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A Case of Gemcitabine and Cisplatin Chemotherapy in a Patient With Metastatic Urothelial Carcinoma Receiving Hemodialysis
Case Report
A Case of Gemcitabine and Cisplatin Chemotherapy in a Patient With Metastatic Urothelial Carcinoma Receiving Hemodialysis Taisuke Ezaki, Kazuhiro Matsumoto, Shinya Morita, Kazunobu Shinoda, Ryuichi Mizuno, Eiji Kikuchi, Mototsugu Oya Clinical Practice Points Gemcitabine and cisplatin (GC) chemotherapy is now
This is the first report in which the plasma concen-
preferred as the first-line chemotherapy for urothelial carcinoma. The optimal doses and schedule of GC chemotherapy for patients receiving hemodialysis (HD) have not been determined yet.
trations of GC under HD were monitored during the therapy. The results indicate that our GC chemotherapy regimen for patients receiving HD is comparatively safe and effective, and can be followed as one of the therapeutic options.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, Cisplatin, Gemcitabine, Hemodialysis, Urothelial carcinoma
Introduction Cisplatin-based chemotherapy regimens, MVAC consisting of methotrexate/vinblastine/doxorubicin/cisplatin (CDDP), or gemcitabine and cisplatin (GC) consisting of gemcitabine (GEM)/ CDDP, are administered to patients with metastatic or locally advanced urothelial carcinoma.1,2 The efficiency of GC is known to be almost the same as that of standard MVAC, but superior in safety and tolerability.2 There is a diversity of opinion about which should be performed as a first-line chemotherapy regimen, dose-dense (high-dose) MVAC, which is possible by routine use of granulocyte colony-stimulating factor,3 or GC. Meanwhile, tolerability with GC clearly is superior to that with dose-dense MVAC.4 Therefore, in patients with high age and comorbidity, GC is preferred clinically because of its lower rate of therapy discontinuation. Urothelial carcinoma sometimes is accompanied by impaired renal function in patients because they might undergo nephrectomy or urinary diversion surgery for the disease, and some require hemodialysis (HD). For them, the optimal doses and schedule of GC,
Department of Urology, Keio University School of Medicine, Tokyo, Japan Submitted: Dec 25, 2015; Revised: Jan 25, 2016; Accepted: Jan 31, 2016 Address for correspondence: Kazuhiro Matsumoto, MD, 35 Shinanomachi, Shinjukuku, Tokyo 160-8582, Japan E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2016.01.015
of which CDDP is cleared rapidly by HD, have not been fully determined yet. Chang et al5 reported 4 patients receiving HD who were treated with a GC regimen based on their experience, but the pharmacokinetics of the drugs were not analyzed. In the present study, we performed GC chemotherapy to treat advanced urothelial carcinoma in a patient with chronic renal failure undergoing HD and monitored his plasma concentrations of GEM and CDDP during the therapy.
Case Presentation A 69-year-old Japanese man, who had a nonfunctional right kidney, was diagnosed with left renal pelvic cancer. He underwent left nephroureterectomy after internal shunt surgery for the initiation of HD. Histopathologic results showed invasive urothelial carcinoma of the renal pelvis, grade 2>3, and pathologic stage T3. He received no adjuvant therapy, and para-aortic lymph node metastases were found by computed tomography (CT) and positron emission tomography CT 19 months later when he was 70 years old. Salvage GC chemotherapy was introduced, and the regimen was as follows. On days 1, 8, and 15, he received 1000 mg/m2 GEM (100% of normal dose) dissolved in 50 mL 5% glucose administered intravenously over 30 minutes. Standard HD for 3 hours was performed 2 hours after the administration of GEM. On day 2, he received 35 mg/m2 CDDP (50% of normal dose) in 250 mL of saline administered intravenously over 1 hour; HD was started 1 hour after completion of the CDDP infusion and was
Clinical Genitourinary Cancer Month 2016
-1
Gemcitabine and Cisplatin Chemotherapy performed for 3 hours. HD was conducted 4 times per week in the first week of the cycle (days 1, 2, 4, and 6) and 3 times per week thereafter. This treatment regimen was repeated every 5 to 6 weeks. For pretreatment, we administered dexamethasone (3.3 mg), cimetidine (20 mg), and ondansetron (4 mg) intravenously 30 minutes before each GEM and CDDP administration. We also prescribed aprepitant orally on days 2, 3, and 4 for the prevention of nausea. In the first and second cycles, blood samples were taken to measure the serum concentrations of GEM and free/total CDDP, and we calculated the areas under the concentration time curve (AUCs) as shown in Figure 1A and B. Until 8 cycles were completed, CT scan demonstrated partial response of para-aortic lymph node metastases (Figure 2), but CT scan after 11 cycles detected the emergence of mediastinal lymph node metastases. During the 11 cycles of GC chemotherapy, grade 3 neutropenia, anemia, and thrombocytopenia occurred, so GEM on days 8 and 15 sometimes was postponed because of bone marrow toxicity. He received administration of granulocyte colony-stimulating factor
(subcutaneous injection of 100 mg lenograstim per day) for 3.7 1.6 days per cycle. He also received red blood cell (in the second cycle) and platelet (in the fourth and eighth cycles) transfusion. In the eighth cycle, febrile neutropenia also developed, which was treated with intravenous antibiotics. Laboratory and physical examinations demonstrated no other adverse events during the 11 cycles.
Discussion The GC regimen used at our center for patients with normal renal function is as follows: 1000 mg/m2 GEM on days 1, 8, and 15, and 70 mg/m2 CDDP on day 2 of a 28-day cycle. The dosage of CDDP is adjusted according to the patient’s renal function, reduction by 25% in patients with a creatinine clearance (CCr) 60 to 45 mL/min and 50% in patients with a CCr 45 to 30 mL/min. GC is not chosen for patients with a CCr < 30 mL/min. In general, when chemotherapy is performed for patients receiving HD, the doses and schedule of HD are determined on a
Figure 1 Plasma Concentration Time Profiles of GEM (A) and CDDP (B)
A
B
2
-
Abbreviations: AUC ¼ area under the concentration time curve; CDDP ¼ methotrexate/vinblastine/doxorubicin/cisplatin; GEM ¼ gemcitabine; HD ¼ hemodialysis.
Clinical Genitourinary Cancer Month 2016
Taisuke Ezaki et al Figure 2 CT Scans Show Para-Aortic Metastases Before Chemotherapy and Partial Response After 8 Cycles
case-by-case basis. There is no established treatment regimen of GC in patients receiving HD, and the appropriate dose and timing of each agent for patients receiving HD are undecided. There have been some reports of urothelial carcinoma treated with cisplatinbased chemotherapy in patients receiving HD, and careful monitoring of drug concentration is recommended to optimize drug exposure, ensure efficacy, and reduce the risk of side effects.6,7 However, few studies have demonstrated the efficacy and safety of GC treatment in patients receiving HD by properly monitoring the concentration of each drug. In the present study, we determined the optimal doses and schedule of GC for patients receiving HD. The administration of GEM for patients receiving HD has been reported to be comparatively safe.8 GEM is rapidly metabolized to 20 ,20 -difluorodeoxyuridine (dFdU) by cytidine deaminase and disappears from plasma. The elimination half-life of GEM is approximately 20 minutes and becomes undetectable at 60 to 90 minutes in patients receiving and not receiving HD.9-11 GEM has cytotoxic activity, whereas dFdU is thought to be a noncytotoxic metabolite. Furthermore, the plasma level of dFdU is known to be reduced by approximately 50% through HD as previously reported.9 Therefore, we administer 100% dose of GEM and start HD 2 hours after the administration when the serum concentration of GEM is under the detection limit and the concentration of dFdU reaches the plateau. In the present case, as shown in Figure 1A, we observed similar patterns of change of GEM concentration compared with those of patients with normal renal function in previous reports.11,12 Yilmaz et al12 reported that the AUC in patients with normal renal function was 11.2 mg. h/L11 or 10.6 7.5 mg. h/L. CDDP binds to blood plasma proteins in blood plasma, and binding CDDP exceeds 90% in a few hours after administration,13 and only free (nonbinding) CDDP has cytotoxicity.14 The AUC of
free CDDP closely correlates with bone marrow toxicity and other side effects.15 On the basis of our previous experience with CDDP kinetics affected by HD, we reduced the dose of CDDP by 50% and performed HD 1 hour later.6 In the present case, pharmacokinetics demonstrated that free CDDP is cleared rapidly by HD, and its level rebounded, suggesting that it is subsequently released from protein-bound CDDP in vivo. The decay curve of the agent showed a biphasic pattern with an initial steep phase and ensuing mild phase. The AUC of free CDDP in the present case was almost comparable to that of patients with normal renal function, which was reported to be 3.66 0.57 mg. h/mL2.16 Contrary to that of GEM, the CDDP concentration changed dramatically by HD as shown in Figure 1B, and we believe that monitoring the serum concentration of CDDP will be required to reduce the risks of CDDP-related side effects.
Conclusions These data indicate that our GC chemotherapy regimen for patients receiving HD is comparatively safe and effective, and can be one of the therapeutic options.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Sternberg CN, Yagoda A, Scher HI, et al. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 1988; 139:461-9. 2. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000; 18:3068-77. 3. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)
Clinical Genitourinary Cancer Month 2016
-3
Gemcitabine and Cisplatin Chemotherapy
4.
5. 6. 7. 8. 9.
4
-
chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001; 19: 2638-46. Bamias A, Dafni U, Karadimou A, et al. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol 2013; 24:1011-7. Chang PY, Dai MS, Ho CL, Yao NS. Administration of gemcitabine and cisplatin in cancer patients with renal failure under hemodialysis. J BUON 2013; 18:1058-61. Matsumoto K. Pharmacokinetics of cisplatin and methotrexate after M-VAC chemotherapy for advanced urothelial cancer in hemodialysis patients. Int J Urol 2008; 15:949-50. Ide H, Satou A, Hoshino K, et al. Successful management of metastatic urothelial carcinoma with gemcitabine and Paclitaxel chemotherapy in a hemodialysis patient. Urol Int 2011; 87:245-7. Janus N, Thariat J, Boulanger H, Deray G, Launay-Vacher V. Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 2010; 21:1395-403. Kiani A, Köhne CH, Franz T, et al. Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment. Cancer Chemother Pharmacol 2003; 51:266-70.
Clinical Genitourinary Cancer Month 2016
10. Masumori N, Kunishima Y, Hirobe M, et al. Measurement of plasma concentration of gemcitabine and its metabolite dFdU in hemodialysis patients with advanced urothelial cancer. Jpn J Clin Oncol 2008; 38:182-5. 11. Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991; 9:491-8. 12. Yilmaz B, Kadioglu YY, Aksoy Y. Investigation of the pharmacokinetics of gemcitabine and 2’,2’-difluorodeoxyuridine in human plasma by liquid chromatography. Anal Biochem 2004; 322:234-7. 13. DeConti RC, Toftness BR, Lange RC, Creasey WA. Clinical and pharmacological studies with cis-diamminedichloroplatinum (II). Cancer Res 1973; 33:1310-5. 14. Himmelstein KJ, Patton TF, Belt RJ, Taylor S, Repta AJ, Sternson LA. Clinical kinetics on intact cisplatin and some related species. Clin Pharmacol Ther 1981; 29: 658-64. 15. Schellens JH, Ma J, Planting AS, et al. Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours. Br J Cancer 1996; 73:1569-75. 16. Tokunaga J, Kikukawa H, Nishi K, et al. Pharmacokinetics of cisplatin and methotrexate in a patient suffering from advanced ureteral tumor accompanied by chronic renal failure, undergoing combined hemodialysis and systemic M-VAC chemotherapy [In Japanese]. Gan To Kagaku Ryoho 2000; 27: 2079-85.
A Case of Gemcitabine and Cisplatin Chemotherapy in a Patient With Metastatic Urothelial Carcinoma Receiving Hemodialysis Taisuke Ezaki, Kazuhiro Matsumoto, Shinya Morita, Kazunobu Shinoda, Ryuichi Mizuno, Eiji Kikuchi, Mototsugu Oya Clinical Practice Points Gemcitabine and cisplatin (GC) chemotherapy is now
This is the first report in which the plasma concen-
preferred as the first-line chemotherapy for urothelial carcinoma. The optimal doses and schedule of GC chemotherapy for patients receiving hemodialysis (HD) have not been determined yet.
trations of GC under HD were monitored during the therapy. The results indicate that our GC chemotherapy regimen for patients receiving HD is comparatively safe and effective, and can be followed as one of the therapeutic options.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, Cisplatin, Gemcitabine, Hemodialysis, Urothelial carcinoma
Introduction Cisplatin-based chemotherapy regimens, MVAC consisting of methotrexate/vinblastine/doxorubicin/cisplatin (CDDP), or gemcitabine and cisplatin (GC) consisting of gemcitabine (GEM)/ CDDP, are administered to patients with metastatic or locally advanced urothelial carcinoma.1,2 The efficiency of GC is known to be almost the same as that of standard MVAC, but superior in safety and tolerability.2 There is a diversity of opinion about which should be performed as a first-line chemotherapy regimen, dose-dense (high-dose) MVAC, which is possible by routine use of granulocyte colony-stimulating factor,3 or GC. Meanwhile, tolerability with GC clearly is superior to that with dose-dense MVAC.4 Therefore, in patients with high age and comorbidity, GC is preferred clinically because of its lower rate of therapy discontinuation. Urothelial carcinoma sometimes is accompanied by impaired renal function in patients because they might undergo nephrectomy or urinary diversion surgery for the disease, and some require hemodialysis (HD). For them, the optimal doses and schedule of GC,
Department of Urology, Keio University School of Medicine, Tokyo, Japan Submitted: Dec 25, 2015; Revised: Jan 25, 2016; Accepted: Jan 31, 2016 Address for correspondence: Kazuhiro Matsumoto, MD, 35 Shinanomachi, Shinjukuku, Tokyo 160-8582, Japan E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2016.01.015
of which CDDP is cleared rapidly by HD, have not been fully determined yet. Chang et al5 reported 4 patients receiving HD who were treated with a GC regimen based on their experience, but the pharmacokinetics of the drugs were not analyzed. In the present study, we performed GC chemotherapy to treat advanced urothelial carcinoma in a patient with chronic renal failure undergoing HD and monitored his plasma concentrations of GEM and CDDP during the therapy.
Case Presentation A 69-year-old Japanese man, who had a nonfunctional right kidney, was diagnosed with left renal pelvic cancer. He underwent left nephroureterectomy after internal shunt surgery for the initiation of HD. Histopathologic results showed invasive urothelial carcinoma of the renal pelvis, grade 2>3, and pathologic stage T3. He received no adjuvant therapy, and para-aortic lymph node metastases were found by computed tomography (CT) and positron emission tomography CT 19 months later when he was 70 years old. Salvage GC chemotherapy was introduced, and the regimen was as follows. On days 1, 8, and 15, he received 1000 mg/m2 GEM (100% of normal dose) dissolved in 50 mL 5% glucose administered intravenously over 30 minutes. Standard HD for 3 hours was performed 2 hours after the administration of GEM. On day 2, he received 35 mg/m2 CDDP (50% of normal dose) in 250 mL of saline administered intravenously over 1 hour; HD was started 1 hour after completion of the CDDP infusion and was
Clinical Genitourinary Cancer Month 2016
-1
Gemcitabine and Cisplatin Chemotherapy performed for 3 hours. HD was conducted 4 times per week in the first week of the cycle (days 1, 2, 4, and 6) and 3 times per week thereafter. This treatment regimen was repeated every 5 to 6 weeks. For pretreatment, we administered dexamethasone (3.3 mg), cimetidine (20 mg), and ondansetron (4 mg) intravenously 30 minutes before each GEM and CDDP administration. We also prescribed aprepitant orally on days 2, 3, and 4 for the prevention of nausea. In the first and second cycles, blood samples were taken to measure the serum concentrations of GEM and free/total CDDP, and we calculated the areas under the concentration time curve (AUCs) as shown in Figure 1A and B. Until 8 cycles were completed, CT scan demonstrated partial response of para-aortic lymph node metastases (Figure 2), but CT scan after 11 cycles detected the emergence of mediastinal lymph node metastases. During the 11 cycles of GC chemotherapy, grade 3 neutropenia, anemia, and thrombocytopenia occurred, so GEM on days 8 and 15 sometimes was postponed because of bone marrow toxicity. He received administration of granulocyte colony-stimulating factor
(subcutaneous injection of 100 mg lenograstim per day) for 3.7 1.6 days per cycle. He also received red blood cell (in the second cycle) and platelet (in the fourth and eighth cycles) transfusion. In the eighth cycle, febrile neutropenia also developed, which was treated with intravenous antibiotics. Laboratory and physical examinations demonstrated no other adverse events during the 11 cycles.
Discussion The GC regimen used at our center for patients with normal renal function is as follows: 1000 mg/m2 GEM on days 1, 8, and 15, and 70 mg/m2 CDDP on day 2 of a 28-day cycle. The dosage of CDDP is adjusted according to the patient’s renal function, reduction by 25% in patients with a creatinine clearance (CCr) 60 to 45 mL/min and 50% in patients with a CCr 45 to 30 mL/min. GC is not chosen for patients with a CCr < 30 mL/min. In general, when chemotherapy is performed for patients receiving HD, the doses and schedule of HD are determined on a
Figure 1 Plasma Concentration Time Profiles of GEM (A) and CDDP (B)
A
B
2
-
Abbreviations: AUC ¼ area under the concentration time curve; CDDP ¼ methotrexate/vinblastine/doxorubicin/cisplatin; GEM ¼ gemcitabine; HD ¼ hemodialysis.
Clinical Genitourinary Cancer Month 2016
Taisuke Ezaki et al Figure 2 CT Scans Show Para-Aortic Metastases Before Chemotherapy and Partial Response After 8 Cycles
case-by-case basis. There is no established treatment regimen of GC in patients receiving HD, and the appropriate dose and timing of each agent for patients receiving HD are undecided. There have been some reports of urothelial carcinoma treated with cisplatinbased chemotherapy in patients receiving HD, and careful monitoring of drug concentration is recommended to optimize drug exposure, ensure efficacy, and reduce the risk of side effects.6,7 However, few studies have demonstrated the efficacy and safety of GC treatment in patients receiving HD by properly monitoring the concentration of each drug. In the present study, we determined the optimal doses and schedule of GC for patients receiving HD. The administration of GEM for patients receiving HD has been reported to be comparatively safe.8 GEM is rapidly metabolized to 20 ,20 -difluorodeoxyuridine (dFdU) by cytidine deaminase and disappears from plasma. The elimination half-life of GEM is approximately 20 minutes and becomes undetectable at 60 to 90 minutes in patients receiving and not receiving HD.9-11 GEM has cytotoxic activity, whereas dFdU is thought to be a noncytotoxic metabolite. Furthermore, the plasma level of dFdU is known to be reduced by approximately 50% through HD as previously reported.9 Therefore, we administer 100% dose of GEM and start HD 2 hours after the administration when the serum concentration of GEM is under the detection limit and the concentration of dFdU reaches the plateau. In the present case, as shown in Figure 1A, we observed similar patterns of change of GEM concentration compared with those of patients with normal renal function in previous reports.11,12 Yilmaz et al12 reported that the AUC in patients with normal renal function was 11.2 mg. h/L11 or 10.6 7.5 mg. h/L. CDDP binds to blood plasma proteins in blood plasma, and binding CDDP exceeds 90% in a few hours after administration,13 and only free (nonbinding) CDDP has cytotoxicity.14 The AUC of
free CDDP closely correlates with bone marrow toxicity and other side effects.15 On the basis of our previous experience with CDDP kinetics affected by HD, we reduced the dose of CDDP by 50% and performed HD 1 hour later.6 In the present case, pharmacokinetics demonstrated that free CDDP is cleared rapidly by HD, and its level rebounded, suggesting that it is subsequently released from protein-bound CDDP in vivo. The decay curve of the agent showed a biphasic pattern with an initial steep phase and ensuing mild phase. The AUC of free CDDP in the present case was almost comparable to that of patients with normal renal function, which was reported to be 3.66 0.57 mg. h/mL2.16 Contrary to that of GEM, the CDDP concentration changed dramatically by HD as shown in Figure 1B, and we believe that monitoring the serum concentration of CDDP will be required to reduce the risks of CDDP-related side effects.
Conclusions These data indicate that our GC chemotherapy regimen for patients receiving HD is comparatively safe and effective, and can be one of the therapeutic options.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Sternberg CN, Yagoda A, Scher HI, et al. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 1988; 139:461-9. 2. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000; 18:3068-77. 3. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)
Clinical Genitourinary Cancer Month 2016
-3
Gemcitabine and Cisplatin Chemotherapy
4.
5. 6. 7. 8. 9.
4
-
chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001; 19: 2638-46. Bamias A, Dafni U, Karadimou A, et al. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol 2013; 24:1011-7. Chang PY, Dai MS, Ho CL, Yao NS. Administration of gemcitabine and cisplatin in cancer patients with renal failure under hemodialysis. J BUON 2013; 18:1058-61. Matsumoto K. Pharmacokinetics of cisplatin and methotrexate after M-VAC chemotherapy for advanced urothelial cancer in hemodialysis patients. Int J Urol 2008; 15:949-50. Ide H, Satou A, Hoshino K, et al. Successful management of metastatic urothelial carcinoma with gemcitabine and Paclitaxel chemotherapy in a hemodialysis patient. Urol Int 2011; 87:245-7. Janus N, Thariat J, Boulanger H, Deray G, Launay-Vacher V. Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 2010; 21:1395-403. Kiani A, Köhne CH, Franz T, et al. Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment. Cancer Chemother Pharmacol 2003; 51:266-70.
Clinical Genitourinary Cancer Month 2016
10. Masumori N, Kunishima Y, Hirobe M, et al. Measurement of plasma concentration of gemcitabine and its metabolite dFdU in hemodialysis patients with advanced urothelial cancer. Jpn J Clin Oncol 2008; 38:182-5. 11. Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991; 9:491-8. 12. Yilmaz B, Kadioglu YY, Aksoy Y. Investigation of the pharmacokinetics of gemcitabine and 2’,2’-difluorodeoxyuridine in human plasma by liquid chromatography. Anal Biochem 2004; 322:234-7. 13. DeConti RC, Toftness BR, Lange RC, Creasey WA. Clinical and pharmacological studies with cis-diamminedichloroplatinum (II). Cancer Res 1973; 33:1310-5. 14. Himmelstein KJ, Patton TF, Belt RJ, Taylor S, Repta AJ, Sternson LA. Clinical kinetics on intact cisplatin and some related species. Clin Pharmacol Ther 1981; 29: 658-64. 15. Schellens JH, Ma J, Planting AS, et al. Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours. Br J Cancer 1996; 73:1569-75. 16. Tokunaga J, Kikukawa H, Nishi K, et al. Pharmacokinetics of cisplatin and methotrexate in a patient suffering from advanced ureteral tumor accompanied by chronic renal failure, undergoing combined hemodialysis and systemic M-VAC chemotherapy [In Japanese]. Gan To Kagaku Ryoho 2000; 27: 2079-85.