Assessment of systemic toxicity in children receiving chemotherapy with cyclosporine for sarcoma
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Medical and Pediatric Oncology 34:242–249 (2000)
Assessment of Systemic Toxicity in Children Receiving Chemotherapy With Cyclosporine for Sarcoma Jochen G.W. Theis, MD,1 Helen S.L. Chan, MB BS,2 Mark L. Greenberg, MB ChB,2 David Malkin, MD,2 Vladimir Karaskov, MD,1 Ileana Moncica, MD,1 Gideon Koren, MD,1 and John Doyle, MD2*
Background. Overexpression of P-glycoprotein in malignant tumors has been associated with poor responses to chemotherapy. It appears biologically plausible that addition of the P-glycoprotein inhibitor cyclosporine (CsA) to standard chemotherapy may improve the outcome. The protective functions of P-glycoprotein in healthy tissues, however, have not been fully elucidated. Addition of CsA may lead to increased systemic chemotherapy toxicity, so we compared the rate and severity of chemotherapy-associated systemic toxicity in the presence and absence of CsA. Procedure. Standard chemotherapy consisted of etoposide/ifosfamide (VP16/IFOS) cycles, alternating with vincristine/dactinomycin/cyclophosphamide (VAC) cycles. CsA was given at a median dose of 20 mg/kg with unaltered doses of the antineoplastic drugs. The analysis of toxicity was performed by comparing clinically significant toxicity events recorded during and after chemotherapy cycles with and without CsA.
Results. Toxicity-related hospital admissions occurred after 93% of VAC cycles with CsA compared to 40% of the cycles without CsA (P < 0.0001); 29% of VP16/IFOS cycles with CsA led to admissions vs. 12% with non-CsA cycles (P = 0.04). Infections or fever and neutropenia were the main reasons for these admissions. Thirty-seven percent of the VAC cycles with CsA were complicated by culture-proved sepsis, which did not occur in cycles without CsA (P < 0.0001). Requirements for blood and platelet transfusions were greatly increased after VAC cycles with CsA compared to VAC cycles without CsA. Conclusions. The chemosensitizer CsA increases the systemic toxicity of VAC chemotherapy in patients with sarcomas. Future trials of chemotherapy with chemosensitizers will have to take into account a potential increase in systemic toxicity. Careful monitoring of chemotherapy-related toxicity becomes mandatory in such studies. Med. Pediatr. Oncol. 34:242–249, 2000. © 2000 Wiley-Liss, Inc.
Key words: cyclosporine; P-glycoprotein; antineoplastic agents; combined clinical trials; sarcoma; children
Resistance of tumor cells to drugs is a major problem in antineoplastic therapy. One such form of drug resistance occurs with a protein encoded by the mdr1 gene, P-glycoprotein [1,2], which actively transports multiple classes of natural products out of resistant cancer cells [3–5]. Overexpression of P-glycoprotein in some neoplasms correlates with poor outcome [6–10]. It is possible, therefore, that inhibition of the function of Pglycoprotein by chemosensitizers might improve the outcome of antineoplastic chemotherapy in patients with P-glycoprotein–overexpressing neoplasms. Cyclosporine A (CsA) has been shown to reverse multidrug resistance in cell cultures and animal experiments  and is tolerated by cancer patients in doses that effectively inhibit P-glycoprotein in vitro [12–18]. P-glycoprotein is also expressed in normal tissues such as the kidney, liver, adrenal cortex, bowel, hema © 2000 Wiley-Liss, Inc.
Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, The Hospital for Sick Children, and Departments of Pediatrics and Pharmacology, The University of Toronto, Toronto, Ontario, Canada
Division of Hematology and Oncology, Department of Pediatrics, The Hospital for Sick Children, and Departments of Pediatrics and Pharmacology, The University of Toronto, Toronto, Ontario, Canada Part of this work was presented as an oral communication at the 2nd Congress of the European Association for Clinical Pharmacology and Therapeutics [see Theis JGW, Chan HSL, Greenberg ML, et al. Chemotherapy combined with the p-glycoprotein inhibitor cyclosporin (CsA) in children: assessment of the systemic toxicity. Eur J Clin Pharmacol 1997;52(Suppl):A102] and one of its satellite symposia [see Theis JGW, Chan HSL, Greenberg ML, et al. Increased systemic toxicity of sarcoma chemotherapy due to combination with the Pglycoprotein inhibitor cyclosporine (extended abstract). Int J Clin Pharmacol Ther 1998;36:61–64]. *Correspondence to: John Doyle, MD, ABMT, FRCPC, Department of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8. Received 10 November 1999; Accepted 26 November 1999
Cyclosporine and Drug Toxicity
topoietic cells, and blood–brain barrier [19–21]. Inhibition of the P-glycoprotein drug efflux pump might, therefore, enhance the toxicity of chemotherapy in these tissues. Furthermore, concomitant therapy with CsA may reduce the clearance of certain drugs, including cytotoxins, resulting in higher tissue exposure and drug toxicity [14–16,22]. Pediatric patients with sarcomas overexpressing Pglycoprotein appear to have a worse prognosis than those with sarcomas not overexpressing P-glycoprotein [8,23]. Consequently, a study was initiated with children whose sarcomas overexpressed P-glycoprotein. This was designed to determine the maximal tolerated dose and the therapeutic and adverse effects of the chemosensitizer CsA given in conjunction with standard chemotherapy [24,25]. The study was approved in 1990 by the Research Ethics Board of The Hospital for Sick Children in Toronto. Our study differs from most other studies of high-dose CsA in combination with chemotherapy with respect to the patient population, the stage and prognosis of the tumor, and the doses of the conventional antineoplastics. The patient population consisted exclusively of children. Their enrollment, including those with a potential for cure, to this protocol was justified 1) because of the generally poor prognosis of patients with sarcomas that overexpress P-glycoprotein and 2) by the biological plausibility that addition of a P-glycoprotein inhibitor might increase the chances for survival. In order not to deprive these patients of maximum therapeutic benefit, the dose of the conventional antineoplastics was not reduced when CsA was added. The observation that CsA can alter the metabolic clearance of cytotoxins [14–16] was not available at the inception of the study. A safety committee was formed to ensure the wellbeing of children on this novel therapeutic approach during this study. The committee members were to conduct their investigations independently of the investigators who had conceived and were conducting the trial. The objectives of the safety committee were to analyze and evaluate the incidence, rate, and severity of documented toxicities. Those that occurred during and after chemotherapy cycles given in conjunction with CsA were to be matched to similar cycles given without CsA. This report details the apparent increase in systemic toxicities associated with the addition of high dose CsA to standard doses of chemotherapy. MATERIALS AND METHODS Design of the Phase I/II Trial
The basis of this toxicity analysis was a single-arm pilot trial of CsA given in conjunction with the chemotherapy cycles described below. CsA was started at 4 mg/kg/day, and individual doses were escalated by 1 mg/
kg increments in cohorts of three patients each, according to the E.O.R.T.C. Guidelines  to establish the maximum tolerated dose. The trial used short infusions of CsA on each day of chemotherapy rather than the prolonged continuous infusions of CsA used in most of the trials for reversal of multidrug resistance that have been reported [12–18]. Chemotherapy Cycles
Sarcoma patients were treated with VP16/IFOS cycles consisting of 1-hr infusions of etoposide (150 mg/m2/ day) on days 1 and 2 and of 3-hr infusions of ifosfamide (3,000 mg/m2/day) on days 1 and 2, alternating every 3 weeks with 5-day VAC cycles consisting of bolus injections of vincristine (0.05 mg/kg/day on days 1 and 5), dactinomycin (15 g/kg/day on days 1–5) and cyclophosphamide (300 mg/m2/day on days 1–5) [27,28]. Trial patients received CsA as 3-hr infusions (1 hr before until 2 hr after days 1–5 VAC) or 5-hr infusions (1 hr before and 4 hr during days 1 and 2 VP16/IFOS), with antiemetics (metoclopramide, dimenhydrinate, granisetron, dexamethasone), antiallergics (hydrocortisone, diphenhydramine), and uroprotector therapy (hydration, mesna). VP16/IFOS and VAC cycles given to sarcoma patients without cotherapy with CsA during the same time period (1991–1994) at the same institution served as controls to evaluate the impact of CsA on efficacy and systemic toxicity of the antineoplastic therapy. These cycles without CsA were given to patients who elected not to participate in the open trial or who no longer received CsA with their antineoplastic therapy (see reasons for discontinuation in Results). Selection of Chemotherapy Cycles for Analysis Inclusion criteria. For comparison of toxicity, all evaluable cycles that were administered between 1991 and 1994 and had delivered at least 50% of the protocol doses of each component of VAC or IFOS/VP16 were included. Exclusion criteria. Cycles of chemotherapy that had been given with additional cytotoxins or during concurrent radiotherapy or within 7 days of completing radiation were excluded. We did not assess those patients who had received fewer than two evaluable cycles of chemotherapy. Cycles that had to be stopped or interrupted because of the occurrence of an acute allergic reaction to CsA were also excluded. Cycles included and excluded. During 1991–1994, 36 patients with soft tissue sarcoma were treated in our institution. Twenty of these patients received at least one dose of intravenous CsA with standard chemotherapy. Overall, CsA was added to 118 chemotherapy cycles in these patients. Forty-three of these CsA cycles had to be excluded because the antineoplastic drugs used were different from the two standard chemotherapy regimens.
Theis et al.
TABLE I. Characteristics of Chemotherapy Cycles* VAC cycles
Cycle characteristics Patient age (days) Patient sex (male/female) Stage (II/III/IV) Radiotherapy prior (yes/no) Time after last chemotherapy (days) Time after first cycle (days) Number of previous cycles Basal blood counts White blood cell count Neutrophil count Platelet count Hemoglobin Antineoplastic drug dose Vincristine/kg Dactinomycin/kg Cyclophosphamide/m2 Etoposide/m2 Ifosfamide/m2 Cyclosporine dose (mg/kg/day)
With CSA (n ⳱ 27)
Without CsA (n ⳱ 53)
With CSA (n ⳱ 34)
Without CsA (n ⳱ 84)
1,547 ± 1,105 8/19 0/11/16 5/22 25 ± 5 125 ± 77 5±4
2,935 ± 1,817 20/33 2/41/10 25/28 27 ± 11 178 ± 99 7±4