The Importance of Drug Scheduling in Cancer Chemotherapy: Etoposide as an Example

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1 The Importance of Drug Scheduling in Cancer Chemotherapy: Etoposide as an Example KENNETH R. HANDE Vanderbilt University School of Medicine, Nashville VA Medical Center, Nashville, Tennessee, USA Key Words. Etoposide Administration schedule Cancer pharmacology Bioavailability Pharmacodynamics Pharmacokinetics ABSTRACT Etoposide is a drug whose antineoplastic activity is dependent on the schedule of drug administration. This article reviews the rationale for a prolonged schedule of etoposide administration and the therapeutic results of use of such a schedule in the treatment INTRODUCTION Most drugs with recognized administration schedule dependence are antimetabolites. In the 1960s, cytosine arabinoside was shown to be inactive unless given as a prolonged infusion or on a multiple-day administration schedule [1]. Toxicity from methotrexate is related to the duration of time a plasma concentration adequate to inhibit dihydrofolate reductase is maintained [2]. The toxicity of 5-fluorouracil depends on its administration schedule, with weekly bolus doses producing more myelosuppression and infusions of several days producing greater gastrointestinal toxicity [3]. For other antineoplastic agents, however, the schedule of drug administration has not been felt to be as important in determining cytotoxicity. However, clinical studies performed over the past few years have shown that the schedule of drug administration is important in altering the cytotoxicity of several antineoplastic drugs, including etoposide and Taxol, which are not classical antimetabolites. The effect of the administration schedule on etoposide cytotoxicity is the subject of this review. RATIONALE FOR CHRONIC ETOPOSIDE THERAPY Several preclinical and clinical findings suggest that the duration of exposure of neoplastic cells to etoposide is important in producing maximal antitumor activity. Mammalian DNA topoisomerase II is the target site for etoposide action. This enzyme normally functions within the cell to carry out necessary breakage-reunion reactions of mammalian DNA. It is a constituent of the mitotic chromosome scaffold. One of the primary physiologic of cancer. The pharmacology of etoposide is also reviewed, with particular attention paid to the pharmacokinetics of oral etoposide and etoposide plasma concentrations associated with cytotoxicity. The Oncologist 1996;1: activities of topoisomerase II is the untangling of daughter chromosomes during mitosis. This process requires passage of an intact double-stranded DNA (dsdna) helix through a transiently formed break made in the backbone of a second helix molecule by topoisomerase II [4]. Etoposide inhibits the ability of topoisomerase II to reseal these transiently formed DNA strand breaks [5]. It causes dose-dependent single-strand and dsdna breaks when incubated with cells. When etoposide is removed, DNA breakage is quickly repaired. The interaction of etoposide and DNA leads to cell cycle arrest in G 2 and subsequent triggering of apoptosis (programmed cell death) [6]. Apoptosis, induced by etoposide, is enhanced by the presence of certain oncogene products, growth factors (such as transforming growth factor α) and the p53 gene, while it is inhibited by the bcl-2 protein [7, 8]. Etoposide s target, topoisomerase II, is significantly expressed only in dividing cells during selected mitotic phases of the cell cycle [9]. Chronic scheduling may therefore be advantageous because it maximizes the likelihood of exposing malignant cells to etoposide during sensitive periods of the cell cycle. Cytotoxicity of topoisomerase II-targeting drugs relates not only to the magnitude of formation of drug-induced, enzyme-mediated DNA strand breaks, but also to the intracellular half-life of these lesions [10]. Therefore, antineoplastic agents or protracted scheduling schemes that prolong the presence of DNA strand breaks in the cell would be expected to result in superior efficacy. In vitro, lymphoma cells exposed to less than 1 µg/ml etoposide for 30 h can be completely killed [11]. Finally, high and Correspondence: Kenneth R. Hande, M.D., Vanderbilt University School of Medicine, Medical Oncology, 1956 The Vanderbilt Clinic, Nashville, TN 37232, USA. Telephone: ; Fax: AlphaMed Press /96/$5.00/0 The Oncologist 1996;1:

2 235 Etoposide low etoposide concentrations exhibit differential effects on cell cycle events. Though not clearly understood, the combination of high concentrations and brief duration of exposure to etoposide appears to result in a relatively protective effect by freezing a proportion of cells in phases of the cell cycle during which the drug is nonlethal. In cellular studies with etoposide, Drewinko and Barlogie [12] demonstrated that a 1 h exposure to 10 µg/ml etoposide resulted in 100-fold less cytotoxicity when compared to prolonged exposure to 1 µg/ml concentrations. Although the importance of drug administration schedule on etoposide s antineoplastic activity was suggested in early preclinical and clinical trials, the most informative studies on the importance of schedule dependence have been conducted by investigators from St. Bartholomew s Hospital in London. In two consecutive studies, the effect of changing the administration schedule of 500 mg etoposide on antineoplastic activity and toxicity was determined. In the first study [13], patients with previously untreated small cell lung cancer (SCLC) were randomized to receive 500 mg/m 2 etoposide either as a 24 h i.v. infusion or as five daily 2 h infusions. Though both patient groups received the same total drug dose, differences in response rates were dramatic. In the one-day treatment arm, 10% of patients responded to therapy, compared to an 89% response rate in the five-day treatment arm (Table 1). Pharmacokinetic data from this trial revealed no significant difference in area under the concentration time curve (AUC) measurements between these two treatment arms. However, prolonged maintenance of low serum etoposide concentrations ( 1 µg/ml) was associated with superior efficacy in the five-day treatment arm. High etoposide concentrations (>10 µg/ml) were maintained for considerably longer periods in the less effective one-day arm than in the superior five-day arm (23 versus 11 h, respectively). In a subsequent study in SCLC [14], a five-day schedule was compared to an eight-day schedule for administration of 500 mg etoposide. In this second study, patients were of poorer performance status than in the initial study and toxicity from etoposide was greater than that seen in the initial trial. The five- and eight-day schedules were found to have equivalent antineoplastic activity (Table 1). Hematologic toxicity was greater in the five-day arm. Duration of time with plasma etoposide concentrations >3 µg/ml was associated with the degree of myelosuppression. These two studies suggest that prolonged exposure to low concentrations of etoposide may improve the therapeutic ratio of this drug. CHRONIC, ORAL ETOPOSIDE ADMINISTRATION In an attempt to determine if an administration schedule longer than the standard three- to five-day regimens would improve the therapeutic index of etoposide, a phase I study was conducted at Vanderbilt using oral etoposide administered daily for 21 days [15]. An oral administration regimen was chosen for the practical reason of making long-term administration simple, and a 21-day duration was chosen to be significantly longer than standard regimens. Myelosuppression was found to be the dose-limiting toxicity. The maximal tolerated dose of etoposide on this schedule was 50 mg/m 2 /day. With this regimen, blood counts were checked weekly and etoposide was discontinued when the WBC count fell below 2,000/µl or platelets below 75,000/µl. Etoposide was not restarted until the WBC was >3,000/µl. In patients having a leukocyte nadir <1,000/µl or who needed to stop the drug before 21 days, a 75% dose reduction was used during the subsequent cycle. With this schedule, leukocyte nadirs occurred between days 21 and 28 of therapy and recovered by days 28-36, in most cases. Toxicity was greater in previously treated patients (Table 2). Other than myelosuppression, this treatment regimen was well tolerated. Red cell transfusions were often needed following multiple cycles of therapy. Alopecia was universal. Nausea, vomiting, mucositis or diarrhea were uncommon or very mild. Several phase II studies using either 50 mg or 50 mg/m 2 etoposide once or twice daily for 14 to 21 days have now been Table 1. Schedule dependency of 500 mg etoposide in small cell lung cancer (from [13] and [14]) Study 1 Study 1 Study 2 Study 2 (1 Day) (5 Day) (5 Day) (8 Day) Response rate 10% 89% 81% 87% Median survival (months) Neutrophil nadir 2,600/µl 2,600/µl 800/µl 1,700/µl Plasma concentration >10 µg/ml 23 h 11 h 11 h 4 h Plasma concentration >5 µg/ml 32 h 34 h 32 h 26 h Plasma concentration >1 µg/ml 46 h 94 h 98 h 106 h AUC (µg/ml h)

3 Hande 236 conducted involving patients with both previously treated and untreated lung cancer [16-18], lymphoma [19], previously treated germ cell tumors [20, 21], soft tissue sarcomas [21], ovarian cancer [22, 23], breast cancer [24, 25], melanoma and renal cell carcinoma. Responses have been seen in all tumor types but were uncommon in melanoma, sarcoma and renal cell carcinomas. Responses have been noteworthy in SCLC, germ cell tumors, and non-hodgkin s lymphoma (Table 3). Overall, response rates have been equal to or greater than expected from historical data from similar patient populations given standard doses and schedules of etoposide. In addition, several patients with SCLC, lymphomas and germ cell tumors who responded to the chronic schedule were previously clinically resistant to standard doses and schedules. While daily oral etoposide has significant activity, is easy to administer, has tolerable toxicity and produces responses in patients who have previously received drugs in other schedules, it does not necessarily improve response rates over standard etoposide-containing regimens in every situation. In a recent study by the Cancer and Leukemia Group B, patients with SCLC were randomized to receive cisplatin with three days of etoposide i.v., or low-dose etoposide p.o. for 21 days [26]. Response rates and median survival were equivalent in the two arms. When used in combination chemotherapy as initial therapy, the administration schedule did not produce significant changes in the therapeutic index of etoposide. ETOPOSIDE PHARMACOLOGY Kinetic parameters associated with i.v. etoposide administration, as determined at Vanderbilt, are shown in Table 4 [27]. The AUC and peak plasma concentrations following i.v. etoposide administration are linearly related to dose [28]. Thirty percent to 40% of an administered dose of drug is excreted unchanged in the urine [28, 29]. Direct biliary excretion of etoposide appears to be a minor route of drug elimination [30]. Obstructive jaundice does not alter the clearance rate of etoposide. Etoposide is highly bound to plasma proteins with an average free plasma fraction of 6%. The etoposide plasma-binding ratio (the amount of bound drug/the amount of free drug) is directly related to the serum albumin level [31]. Many patients with cancer have reduced serum albumin levels and, therefore, a higher free etoposide fraction (13%) than normal volunteers (4%). Since the free drug is biologically active, conditions which decrease protein binding may increase the pharmacologic effect of a given dose. The use of oral etoposide provides a convenient, tolerable treatment regimen which avoids the need for hospitalization. Depending on the cost of intravenous fluids, supplies used for chemotherapy administration and drug Table 2. Hematologic toxicity of 50 mg/m 2 /day 21 days oral etoposide (from [15, 17 19]) Toxicity Previously treated patients Untreated patients Leukocytes < /l 20% 6% Platelets < /l 20% 0% Erythrocyte transfusion 45% 36% Table 3. Activity of chronic, low-dose oral etoposide Disease Response rate Reference Small cell lung cancer 45% (n = 22) [16] 60% (n = 27) [17] Non-small cell lung cancer 20% (n = 25) [18] Lymphoma 60% (n = 25) [19] Germinal tumors 19% (n = 17) [20] 60% (n = 5) [21] Ovarian cancer 18% (n = 17) [21] 6% (n = 18) [22] 26% (n = 28) [23] Breast cancer 35% (n = 43) [24] 20% (n = 36) [25] Table 4. Etoposide pharmacokinetic parameters (from [27]) Volume of distribution 13.8 ± 7.4 l/min Clearance (plasma) 26.5 ± 9.6 ml/min/m 2 Clearance (renal) 9.3 ± 3.9 ml/min/m 2 Half-life 6.4 ± 2.4 h costs, oral etoposide therapy may be more economical than the use of an intravenous regimen [32]. There are, however, drawbacks to oral etoposide therapy. One disadvantage of oral etoposide is the wide variability from patient to patient in oral etoposide absorption. Table 5 summarizes a series of studies from Vanderbilt and compares the variability in apparent drug clearance as a function of the route of drug administration. Between-patient variability is significantly greater than withinpatient variability. However, administration of drug by the oral route increases variability both within and between patients. As a drug s clearance is equal to the dose of drug given divided by the AUC (Cl = Dose/AUC), the significant interpatient and intrapatient variability in oral etoposide absorption makes it difficult to predict the AUC for any individual oral dose of drug. Careful monitoring of blood counts is thus critical in each patient to assume adequate, but not excessive, drug exposure.

4 237 Etoposide Table 5. Variation in etoposide clearance with different routes of administration Group Administration Coefficient of variation Within same patient i.v. 10.7% (n = 12) Within same patient p.o. 15.7% (n = 11) Between patients i.v. 29.8% (n = 48) Between patients p.o. 38.6% (n = 16) The bioavailability of oral etoposide ranges from 40%-75% with, as mentioned, significant within- and between-patient variability. The absorption of etoposide varies with dose. Table 6 compares kinetic parameters seen following a 100 mg and a 400 mg oral dose of etoposide with those seen following i.v. administration. Oral absorption is linear to doses up to 250 mg. Bioavailability decreases with doses greater than 300 mg. Once absorbed, there is no pharmacologic difference between oral and intravenous etoposide with respect to mechanism of action, half-life or mode of drug elimination. LOW-DOSE INFUSIONAL ETOPOSIDE As previously noted, oral etoposide administration, while convenient, is compromised by variable drug absorption. In addition, administration of 100 mg oral drug produces peak plasma concentrations of 2-4 µg/ml. Since myelosuppression may be dependent on peak etoposide serum levels, while antitumor effect may be related to duration of exposure to a relatively low serum level, the chronic scheduling of etoposide using a long-term low-dose continuous infusion has been investigated as a means of avoiding high peak serum etoposide levels. In a phase I/II clinical trial, etoposide was administered as a continuous infusion by portable infusion pump; the drug was mixed in normal saline at a maximum concentration of 0.4 mg/ml. Twentyfive mg/m 2 /day was selected as the initial dose level. Initially, a 21-day infusion was planned, followed by a oneweek rest. It soon became evident that infusions of more than 21 consecutive days were possible in most patients, and subsequent patients were treated continuously as long as their WBC remained >2,000/mm 2, platelets >75,000/mm 2 and tumor progression was not evident. Patients receiving infusions of 25 mg/m 2 /d who developed myelotoxicity necessitating an interruption of therapy were restarted at a 75% dose reduction. Forty patients were treated in this phase I study [34]. Continuous etoposide infusions could be given for prolonged periods. The duration of etoposide therapy ranged from 2 to 80 weeks (median 17 weeks). The total etoposide dose administered ranged from 375-8,838 mg/m 2 (median 1,620 mg/m 2 ). Myelosuppression was the major toxicity produced by infusional etoposide. Moderate leukopenia (WBC 2,000-3,000/µl) was seen in most patients but precipitous drops in counts from week to week were not seen. A leukocyte count of less than 1,000/µl was experienced in five patients accounting for only 5 of 353 total weeks on therapy. Following discontinuation of therapy, the WBC recovered quickly (two to six days). Two patients developed thrombocytopenia. Anemia requiring a transfusion was observed in 21 patients. Alopecia was universal. Other side effects (anorexia, nausea, fatigue) were mild. Objective responses were seen in 5 of 10 patients with previously treated non-hodgkin s lymphoma and two of three patents with previously untreated SCLC [35]. The mean plasma etoposide concentration in patients receiving 25 mg/m 2 /day was 0.78 ± 0.4 µg/ml (range µg/ml). This study suggests that plasma etoposide concentration of roughly 1 µg/ml can be maintained with minimal myelosuppression and that these concentrations are sufficient for antineoplastic activity, at least against SCLC and lymphoma. Other investigators have also administered infusional etoposide and have attempted to correlate steady-state plasma etoposide concentrations with tumor response. In SCLC, Sarkar et al. [36] found no responses in six patients who maintained etoposide plasma concentrations of <0.75 µg/ml, while 6 of 10 patients with plasma etoposide concentrations of µg/ml responded to infusional etoposide. In non-sclc, responses were seen in 1 of 10 patients with plasma etoposide concentrations less than 1.0 µg/ml, while 7 Table 6. Etoposide kinetics (from [30, 33]) Intravenous 100 mg 400 mg dose oral dose oral dose Peak plasma concentration 3.0 ± 1.8 µg/ml 8.6 ± 2.5 µg/ml Time to peak 2.8 ± 1.8 h 2.9 ± 1.7 h Half-life 6.4 ± 1.8 h 6.6 ± 1.6 h 6.6 ± 1.6 h Clearance 2.7 ± 1.0 l/h 3.8 ± 1.5 l/h 5.1 ± 1.6 l/h Bioavailability 76 ± 22% 48 ± 18%

5 Hande 238 of 17 patients with plasma concentrations of µg/ml responded [37]. These data suggest that etoposide concentrations of µg/ml are required for cytotoxicity but that the specific threshold may vary depending upon tumor type. SUMMARY Preclinical and clinical studies have demonstrated the importance of a more prolonged administration schedule for maximizing the therapeutic index of etoposide. While an optimal treatment regimen remains unknown, a 21-day low-dose oral etoposide regimen has demonstrated significant antitumor activity against a variety of neoplasms. This regimen is convenient to administer and well tolerated when myelosuppression is carefully monitored. It can produce responses in patients who have previously been treated with other etoposide administration regimens. Disadvantages of oral etoposide include the significant variability in drug clearance and the potential for development of a treatmentrelated leukemia [38-40], although this has not been seen with this treatment regimen to date. Plasma etoposide concentrations of µg/ml appear to be associated with cytotoxicity. Higher plasma concentrations may lead to additional myelosuppression. From Advances in Cancer Treatment: The Chabner Symposium. STEM CELLS 1996;14: REFERENCES 1 Frei E, Bickers JN, Hewlett JS et al. Dose schedule and antitumor studies of arabinosyl cytosine. Cancer Res 1969;29: Pinedo HM, Zaharko DS, Bull JM et al. The relative contribution of drug concentration and duration of exposure to mouse bone marrow toxicity during continuous methotrexate infusion. Cancer Res 1977;37: Grem JL. Fluorinated pyrimidines. In: Chabner BA, Collins JM, eds. Cancer Chemotherapy: Principles and Practice. Philadelphia: JB Lippincott, 1990: Osheroff N, Zechiedrich EL, Gale KC. Catalytic function of DNA topoisomerase II. Bioessays 1991;13: Liu LF. DNA topoisomerase poisons as antitumor drugs. Ann Rev Biochem 1989;58: Walker PR, Smith C, Youdale T et al. Topoisomerase II-reactive chemotherapeutic drugs induce apoptosis in thymocytes. Cancer Res 1991;51: Lowe SW, Ruley BE, Jacks T et al. p53-dependent apoptosis modulates the cytotoxicity of anticancer drugs. Cell 1993;74: Kamesaki S, Kamesaki H, Jorgensen TJ et al. Bcl-2 protein inhibits etoposide-induced apoptosis through its effect on events subsequent to topoisomerase II-induced DNA strand breaks and their repair. Cancer Res 1993;53: Heck MMS, Hittelman AN, Earnshaw WC. Differential expression of DNA topoisomerases I and II during the eukaryotic cell cycle. Proc Natl Acad Sci USA 1988;85: Fox ME, Smith PJ. Long-term inhibition of DNA synthesis and the persistence of trapped topoisomerase II complexes in determining the toxicity of the antitumor DNA intercalators mamsa and mitoxantrone. Cancer Res 1990;50: Wolff SN, Grosh WW, Prater K et al. In vitro pharmacodynamic evaluation of VP and implications for chemotherapy. Cancer Chemother Pharmacol 1987;19: Drewinko B, Barlogie B. Survival and cycle-progression delay of human lymphoma cells in vitro exposed to VP Cancer Treat Rep 1976;60: Slevin ML, Clark PI, Joel SP et al. A randomized trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. J Clin Oncol 1989;7: Clark PI, Slevin NE, Joel SP et al. A randomized trial of two etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy and toxicity. J Clin Oncol 1994;12: Hainsworth JD, Johnson DH, Frazier SR et al. Chronic daily administration of oral etoposide a phase I trial. J Clin Oncol 1989;7: Johnson DH, Greco FA, Strupp D et al. Prolonged administration of oral etoposide in patients with relapsed or refractory small cell lung cancer: a phase I trial. J Clin Oncol 1990;8: Sessa C, Zucchetti K, Torri V et al. Chronic oral etoposide in small cell lung cancer: clinical and pharmacokinetic results. Ann Oncol 1993;4: Waits TK, Johnson DH, Hainsworth JD et al. Prolonged administration of oral etoposide in non-small cell lung cancer: a phase II trial. J Clin Oncol 1992;10: Hainsworth JD, Johnson DK, Frazier SR et al. Chronic daily administration of oral etoposide in refractory lymphoma. Eur J Cancer 1990;26: Miller JC, Einhorn LH. Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 1990;17: Greco FA. Chronic etoposide administration: overview of clinical experience. Cancer Treat Rev 1993;19(suppl): Markman M, Hakes T, Reichman B et al. Phase II trial of chronic low-dose oral etoposide as salvage therapy of platinum-refractory ovarian cancer. J Cancer Res Clin Oncol 1992;119: Hoskins PJ, Swenerton KD. Oral etoposide is active against platinum-resistant epithelial ovarian cancer. J Clin Oncol 1994;12: Martin M, Lluch A, Casadro A et al. Clinical activity of chronic oral etoposide in previously treated metastatic breast cancer. J Clin Oncol 1994;12:

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