1 Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai; 2 Department of Molecular Medicine and Gene Transfer Research; 3 Department of Respiratory Medicine, Japanese Red Cross Sendai Hospital, Sendai; 4 Department of Blood Purification, Tohoku University Graduate School of Medicine, Sendai, Japan
Received 25 April 2003; revised 6 August 2003; accepted 13 August 2003
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ABSTRACT |
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The aim of this study was to use pharmacokinetic analysis to investigate the efficacy and toxicity of combined chemotherapy with carboplatin (CBDCA) and etoposide (ETP) in small-cell lung cancer (SCLC) patients with chronic renal failure undergoing hemodialysis (HD).
Patients and methods:
Three SCLC patients with chronic renal failure undergoing HD were treated with CBDCA (300 mg/m2) on day 1 and ETP (50 mg/m2) on days 1 and 3, followed by HD 1 h after completing the administration of anticancer agents on each day. The pharmacokinetic analysis of CBDCA and ETP was planned for at least the first two courses of the chemotherapy in each patient.
Results:
Two complete responses and one partial response were achieved in the three patients. Two patients experienced grade 3/4 neutropenia and required blood transfusion due to thrombocytopenia and anemia. Non-hematological toxicities were moderate. The pharmacokinetic analysis revealed that the platinum and the ETP concentrations in the plasma were similar to those in patients with normal renal function during the first 24 h, while the platinum still remained in the plasma for over 90 h.
Conclusions:
Chemotherapy with CBDCA (300 mg/m2 on day 1) and ETP (50 mg/m2 on day 1, 3) as used in the present study may be a suitable regimen for SCLC patients undergoing HD, although careful attention should be given to hematological toxicities.
Key words: carboplatin, chemotherapy, hemodialysis, pharmacokinetics, small-cell lung cancer
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Introduction |
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Chronic renal failure is also one of the common diseases, for which not a few patients undergo hemodialysis (HD). Unsurprisingly, many patients undergoing HD suffer from various types of cancer [3]. However, the feasibility and effects of chemotherapy for such patients have not been fully studied. Carboplatin (CBDCA), a well-known platinum compound with significant activity against various types of cancer including SCLC, has less nephrotoxicity than cisplatin and is therefore generally used for patients with impaired renal function. Moreover, CBDCA has a favorable profile for treatment with HD in that the platinum in the plasma of patients receiving CBDCA is much more filterable than is the case with cisplatin [4].
Thus, we treated SCLC patients with chronic renal failure undergoing HD with CBDCA-based chemotherapy combined with etoposide (ETP). We also carried out a pharmacokinetic (PK) analysis of CBDCA and ETP during the course of chemotherapy.
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Patients and methods |
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Patients 1 and 3, both with multiple brain metastases, were treated with whole-brain irradiation (2 Gy/day, total 40 Gy) concurrently during the chemotherapy. Patient 2 with limited-disease SCLC was treated with thoracic irradiation (2 Gy/day, total 50 Gy) concurrently during the chemotherapy.
Hemodialysis
The dialyzer (BG-1.8U; Toray Medical, Tokyo, Japan; AM-BC13F and 11F; Asahi Medical, Tokyo, Japan) and HD schedule including the frequency and duration were determined individually. Model DDB72 (Nikkiso, Shizuoka, Japan) and Kindary solution AF-2 were used as the HD apparatus and dialysis solution, respectively. The details of the HD procedure for each patient are summarized in Table 2. Fluid removal was programmed individually to obtain the desired dry weight. Low molecular weight heparin was used as an anticoagulant. HD was started 1 h after completing the administration of CBDCA and ETP on days 1 and 3.
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Results |
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Pharmacokinetic analysis
Figure 1 shows the PK of CBDCA (total platinum) on day 1 of the chemotherapy for each patient. The total platinum concentrations in the plasma at the initiation of HD were 14.315.0 µg/ml and decreased to 0.791.53 µg/ml at 24 h after the administration of CBDCA. This pattern of PK was similar to those in patients with normal renal function [8]. In accord with the dose reduction of CBDCA in the second and third courses in patient 3, the platinum concentrations decreased comparably at each point. However, the platinum concentration did not decrease dose-dependently in patient 2, although the dose of CBDCA in the second course was reduced. In the third course for patient 3, the PK analysis carried out from day 1 to day 5 showed that the platinum remained in the plasma more than 90 h, with gradual dissipation after the administration.
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Discussion |
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The PK analysis revealed that the platinum concentrations in the plasma of patients undergoing HD were comparable with those in patients with normal renal function during the first 24 h after the administration of CBDCA [8]. However, it is easily conceivable that the remnant platinum in the plasma after HD remains longer in patients with impaired renal function than in patients with normal renal function, and could cause severe and prolonged myelosuppression. In this context, physicians should pay careful attention to the peripheral blood cell count during chemotherapy and consider a dose reduction in subsequent courses according to the severity of the hematological toxicity. In fact, the PK data of patient 3 showed that dose reduction in the second and third courses resulted in a decreased platinum concentration in the plasma and a reduction in the hematological toxicity.
Of interest, the platinum concentration of patient 2 did not change dose-dependently in spite of the dose reduction. Although the reason why the PK data of patient 2 were less dose-dependent is difficult to interpret, we hypothesized that it might be attributed to the remnant renal function of patient 2. Because her own urinalysis was relatively better than those of the other patients (e.g. the creatinine clearance of patients 2 and 3 were 10 and 6 ml/min, respectively), the clearance of the platinum of patient 2 might also have been influenced by the renal condition more than those of others.
The HD setting after the administration of anticancer agents is also a very important factor that influences the concentration of anticancer agents in the plasma and therefore influences the efficacy and the safety of the chemotherapy. Although our treatment regimen appeared to be safe and appropriate, further study is needed.
In conclusion, the CBDCA (300 mg/m2 on day 1) and ETP (50 mg/m2 on days 1 and 3) chemotherapy of the present study may be a suitable regimen for SCLC patients undergoing HD, although careful attention should be paid to hematological toxicity.
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Acknowledgements |
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FOOTNOTES |
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REFERENCES |
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