Cancer Chemotherapy Update

Hospital Pharmacy Volume 41, Number 2, pp 124–132 2006 Wolters Kluwer Health, Inc.

Cancer Chemotherapy Update Carmustine, Cisplatin, Dacarbazine, and Tamoxifen (Dartmouth Regimen) for Metastatic Melanoma J. Aubrey Waddell, PharmD, FAPhA, BCOP and Dominic A. Solimando, Jr, MA, FAPhA, FASHP, BCOP The increasing complexity of cancer chemotherapy heightens the requirement that pharmacists be familiar with these highly toxic agents. This column will review various issues related to preparation, dispensing, and administration of cancer chemotherapy. It will also serve as a review of various agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr., President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, E-mail: [email protected]; or J. Aubrey Waddell, Associate Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 East Lamar Alexander Parkway, Maryville, TN 37804; E-mail: waddfour@ charter.net.

Regimen Name: Dartmouth Regimen (Carmustine, Cisplatin, Dacarbazine, and Tamoxifen) Origin of Name: The Dartmouth regimen was developed by researchers affiliated with the Dartmouth Medical School.1 INDICATION(S) The Dartmouth regimen is used to treat metastatic melanoma.1–11 COMMENTS Single agent or combination chemotherapy has little effect on survival in metastatic melanoma.4,5 However, clinicians continue to use this modality due to the response rates achievable and the fact that a small percentage of patients achieve durable complete responses.4 Since the early 1970s, clinicians have recognized dacarbazine as the most effective single agent for metastatic melanoma, with a consistent response rate of about 20% (4% to 5% complete responses).5

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In the mid-1970s, estrogen receptors were discovered on cells derived from metastatic melanomas,12 leading to the use of tamoxifen as a single agent in this disease.5 Tamoxifen was first combined with dacarbazine-based chemotherapy for metastatic melanoma in the early 1980s, when Del Prete et al introduced the carmustine, cisplatin, dacarbazine, and tamoxifen regimen, now known as the Dartmouth regimen. They achieved a 55% response rate in a small study of 20 patients (20% complete responses and 35% partial responses), a much higher response rate than previously achieved in this disease.1 This caused much interest in the melanoma community, with many phase 2 and 3 trials following in the next 2 decades. A recent analysis of 545 phase 2 patients from 11 trials and 370 phase 3 patients from four trials reported a 36% phase 2 response rate (25% partial responses and 11% complete responses) and a 25% phase 3 response rate (24% partial responses and 1% complete responses).4 This phase 3 response rate is not significantly better than dacarbazine alone. Further, a large, randomized trial showed no significant difference in overall response rates between the Dartmouth regimen and dacarbazine alone.11 Two additional large, randomized trials showed that tamoxifen administration may be unrelated to the response rates produced by the Dartmouth regimen.10,13 However, the original Dartmouth regimen continues to be one of the dacarbazine-based regimens used, when combination chemotherapy is indicated for metastatic melanoma.4 DRUG PREPARATION A. Carmustine 1. Follow institutional policies for preparation of hazardous medications when preparing carmustine. 2. Use powder for injection, 100 mg vial. 3. Reconstitute with 3 mL absolute alcohol; dilute with sterile water for injection, 0.9% sodium

Cancer Chemotherapy Update

Table 1. Dartmouth Regimen1,6–11 Drug

Dose

Route of Administration

Administered on Day(s)

Total Dose/Cycle

Carmustine

150 mg/m2

IV

1

150 mg/m2

Cisplatin

25 mg/m2

IV

1,2,3,22,23,24

150 mg/m2

Dacarbazine

220 mg/m

IV

1,2,3,22,23,24

1,320 mg/m2

20 mg

Oral

1 through 42

840 mg

Tamoxifen

2

Cycle repeats: Every 42 days Variations 1. Rusthoven et al gave tamoxifen 160 mg orally each day for 7 days before day 1 of the first cycle, then 40 mg orally each day. Carmustine, cisplatin, and dacarbazine were given as above.13 2. McClay et al gave carmustine 150 mg/m2 IV day 1, cisplatin 25 mg/m2, and dacarbazine 220 mg/m2 IV days 1, 2, 3, 29, 30, 31, and tamoxifen 20 mg orally each day with cycle repeating every 56 days.16 IV = intravenous

chloride or 5% dextrose in water to a concentration of 3.3 mg/mL to 20 mg/mL. 4. Dilute in 250 to 500 mL of 5% dextrose in water or 0.9% sodium chloride. 5. Dispense in a non-PVC container. 6. Carmustine is light-sensitive and should be protected from light immediately following preparation. B. Cisplatin 1. Follow institutional policies for preparation of hazardous medications when preparing cisplatin. 2. Use cisplatin injection 1 mg/mL. 3. Dilute with 250 to 1,000 mL 0.9% sodium chloride or a dextrose/saline solution. 4. To ensure the stability of cisplatin, the infusion solution must have a final chloride concentration of at least 0.2%. C. Dacarbazine 1. Follow institutional policies for preparation of hazardous medications when preparing dacarbazine. 2. Reconstitute to a concentra-

tion of 10 to 20 mg/mL with sterile water for injection, 5% dextrose in water, or 0.9% sodium chloride. 3. Dilute with 250 to 500 mL 5% dextrose in water or 0.9% sodium chloride. 4. Dacarbazine is light-sensitive and should be protected from light immediately following preparation. D.Tamoxifen 1. Follow institutional policies for preparation of hazardous medications when dispensing tamoxifen. 2. Use tamoxifen 10 or 20 mg tablets. DRUG ADMINISTRATION: A. Carmustine 1. Administer as a 2-hour intravenous (IV) infusion. 2. Infusion times less than 1 hour may cause venous irritation. 3. Use non-PVC tubing and infusion sets. B. Cisplatin 1. Administer as a 30-minute to 2-hour IV infusion. C. Dacarbazine 1. Administer as a 1 to 2-hour

IV infusion. 2. If given peripherally, infusion times less than 60 minutes may cause venous irritation, phlebitis or/and pain during the infusion. 3. Dacarbazine is light-sensitive and should be protected from light during administration. D.Tamoxifen 1. Tamoxifen is given orally. 2. The dose may be given once daily; or divided into two doses. SUPPORTIVE CARE A. Acute Emesis Prophylaxis14,15 The Dartmouth regimen is predicted to cause acute emesis in greater than 90% of patients on treatment days 1 through 3, and 22 through 24.14,15 The studies reviewed reported nausea or vomiting in 40% to 100% of patients.6,9,13,16 Appropriate acute emesis prophylaxis will include a serotonin antagonist and a corticosteroid. One of the following regimens is suggested: 1. Ondansetron 24 mg orally and dexamethasone 20 mg orally, given 30 minutes before Dartmouth regimen,

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or 2. Granisetron 2 mg orally and dexamethasone 20 mg orally, given 30 minutes before Dartmouth regimen, or 3. Dolasetron 100 mg orally and dexamethasone 20 mg orally, given 30 minutes before Dartmouth regimen, or 4. Palonosetron 0.25 mg IV, given 30 minutes before Dartmouth regimen on day-1 and day-22 only, and dexamethasone 20 mg orally or IV, given 30 minutes before Dartmouth regimen. Due to prolonged emesis from dacarbazine and carmustine and delayed emesis from cisplatin, the antiemetic therapy should continue for at least 3 days after day-3 and day-24 of the Dartmouth regimen. One of the following regimens is suggested (Note: for patients who received palonosetron on day-1 or day-22, only regimens 4, 5, and 6 below should be considered): 1. Ondansetron 8 mg twice a day and dexamethasone 4 mg orally twice a day for 3 days, starting on day-4 and day-25 of Dartmouth regimen, or 2. Granisetron 2 mg once a day, or 1 mg twice a day and dexamethasone 4 mg orally twice a day for 3 days, starting on day-4 and day-25 of Dartmouth regimen, or 3. Dolasetron 100 or 200 mg daily and dexamethasone 4 mg orally twice a day for 3 days, starting on day-4 and day-25 of Dartmouth regimen, or 4. Metoclopramide 0.5 mg/kg orally four times a day ± diphenhydramine 25 to 50 mg orally every 6 hours and dexamethasone 4 mg orally twice a day for 3 days, start-

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ing on day-4 and day-25 of Dartmouth regimen, 5. Prochlorperazine 10 mg orally every 4 to 6 hours ± diphenhydramine 25 to 50 mg orally every 6 hours and dexamethasone 4 mg orally twice a day for 3 days, starting on day-4 and day-25 of Dartmouth regimen, or 6. Promethazine 25 to 50 mg orally every 6 hours ± diphenhydramine 25 to 50 mg orally every 6 hours and dexamethasone 4 mg orally twice a day for 3 days, starting on day-4 and day-25 of Dartmouth regimen. Although some groups recommend use of an NK1 receptor antagonist (eg, aprepitant), as part of the initial antiemetic regimen, this approach has not been universally adopted.15 If an NK1 antagonist is used, it should be added to one of the serotonin antagonist/steroid regimens listed above. One of the following regimens is suggested: 1. Ondansetron 24 mg orally, dexamethasone 12 mg orally, and aprepitant 125 mg orally, given 30 minutes before day1 and day-22 of Dartmouth regimen; ondansetron 24 mg orally, dexamethasone 12 mg orally, and aprepitant 80 mg orally, given 30 minutes before days-2 through -3 and days-23 through -24 of Dartmouth regimen; dexamethasone 4 or 8 mg orally twice a day and aprepitant 80 mg orally on days-4 through -6 and days-25 through -27 of Dartmouth regimen. 2. Granisetron 2 mg orally, dexamethasone 12 mg orally, and aprepitant 125 mg orally, given 30 minutes before day1 and day-22 of Dartmouth regimen; granisetron 2 mg

orally, dexamethasone 12 mg orally, and aprepitant 80 mg orally, given 30 minutes before days-2 through -3 and days-23 through -24 of Dartmouth regimen; dexamethasone 4 or 8 mg orally twice a day and aprepitant 80 mg orally on days-4 through -6 and days-25 through -27 of Dartmouth regimen. 3. Dolasetron 100 mg orally, dexamethasone 12 mg orally, and aprepitant 125 mg orally, given 30 minutes before day1 and -22 of Dartmouth regimen; dolasetron 100 mg orally, dexamethasone 12 mg orally, and aprepitant 80 mg orally, given 30 minutes before days-2 through -3 and days-23 through -24 of Dartmouth regimen; dexamethasone 4 or 8 mg orally twice a day and aprepitant 80 mg orally on days-4 through -6 and days-25 through -27 of Dartmouth regimen. 4. Palonosetron 0.25 mg IV, dexamethasone 12 mg orally, and aprepitant 125 mg orally, given 30 minutes before day1 and -22 of Dartmouth regimen; dexamethasone 12 mg orally and aprepitant 80 mg orally, given 30 minutes before days-2 and -3 and days-23 and -24 of Dartmouth regimen; dexamethasone 4 or 8 mg orally twice a day and aprepitant 80 mg orally on days-4 through -6 and days-25 through -27 of Dartmouth regimen. B. Breakthrough Nausea and Vomiting15 Patients should receive an antiemetic prescription to treat breakthrough nausea. The following regimens are suggested: 1. Metoclopramide 20 to 40 mg orally every 4 to 6 hours as


needed, ± diphenhydramine 25 to 50 mg orally every 4 to 6 hours. 2. Prochlorperazine 10 mg orally every 4 to 6 hours as needed, or 3. Prochlorperazine 25 mg rectally every 6 hours as needed. 4. Promethazine 25 to 50 mg orally every 6 hours as needed. C. Hydration Cisplatin can cause irreversible kidney damage by acute tubular necrosis. Maintenance of a urine output of 75 to 100 mL/h for several hours before and after each cisplatin dose is the best prophylaxis for cisplatininduced nephrotoxicity. A wide variety of hydration and diuretic regimens for this purpose have been reported. Cornelison and Reed reported that, with the possible exception of the first treatment cycle, diuretics add nothing to vigorous hydration for prevention of cisplatin nephrotoxicity.17 Kintzel noted the mechanism of action of diuretics intuitively supports their use to prevent cisplatininduced nephrotoxicity; but there is no evidence to recommend them over vigorous hydration.18 A suggested hydration regimen is 5% dextrose/0.9% sodium chloride injection or 0.9% sodium chloride injection, infused at 250 mL/h for 2 to 4 hours before and after each cisplatin dose. Oral hydration regimens are also used, but the increased chloride from IV sodium chloride injections may offer better renal protection.17 D.Hypersensitivity Precautions No special precautions are required.19,20 E. Hematopoietic Growth Factors Accepted practice guidelines

and pharmacoeconomic analysis suggest that an antineoplastic regimen have a greater than 18% to 40% (depending on institutional cost differences) incidence of febrile neutropenia before prophylactic use of colony stimulating factors is warranted.21–23 Since febrile neutropenia was reported in only 11% to 13% of patients in the trials reviewed,9,13 prophylactic use of colony stimulating factors is not recommended. Colony stimulating factors may be considered if a patient experiences febrile neutropenia or grade 4 neutropenia in a prior cycle of Dartmouth regimen. F. Extravasation No special precautions are required.24–26 MAJOR TOXICITIES Most of the toxicities listed below are presented according to their degree of severity. Higher grades represent more severe toxicities. Although there are several grading systems for cancer chemotherapy toxicities, all are similar. One of the frequently used systems is the National Cancer Institute (NCI) Common Toxicity Criteria (http://ctep.info.nih.gov). Oncologists generally do not adjust doses or change therapy for grade 1 or 2 toxicities; but make, or consider, dosage reductions or therapy changes for grade 3 or 4 toxicities. A. Cardiovascular: Deep vein thrombosis 4% to 30%;6,13 phlebitis (grade 2) 1%.10 B. Dermatologic: Alopecia (grade 1 or 2) 29%,9 (grade 3 or 4) 4%.9 C. Gastrointestinal: Diarrhea (grade 1 or 2) 8%;9 gastrointestinal bleeding (grade 3) 1%;10 nausea (all grades) 80% to

100%,6,7 (grade 2) 52%,13 (grade 3 or 4) 10%;10 nausea and vomiting (grade 1 or 2) 59%,9 (grade 3 or 4) 17% to 18%,9,11 (all grades) 100%;16 stomatitis (grade 1 or 2) 13%;9 vomiting (all grades) 40% to 60%,6,13 (grade 3 or 4) 9%.10 D.Hematologic: Anemia (all grades) 90%,6 (grade 1 or 2) 66%,9 (grade 3 or 4) 24% to 32%,9,11 (requiring at least one transfusion) 45%;6 cerebral hemorrhage with thrombocytopenia 1%;11 febrile neutropenia 11% to 13%;9,13 hemorrhage requiring transfusion 11%;13 leucopenia (grade 1 or 2) 35%,9 (grade 2 or 3) 65%,6 (grade 3 or 4) 5% to 52%;6,9,10 neutropenia (grade 3 or 4) 32% to 39%;11,13 thrombocytopenia (all grades) 60%,6 (grade 1 or 2) 22%,9 (grade 3 or 4) 57% to 67%,9–11 (grade 4) 44%.13 E. Hepatic: Serum alkaline phosphatase elevations (grade 1 or 2) 17%,9 (grade 3 or 4) 4%;9 serum bilirubin elevations (grade 1 or 2) 4%,9 (grade 3 or 4) 4%;9 serum transaminase elevations (grade 1 or 2) 22%,9 (grade 3 or 4) 9%.9 F. Infection: (grade 1 or 2) 13%,9 (grade 3 or 4) 13%.9 G.Metabolic/Endocrine: Fatigue (grade 3 or 4) 7%;11 hot flashes (grade 3) 3%;13 lethargy (grade 3 or 4) 12%.10 H.Neurologic: Unspecified neuromotor toxicity (grade 3 or 4) 5%.10 I. Pulmonary: Chest X-ray changes and pulmonary function test abnormalities attributed to carmustine 5%;1 diffuse pneumonitis attributed to carmustine 1%;13 intrapulmonary hemorrhage with thrombocypulmonary topenia 2%;9 embolism 20%;6 shortness of breath (grade 1 or 2) 18%,9

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(grade 3 or 4) 5% to 6%.9,11 J. Renal: Hypomagnesemia (less than 1.4 meq/L) 80%;6 serum creatinine elevations (mild) 10%,1 (greater than 2 mg/dL) 15%,6 (grade 1 or 2) 26%,9 (grade 3 or 4) 2% to 3%.9,11 K. Treatment-Related Deaths: Cerebral hemorrhage with thrombocytopenia 1%;11 intrapulmonary hemorrhage with thrombocytopenia 2%;9 neutropenic sepsis 2%;9 diffuse pneumonitis attributed to carmustine 1%.13 PRETREATMENT LABORATORY STUDIES NEEDED A. Baseline 1. AST/ALT 2. Total bilirubin 3. Serum creatinine 4. CBC with differential B. Prior to each treatment 1. CBC with differential 2. Serum creatinine RECOMMENDED PRETREATMENT VALUES The minimally acceptable pretreatment laboratory values required to begin full-dose therapy in the protocols reviewed were: 1. White blood cell count (WBC) greater than 3,500 to 4,000 cells/mcL.8,10,11 2. Absolute neutrophil count greater than 1,500 cells/mcL.9 3. Platelet count greater than 100,000 to 160,000 cells/ mcL.8–11 4. Serum creatinine less than 1.25 x ULN10 or less than 1.4 mg/dL.11 5. Creatinine Clearance (CrCl) greater than 50 to 60 mL/min.8,9 6. Serum bilirubin less than 1.5 x ULN9,10 or less than 1.5 mg/dL.11 7. AST less than 2 to 3 x ULN.9,10 In clinical practice, a pretreatment absolute neutrophil count

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(ANC) of 1,000 cells/mcL, platelets of 75,000 cells/mcL, and CrCl greater than 60 mL/min are usually considered acceptable. Serum bilirubin, AST, and ALT are not usually necessary for dosing purposes in Dartmouth regimen therapy, but are sometimes used to monitor for dacarbazine-induced liver damage, an uncommon but well-documented adverse event.27 DOSAGE MODIFICATIONS A. Liver Function27 No dosage modifications necessary. B. Renal Function28,29 1. Carmustine a. Reduce dose by 20% if CrCl is 46 to 60 mL/min. b. Reduce dose by 25% if CrCl is 31 to 45 mL/min. c. Omit dose if CrCl is less than or equal to 30 mL/min. C. Cisplatin 1. Reduce dose by 25% if CrCl is 46 to 60 mL/min. 2. Reduce dose by 50% if CrCl is 31 to 45 mL/min. 3. Omit dose if CrCl is less than or equal to 30 mL/min. D.Dacarbazine 1. Reduce dose by 20% if CrCl is 46 to 60 mL/min. 2. Reduce dose by 25% if CrCl is 31 to 45 mL/min. 3. Reduce dose by 30% if CrCl is 10 to 30 mL/min. 4. Omit dose if CrCl is less than 10 mL/min. C. Myelosuppression Richards et al delayed treatment until ANC was greater than 1,500 cells/mcL and platelet count greater than 100,000 cells/mcL and terminated treatment if ANC was less than 500 cells/mcL or platelet count less

than 20,000 cells/mcL or if treatment was delayed more than 3 weeks for myelosuppression.7 REFERENCES 1. Del Prete SA, Maurer LH, O’Donnell J, Forcier RJ, LeMarbre P. Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep. 1984;68(11):1403–1405. 2. National Comprehensive Cancer Network. NCCN melanoma clinical practice guidelines version 1.2006. Available at: http://www.nccn.com/. Accessed on November 26, 2005. 3. National Cancer Institute. Melanoma (PDQ) treatment, health professional version. Available at: http://www.cancer.gov/. Accessed on November 26, 2005. 4. Li Y, McClay EF. Systemic chemotherapy for the treatment of metastatic melanoma. Semin Oncol. 2002; 29(5):413–426. 5. Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirtyyear experience overview. J Exp Clin Cancer Res. 2000;19(1):21–34. 6. McClay EF, Mastrangelo MJ, Bellet RE, Berd D. Combination chemotherapy and hormonal therapy in the treatment of malignant melanoma. Cancer Treat Rep. 1987;71(5):465–469. 7. Richards JM, Gilewski TA, Ramming K, Mitchel B, Doane LL, Vogelzang NJ. Effective chemotherapy for melanoma after treatment with interleukin-2. Cancer. 1992;69(2):427–429. 8. Crowell EB, Higa GM. The chemohormonal therapy of metastatic melanoma: possible benefit of tamoxifen. W V Med J. 1993;89:233–235. 9. Middleton MR, Lorigan P, Owen J, et al. A randomized phase 3 study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer. 2000;82(6):1158–1162. 10. Creagan ET, Suman VJ, Dalton RJ, et al. Phase 3 clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant


melanoma. J Clin 17(6):1884-1890.

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11. Chapman PB, Einhorn LH, Meyers ML, et al. Phase 3 multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999; 17(9):2745–2751.

chemo/hormonal therapy for malignant melanoma: experience with three consecutive trials. Int J Cancer. 1992;50:553– 556.

for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 2000;18(20):3558–3585.

17. Cornelison TL, Reed E. Nephrotoxicity and hydration management for cisplatin, carboplatin, and ormaplatin. Gynecol Oncol. 1993;50(2):147–158.

24. Larson DL. Treatment of tissue extravasation by antitumor agents. Cancer. 1982;49(9):1796-1799.

12. Fisher RI, Neifeld JP, Lippman ME. Oestrogen receptors in human malignant melanoma. Lancet. 1976;2(7981):337– 339.

18. Kintzel PE. Anticancer drug-induced kidney disorders — incidence, prevention and management. Drug Saf. 2001;24(1):19–38.

13. Rusthoven JJ, Quirt IC, Iscoe NA, et al. Randomized, double-blind, placebocontrolled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. J Clin Oncol. 1996;14(7):2083–2090.

19. Weiss RB. Hypersensitivity reactions. Semin Oncol. 1992;19(5):458– 477.

14. Hesketh PJ, Kris MG, Grunberg SM et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15(1):103–109. 15. National Comprehensive Cancer Network. NCCN antiemesis practice guidelines. Available at: http://www. nccn.com/. Accessed on November 27, 2005. 16. McClay EF, Mastrangelo MJ, Berd D, Bellet RE. Effective combination

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20. Zanotti KM, Markham M. Prevention and management of antineoplasticinduced hypersensitivity reactions. Drug Saf. 2001;24(10):767–779. 21. Lyman GH, Balducci L. A cost analysis of hematopoietic colony-stimulating factors. Oncology. 1995;9(suppl 11):85–91. 22. Lyman GH. Balancing the benefits and costs of colony-stimulating factors: a current perspective. Semin Oncol. 2003;30(suppl 13):10–17. 23. Ozer H, Armitage JO, Bennett CL, et al. 2000 update of recommendations

25. Larson DL. What is the appropriate management of tissue extravasation by antitumor agents? Plast Reconstr Surg. 1985;75(3):397–405. 26. Mullin S, Beckwith MC, Tyler LS. Prevention and management of antineoplastic extravasation injury. Hosp Pharm. 2000;35(1):57-74. 27. King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist. 2001; 6(2):162–176. 28. Patterson WP, Reams GP. Renal and electrolyte abnormalities due to chemotherapy. In: Perry MC, ed. The Chemotherapy Sourcebook. 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:494–504. 29. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev. 1995;21:33–64. ■