range)b 75 (50–250) mg/m2 75 (50–800) mg/m2 Mean (SEM)b 35 (Ϯ17) 89 (Ϯ41)

aNHL, non-Hodgkin’s lymphoma. bP Ͼ 0.05.

Figure 2. Changes of inulin clearance before and after completion of chemotherapy. Figure 3. Intraindividual changes of GFR in placebo group (clearance 1 and 2). mg/L (9.41 Ϯ 0.4 mg/L) after the end of the intravenous application. creatinine, proteinuria, and acute renal failure (ARF) (19). It is Discussion known that cisplatin induces a persistent reduction of GFR in a The exact mechanisms of cisplatin-induced nephrotoxicity range of 20 to 40% from baseline in long-term follow-up studies have not been fully elucidated. Like several nephrotoxic heavy (3), suggesting that these changes are partly irreversible. Today, metals (e.g., mercury), cisplatin may accumulate in the kidney, intensive prophylactic hydration and forced diuresis is used for where it can interact with sulfhydryl compounds, resulting in preservation of kidney function (20). increased membrane fragility and depletion of intracellular Adenosine has been proposed to exert important regulatory glutathione. There is some evidence that cisplatin can induce functions in the kidney, affecting renal blood flow, GFR, tubu- apoptosis and necrosis of kidney cells in a dose-dependent lar water and electrolyte transport, tubuloglomerular feedback, manner (16–18). Renal damage is associated with several pat- and secretion of renin (7,21). In contrast to other vascular beds terns of histologic changes, such as acute focal tubular necrosis (e.g., brain, heart), vessels in the kidney respond to exogenous and dilation of convoluted tubules and collecting ducts. Clini- or endogenous adenosine with vasoconstriction of the afferent cal manifestations are elevations in blood urea nitrogen, serum arterioles (5). This vasoconstriction is mediated by the adeno- J Am Soc Nephrol 16: ???-???, 2005 Nephroprotection by Theophylline in Patients with Cisplatin Chemotherapy 5

Several supportive measures have been proposed to prevent cisplatin-induced nephrotoxicity. Besides adequate hydration before and during cisplatin administration and afterward in combination with an osmotic diuretic such as mannitol (the current standard method), e.g., prolongation of the infusion time of cisplatin (e.g., 6 h instead of 2 h), dose fractionation over several days, the use of a chronomodulated schedule, and the use of nephroprotective agents such as organic thiosulfate compounds have been investigated in this setting (18,27–31). How- ever, in general practice, a single-dose application of cisplatin as a 1-h infusion remains the common standard, and only dose fractionation over several days is being used in some cancer types (2,3). Experimental study drugs that may be useful in renal protection include BNP7787 (dimesna), selenium, amifostine, and silibinin (16,27–30,32–35). Figure 4. Intraindividual changes of GFR in the theophylline Amifostine (WR-2721, ethyofos, 2-[3-aminopropyl)amino]- group (clearance 1 and 2). ethylphosphorothioic acid), an organic thiophosphate, is a pro- drug that has cytoprotective properties as a result of free radical sine A1 receptor and can be blocked by the nonselective aden- scavenging, hydrogen ion donation, or removal of DNA plati- osine receptor antagonist theophylline (7,10). Experiments in num adducts (36). In a randomized study of 242 patients who animals have shown that adenosine receptor antagonists such had advanced ovarian cancer and received intravenous cispla- as xanthinderivates (e.g., theophylline) ameliorate or prevent tin 100 mg/m2 and cyclophosphamide 1000 mg/m2 once every the severity of ARF. These experimental models of ARF include 3 wk, the calculated creatinine clearance decreased by Ͼ40% in renal ischemia, glycerol injection, drug-induced nephrotoxicity, two thirds of the control group compared with 12% of those in and radiocontrast media as the underlying causative factors the group that received amifostine in a dosage of 910 mg/m2 (7,22,23). In addition, a recent study demonstrated an upregu- (37). In other studies, intravenous amifostine applied before lation of adenosine A1 receptor in the rat kidney on day 3 cisplatin preserved GFR measured by creatinine clearance induced by cisplatin infusion (24), indicating an increased sen- when it was co-administered with standard-dose cisplatin– sitivity to adenosine in the case of repetitive applications of containing or high-dose carboplatin–containing (Ͼ1.5 g/m2) cisplatin. regimens. Even after two cycles that contain intravenous cis- To our knowledge, this is the first study to demonstrate a platin 50 mg/m2 plus intravenous ifosfamide and etoposide or nephroprotective effect of theophylline in patients who receive paclitaxel, GFR can decrease by Ͼ30%, but concomitant use of cisplatin-containing chemotherapy. Despite hydration and amifostine was able to counteract this decay (38,39). In a few forced diuresis, patients in the placebo arm had a significant studies, some preventive effects on renal tubulus function have decrease of GFR (median, Ϫ21%; range, 11 to 31%; P Ͻ 0.01) also been observed, and even lower dosages of intravenous measured by the most sensitive available method (inulin clear- amifostine (e.g., 740 mg/m2) may be effective (38,40). In con- ance) after a single cycle of standard-dosage cisplatin (50 trast to amifostine, the treatment with aminophyllines results in mg/m2) chemotherapy. Theophylline, a competitive adenosine a more cost-effective prevention strategy because theophylline receptor antagonist, administered before and during the main- seems to have the same magnitude of GFR preservation com- tenance phase, completely preserved kidney function in terms pared with amifostine, and it is associated with a more conve- of GFR (median decrease, 1%; range, Ϫ4 to 5%). Side effects of nient toxicity profile. theophylline were not observed, and the application was sub- In some studies, glutathione has been shown to reduce cis- jectively well tolerated. The results of this trial confirmed ani- platin-related toxicity without impairing its antineoplastic ac- mal data that have demonstrated a nephroprotective effect of tivity (41). However, a cisplatin dose-escalation study with adenosine receptor antagonists after cisplatin application (14). concomitant administration of glutathione had to be terminated No significant changes in serum creatinine, serum magnesium, prematurely because of unacceptable ototoxicity (42), and glu- or proteinuria were observed. Serum creatinine, as shown ear- tathione has not yet received Food and Drug Administration lier (2), is an insensitive marker to detect acute glomerular approval for chemoprotection. impairment. A relevant effect of theophylline on proteinuria In the present trial, only the acute nephrotoxicity of cisplatin was not detected in our study; however, this can also be caused was examined. Therefore, further studies have to evaluate po- by tubular effects of cisplatin, which are not influenced by tential long-term effects of theophylline on kidney function. theophylline. This is of great importance because cisplatin-based chemother- Other clinical investigations of theophylline have shown that apy is used in a variety of patients with potentially curable this drug can prevent radiocontrast media–induced renal im- cancer (e.g., metastatic testicular cancer, ovarian carcinoma) pairment (25). In addition, efficacy was demonstrated in pa- and hematologic malignancies or in the adjuvant setting for tients with chronic renal insufficiency and application of radio- ovarian carcinoma or as recently published for non–small-cell contrast media (26). lung cancer (43). In addition, the present trial included only 6 Journal of the American Society of Nephrology J Am Soc Nephrol 16: ???-???, 2005

Table 3. Urinary protein excretion analysis

Urinary Protein Excretion Ϯ Ϯ (mg/g creatinine) Verum Arm (Mean SEM) % Change Placebo Arm (Mean SEM) % Change

Day Ϫ3 128 Ϯ 35 71 Ϯ 10 Day 5 317 Ϯ 69 147 145 Ϯ 30 104

Table 4. Hemodynamic parameters

Verum Arm (Mean Ϯ SEM) Placebo Arm (Mean Ϯ SEM) P

Systolic BP (mmHg) day Ϫ3 113 Ϯ 2.65 120 Ϯ 2.89 NS day 5 118 Ϯ 2.91 117 Ϯ 2.91 NS P NS NS Diastolic BP (mmHg) day Ϫ378Ϯ 1.21 77 Ϯ 1.76 NS day 5 77 Ϯ 2.15 75 Ϯ 1.81 NS P NS NS Pulse rate (bpm) day Ϫ372Ϯ 1.93 76 Ϯ 2.1 NS day 5 77 Ϯ 1.21 76 Ϯ 1.8 NS P NS NS

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