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 Göttingen, Göttingen, Germany; and Medical Center II, Department of Hematology and Oncology, Immunology, Rheumatology and Pneumonology and Department of Pharmacology and Toxicology, Eberhard-Karls University of Tübingen, Tübingen, Germany
Address correspondence to: Dr. Peter Benöhr, Department of Nephrology and Rheumatology, Georg-August-University, Robert-Koch Strasse 40, 37075 Göttingen, Germany. Phone: +49-551-39-8509; Fax: +49-551-39-8507; E-mail pbenoeh{at}gwdg.de
The aim of the present study was to assess the possible preventionof cisplatin-induced impairment of GFR by theophylline in patientswith various malignancies. The trial design was parallel, randomized,single blinded, and placebo controlled. Patients received cisplatinat a dosage of 50 mg/m2 either combined with etoposide, ifosfamide,and epirubicin or with paclitaxel and 5-fluorouracil/folinicacid with the usual precautions, including a standard hydrationscheme before application of cisplatin in both arms. In thecontrol arm, placebo was administered; in the verum arm, patientsreceived theophylline in a loading dose of 4 mg/kg intravenouslyover 30 min before cisplatin, followed by 0.4 mg/kg per minover a minimum of 6 h, and then 350 mg three times daily orallyfor 4 consecutive days after completion of chemotherapy. GFRof each patient was assessed by renal clearance of inulin within3 d before and at day 5 after cisplatin chemotherapy. Despiteusual precautions, patients in the placebo group had a 21% decrease(range, 11 to 31%) of inulin clearance after a single cycleof cisplatin-containing chemotherapy (92.9 ± 3.4 versus71.8 ± 3.5 ml/min; P < 0.01). Patients who receivedtheophylline had no deterioration of GFR (91.5 ± 3.7versus 90.0 ± 3.8 ml/min; P > 0.05). No adverse effectshave been observed during theophylline application. Conventionalprecautions such as hydration and osmotic diuresis cannot preventa significant decrease of GFR after a single cycle of cisplatin-containingchemotherapy. The prophylactic application of theophylline asan intravenous loading dose and oral maintenance regimen maypreserve kidney function in terms of GFR.
Cisplatin is a potent antineoplastic drug that is usually combinedwith other chemotherapeutic agents in the treatment of variouscancer types. Its clinical use is limited by relevant organtoxicities such as nephrotoxicity, ototoxicity, gastrointestinaltoxicity, myelosuppression, and allergic reactions (1,2). Adecrease of GFR up to 30% was observed after two cycles of cisplatin-basedchemotherapy despite precautions such as hydration and the useof diuretics (2,3). In addition, cisplatin leads to tubularenzymuria and electrolyte disturbances. This renal damage maybe associated with several patterns of histologic changes, includingacute focal necrosis of the distal convoluted tubules and thecollecting ducts. In rats, cisplatin-induced nephrotoxicityhas its maximum on days 3 to 5 with several structural and ultrastructuralchanges (e.g., focal loss of brush border, cellular swelling,cytoplasmic vacuolization, condensation of nuclear chromatin).
Adenosine is involved in the regulation of renal hemodynamics,tubular function, and hormone release. In contrast to othervascular beds, adenosine induces vasoconstriction in kidneyvessels, thereby coupling renal perfusion to the metabolic rateof the organ (4,5). To limit renal energy expenditure, afferentarteriolar tone and glomerular perfusion are regulated by anegative feedback mechanism (tubuloglomerular feedback), dependenton the tubular load with fluid and solutes (6,7). Substantialexperimental evidence exists that adenosine is involved in signaltransmission and serves as a principal mediator of tubuloglomerularfeedback response (4,8,9). The renal actions of adenosine areprimarily mediated via activation of the membrane-bound adenosinereceptor subtype and susceptible to antagonism by theophylline(10,11). Various experimental investigations have demonstratedelevated tissue adenosine concentrations after increased metabolicload (12), renal ischemia (11), or drug-induced nephrotoxicity(13) consecutively causing a decrease of GFR.
In rats, continuously applied aminophylline treatment was ableto prevent the reduction of GFR induced by cisplatin (14). Therefore,this study examined the potential nephroprotective effect oftheophylline at established pharmacologic doses during cisplatin-basedchemotherapy in cancer patients with normal kidney function.
Eligibility
The trial design was parallel, prospective, randomized, placebocontrolled, and single blinded. It was performed after the approvalof the local institutional ethic committee review board of theEberhard-Karls University of Tübingen. Written informedconsent was given by each patient before study inclusion. Thestudy followed the Declaration of Helsinki and good clinicalpractice guidelines.
Patients who had various types of cancer and were allocatedto cisplatin-based combination chemotherapy and had normal renalfunction (measured by creatinine clearance >60 ml/min) wereeligible for the trial. Other eligibility criteria includedage 18 yr, predicted life expectancy >2 mo, Karnofsky status60%, and adequate baseline organ functions.
Patients were excluded when they had received previous treatmentwith aminophylline derivatives immediately before study entry;had an uncontrolled coronary heart disease, angina pectoris,arrhythmia, hyperthyroidism, acute infection, bilateral lossof hearing >°II according to World Health Organizationcriteria, sensory peripheral neuropathy, known adverse eventsin association with theophylline; or were pregnant and lactatingor noncompliant.
Study Medication
The intravenous study medication (Bronchoparat, Klinge, Germany)was prepared in the Chemistry department of the University ofTübingen under sterile conditions and distributed in ablinded manner. Study medication was infused using an initialdosage of 4 mg/kg body wt intravenously within 30 min beforecisplatin, then the infusion rate was reduced to 0.4 mg/kg bodywt intravenously for a minimum duration of 6 h. After intravenousapplication, a peroral medication (350 mg three times daily;Theophylline retard ratiopharm, Ratiopharm, Germany) was startedfor 4 consecutive days until assessment on day 5 (see Figure 1for details).
Chemotherapy Regimens and Precautions
Cisplatin was applied at a dosage of 50 mg/m2 at day 1 combinedwith etoposide (500 mg/m2), ifosfamide (4 g/m2), and epirubicin(50 mg/m2; VIP-E) or with paclitaxel (80 mg/m2), 5-fluorouracil(2 g/m2), and folinic acid (500 mg/m2; T-PLF). In addition,each patient received 3000 ml of isotonic electrolyte solution,including 60 mmol of magnesium and 6.9 mmol of calcium per 24h and mannitol, 250 ml (20%), immediately before and after applicationof cisplatin in the control arm and in the verum arm.
Collection of Samples and Clearance Investigations
Before the start of treatment GFR (measured by inulin clearance),clinical parameters, and proteinuria were determined. GFR wasassessed by renal clearance of inulin. Indwelling catheterswere inserted into a vein of both forearms for infusion andcontralateral blood sampling. Patients received a priming doseof 113 mg of inulin (InU test; Fresenius Pharma Austria, Linz,Austria) expressed per kilogram of body weight dissolved insodium chloride solution (250 ml, 0.9%) infused within 30 min.Thereafter, inulin was continuously infused at a rate of 313mg/kg body wt, dissolved in sodium chloride solution (500 ml,0.9%) at a rate of 80 ml/h. After the equilibration period of1 h, four 30-min baseline clearance periods were performed,during which urinary fluid losses were substituted orally bymedicinal water (total time period 180 min). Urine was collectedby spontaneous voiding, and blood samples were drawn at themidpoint of each urine collection period.
On day 5, a second inulin clearance, clinical parameters, andproteinuria were assessed. Concentrations of inulin in plasmaand urine were determined by a colorimetric assay (15), plasmalevels of theophylline and clinical parameters using standardmethods in the laboratory of the University of Tübingen,and urinary protein excretion with a nephelometric assay.
Statistical Analyses
After inclusion, patients were randomly allocated to receiveeither placebo or study medication. A computer-based randomizationprocedure was used. A sample size of 40 patients was planned.Patients were stratified according to chemotherapeutic pretreatment.Statistical differences between groups were evaluated by t testfor paired and unpaired samples. All values are expressed asthe mean ± SEM. P values were determined by a two-sidedcalculation. Results were considered to be statistically significantat P < 0.05.
Patients
Forty-one patients entered the study at the Medical Center II,Department of Oncology and Hematology, University of Tübingen,Germany. Five patients were ineligible (n = 2 fulminant tumorprogression, n = 2 withdraw of consent, n = 1 exacerbated depression).In total, 17 patients received theophylline and 19 patientsreceived placebo and completed all study examinations. Therewere no statistical differences in the baseline patients’characteristics, e.g., in terms of age distribution, gender,type of malignancy, pretreatment, previously applied cumulativecisplatin dose, serum creatinine and serum magnesium values,creatinine clearance, and proteinuria before start of treatment(P > 0.05; Table 1). Patient characteristics are listed inTable 2. In total, 16 patients were treated with VIP-E chemotherapy(eight patients in the verum and eight patients in the placeboarm), and 20 patients were treated with T-PLF chemotherapy (ninepatients in the verum arm and 11 patients in the placebo arm).All 36 patients were evaluated for serum creatinine, inulinclearance, magnesium serum values, and urinary marker excretionanalysis. Patients in both arms had received the same volumeload of electrolytes solution as well as the same diuretic regimen,e.g., mannitol.
Effects on GFR
High urine volumes were observed in both groups during the clearanceinvestigations on day –3 and day 5 (10.3 ± 0.71ml/min for placebo and 10.7 ± 0.75 ml/min for verum onday –3; 9.4 ± 0.71 ml/min for placebo and 9.3 ±0.65 ml/min for verum on day 5). After a single cycle of cisplatin-basedcombination chemotherapy, the median GFR values decreased by21% (range, 11 to 31%) from 90.0 ml/min (±3.8) at baselineto 71.8 ml/min (±3.5) at day 5 in control patients (P< 0.01). In contrast, in the theophylline arm, the GFR wascompletely preserved with 91.5 ml/min (±3.7) before and92.9 ml/min (±3.4) after application of chemotherapy(Figures 2 through 4). Twenty-six percent of patients (n = 5)who were treated with chemotherapy plus placebo had a GFR <60ml/min at day 5 after treatment compared with 6% of patientsin the verum arm (Table 1). Seven patients in the placebo armhad a >20% decrease of GFR compared with baseline, whereasthis occurred in none of the patients who were treated withchemotherapy plus theophylline.
Figure 4. Intraindividual changes of GFR in the theophylline group (clearance 1 and 2).
Effects on Serum Parameters
Neither differences among both treatment groups nor significantchanges within the two treatment arms from pre- to postchemotherapymeasurements in terms of serum magnesium or creatinine valueswere observed.
Effects on Urinary Protein Excretion
In the theophylline group, baseline protein excretion was slightlyhigher compared with the placebo arm (128 ± 35 versus71 ± 10 mg/g creatinine). On day 5 after therapy, urinaryprotein excretion increased significantly in the verum groupto 317 ± 69 mg/g creatinine and to a somewhat smallerextent in the placebo group (145 ± 30 mg/g creatinine).In total, urinary protein excretion was elevated approximatelytwo- to threefold after chemotherapy in both groups at day 5(Table 3). There were no signs of any pre- or postrenal causesfor these changes, e.g., hemorrhagic cystitis.
Adverse Effects of Study Medication
All patients had received chemotherapy, study medication, orplacebo on a phase I study ward. Online monitoring for BP andpulse rate were performed, and no toxicity related to studymedication was observed (Table 4). All patients had taken thefull oral dose of theophylline on 4 consecutive days after completionof treatment and discharge from the ward.
Theophylline Serum Concentrations
For all patients in the verum arm, blood samples revealed atheophylline serum level in the therapeutic range of 5 to 15mg/L (9.41 ± 0.4 mg/L) after the end of the intravenousapplication.
The exact mechanisms of cisplatin-induced nephrotoxicity havenot been fully elucidated. Like several nephrotoxic heavy metals(e.g., mercury), cisplatin may accumulate in the kidney, whereit can interact with sulfhydryl compounds, resulting in increasedmembrane fragility and depletion of intracellular glutathione.There is some evidence that cisplatin can induce apoptosis andnecrosis of kidney cells in a dose-dependent manner (16–18).Renal damage is associated with several patterns of histologicchanges, such as acute focal tubular necrosis and dilation ofconvoluted tubules and collecting ducts. Clinical manifestationsare elevations in blood urea nitrogen, serum creatinine, proteinuria,and acute renal failure (ARF) (19). It is known that cisplatininduces a persistent reduction of GFR in a range of 20 to 40%from baseline in long-term follow-up studies (3), suggestingthat these changes are partly irreversible. Today, intensiveprophylactic hydration and forced diuresis is used for preservationof kidney function (20).
Adenosine has been proposed to exert important regulatory functionsin the kidney, affecting renal blood flow, GFR, tubular waterand electrolyte transport, tubuloglomerular feedback, and secretionof renin (7,21). In contrast to other vascular beds (e.g., brain,heart), vessels in the kidney respond to exogenous or endogenousadenosine with vasoconstriction of the afferent arterioles (5).This vasoconstriction is mediated by the adenosine A1 receptorand can be blocked by the nonselective adenosine receptor antagonisttheophylline (7,10). Experiments in animals have shown thatadenosine receptor antagonists such as xanthinderivates (e.g.,theophylline) ameliorate or prevent the severity of ARF. Theseexperimental models of ARF include renal ischemia, glycerolinjection, drug-induced nephrotoxicity, and radiocontrast mediaas the underlying causative factors (7,22,23). In addition,a recent study demonstrated an upregulation of adenosine A1receptor in the rat kidney on day 3 induced by cisplatin infusion(24), indicating an increased sensitivity to adenosine in thecase of repetitive applications of cisplatin.
To our knowledge, this is the first study to demonstrate a nephroprotectiveeffect of theophylline in patients who receive cisplatin-containingchemotherapy. Despite hydration and forced diuresis, patientsin the placebo arm had a significant decrease of GFR (median,–21%; range, 11 to 31%; P < 0.01) measured by the mostsensitive available method (inulin clearance) after a singlecycle of standard-dosage cisplatin (50 mg/m2) chemotherapy.Theophylline, a competitive adenosine receptor antagonist, administeredbefore and during the maintenance phase, completely preservedkidney function in terms of GFR (median decrease, 1%; range,–4 to 5%). Side effects of theophylline were not observed,and the application was subjectively well tolerated. The resultsof this trial confirmed animal data that have demonstrated anephroprotective effect of adenosine receptor antagonists aftercisplatin application (14). No significant changes in serumcreatinine, serum magnesium, or proteinuria were observed. Serumcreatinine, as shown earlier (2), is an insensitive marker todetect acute glomerular impairment. A relevant effect of theophyllineon proteinuria was not detected in our study; however, thiscan also be caused by tubular effects of cisplatin, which arenot influenced by theophylline.
Other clinical investigations of theophylline have shown thatthis drug can prevent radiocontrast media–induced renalimpairment (25). In addition, efficacy was demonstrated in patientswith chronic renal insufficiency and application of radiocontrastmedia (26).
Several supportive measures have been proposed to prevent cisplatin-inducednephrotoxicity. Besides adequate hydration before and duringcisplatin administration and afterward in combination with anosmotic 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, theuse of a chronomodulated schedule, and the use of nephroprotectiveagents such as organic thiosulfate compounds have been investigatedin this setting (18,27–31). However, in general practice,a single-dose application of cisplatin as a 1-h infusion remainsthe common standard, and only dose fractionation over severaldays is being used in some cancer types (2,3). Experimentalstudy drugs that may be useful in renal protection include BNP7787(dimesna), selenium, amifostine, and silibinin (16,27–30,32–35).
Amifostine (WR-2721, ethyofos, 2-[3-aminopropyl)amino]ethylphosphorothioicacid), an organic thiophosphate, is a prodrug that has cytoprotectiveproperties as a result of free radical scavenging, hydrogenion donation, or removal of DNA platinum adducts (36). In arandomized study of 242 patients who had advanced ovarian cancerand received intravenous cisplatin 100 mg/m2 and cyclophosphamide1000 mg/m2 once every 3 wk, the calculated creatinine clearancedecreased by >40% in two thirds of the control group comparedwith 12% of those in the group that received amifostine in adosage of 910 mg/m2 (37). In other studies, intravenous amifostineapplied before cisplatin preserved GFR measured by creatinineclearance when it was co-administered with standard-dose cisplatin–containingor high-dose carboplatin–containing (>1.5 g/m2) regimens.Even after two cycles that contain intravenous cisplatin 50mg/m2 plus intravenous ifosfamide and etoposide or paclitaxel,GFR can decrease by >30%, but concomitant use of amifostinewas able to counteract this decay (38,39). In a few studies,some preventive effects on renal tubulus function have alsobeen observed, and even lower dosages of intravenous amifostine(e.g., 740 mg/m2) may be effective (38,40). In contrast to amifostine,the treatment with aminophyllines results in a more cost-effectiveprevention strategy because theophylline seems to have the samemagnitude of GFR preservation compared with amifostine, andit is associated with a more convenient toxicity profile.
In some studies, glutathione has been shown to reduce cisplatin-relatedtoxicity without impairing its antineoplastic activity (41).However, a cisplatin dose-escalation study with concomitantadministration of glutathione had to be terminated prematurelybecause of unacceptable ototoxicity (42), and glutathione hasnot yet received Food and Drug Administration approval for chemoprotection.
In the present trial, only the acute nephrotoxicity of cisplatinwas examined. Therefore, further studies have to evaluate potentiallong-term effects of theophylline on kidney function. This isof great importance because cisplatin-based chemotherapy isused in a variety of patients with potentially curable cancer(e.g., metastatic testicular cancer, ovarian carcinoma) andhematologic malignancies or in the adjuvant setting for ovariancarcinoma or as recently published for non–small-celllung cancer (43). In addition, the present trial included onlypatients with normal creatinine clearance at baseline, and thepotential nephroprotection of theophylline in patients withimpaired kidney function or in patients who were treated withhigher dosages of cisplatin (100 to 120 mg/m2) still remainsto be determined.
Several drugs alter the pharmacokinetics of theophylline; however,there is no drug interaction described with cisplatin or othercytostatics used in this series (44) (Drugdex database search).
In conclusion, the current pilot trial demonstrated that theophyllinemay effectively prevent the acute decrease of GFR induced bycisplatin-based chemotherapy in combination with forced diuresisand hydration compared with forced diuresis and hydration alone.
Acknowledgments
This work was supported by a grant from the Bundesministeriumfür Bildung und Forschung (01/EC 0001) and Angewandte KlinischeForschung of the University of Tübingen (AKF 18-0-0).
We gratefully acknowledge the skillful assistance of WalterBeer.
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Received for publication March 23, 2004.
Accepted for publication October 19, 2004.
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Abstract
Introduction
18 yr, predicted life expectancy >2 mo, Karnofsky status 
