Etoposide,Doxorubicin,Vincristine,Cyclophosphamide,Prednisone (EPOCH) for Treatment of Lymphomas

Abstract

The increasing complexity of cancer chemotherapy now requires that pharmacists be familiar with these highly toxic agents. This column will review various issues related to preparation, dispensing, and administration of cancer chemotherapy, and review various agents, both commercially available and investigational, used to treat malignant diseases.

The views expressed in this article are those of the author(s) and do not reflect the official policy of the Department of Army, Department of Defense, or US Government.

Keywords

EPOCH EPOCH is an acronym for the five drugs in the regimen

Indications

EPOCH has been studied as salvage treatment for relapsed or refractory Hodgkin and non-Hodgkin lymphomas,^1-5 and as initial therapy for non-Hodgkin lymphomas.^2,6,7 Current guidelines for treatment of non-Hodgkin lymphomas list EPOCH, with rituximab, as an initial regimen for mantle cell and diffuse large B-cell lymphomas. It is also recommended (without rituximab) as initial therapy for acquired immunodeficiency syndrome (AIDS)-related B-cell and peripheral T-cell lymphomas.⁸

Drug Preparation

Etoposide 1.

Follow institutional policies for preparation of hazardous medications when preparing etoposide.

Use etoposide injection 20 mg/mL.

Dilute with 0.9% sodium chloride or 5% dextrose in water to a final concentration of 0.2 to 0.4 mg/mL.

Etoposide can be mixed in the same container as the doxorubicin and vincristine, so the 3 drugs can be administered as a single infusion.⁹

Doxorubicin 1.

Follow institutional policies for preparation of hazardous medications when preparing doxorubicin.

Use doxorubicin injection 2 mg/mL or doxorubicin powder for injection.

If the powder for injection is used, it should be reconstituted to a concentration of 2 mg/mL with 0.9% sodium chloride.

Dilute in 250 to 1,000 mL of 0.9% sodium chloride, 5% dextrose in water, or a saline/dextrose solution for infusion.

Doxorubicin can be mixed in the same container as the etoposide and vincristine, and the 3 drugs administered as a single infusion.⁹

Vincristine 1.

Follow institutional policies for preparation of hazardous medications when preparing vincristine.

Use vincristine sulfate injection 1 mg/mL.

Withdraw the volume required.

Dilute in 250 to 1,000 mL of 0.9% sodium chloride, 5% dextrose in water, or a saline/dextrose solution for infusion.

Table 1.

Etoposide, Doxorubicin, Vincristine, Cyclophosphamide, Prednisone (EPOCH) Regimen^1-3

Drug	Dose	Route of Administration	Administered on Day(s)	Total Dose/Cycle
Etoposide	50 mg/m²	CIVI	1,2,3,4	200 mg/m²
Doxorubicin	10 mg/m²	CIVI	1,2,3,4	40 mg/m²
Vincristine	0.4 mg/m²	CIVI	1,2,3,4	1.6 mg/m²
Cyclophosphamide	750 mg/m²	IV	6	750 mg/m²
Prednisone	60 mg/m²	PO	1,2,3,4,5,6	360 mg/m²
Cycle repeats: every 3 weeks
Variations
1. Gutierrez et al. (2000) and Wilson et al. (2002) gave EPOCH as listed above, but changed the prednisone to days 1 through 5 and cyclophosphamide to day 5.^4,6
2. Wilder et al. (2001) used EPOCH as listed above, but used prednisone 100 mg/day days 1 through 6 and cyclophosphamide on day 5.⁵
3. Jermann et al. (2004) added rituximab 375 mg/m² on day 1 and used etoposide 65 mg/m², vincristine 0.5 mg/m², and doxorubicin 15 mg/m² on days 2 through 4, prednisone 60 mg/m² days 1 through 14, and cyclophosphamide 750 mg/m² on day 5.⁷

CIVI = continuous (24-hour) intravenous infusion; IV = intravenous; PO = oral.

Vincristine can be mixed in the same container as the doxorubicin and etoposide, so the 3 drugs can be administered as a single infusion.

Cyclophosphamide 1.

Follow institutional policies for preparation of hazardous medications when preparing cyclophosphamide.

Use cyclophosphamide powder for injection.

Reconstitute cyclophosphamide to a concentration of 20 mg/mL with sterile water for injection or 0.9% sodium chloride.

Dilute with 100 to 250 mL of 0.9% sodium chloride injection or 5% dextrose injection.

Prednisone 1.

No special precautions are required.

Prednisone is available in 1,2,5, 5, 10, 20, and 50 mg tablets and as 1 and 5 mg/mL oral solutions.

Store at controlled room temperature (15° to 30° C).

Drug Administration

In the EPOCH regimen, doxorubicin, etoposide, and vincristine are all administered by continuous intravenous (IV) infusion.

Cyclophosphamide is administered by IV infusion over 10 to 30 minutes. Some institutions allow doses less than 1,000 mg to be administered as a slow (1-to 10-minute) IV push.

Prednisone: 1.

Prednisone is given orally (PO) and usually as a single-daily dose.

Administration with, or immediately after a meal, milk, or a small snack, is recommended to minimize gastric irritation.

Supportive Care

Acute and Delayed Emesis Prophylaxis: The EPOCH regimen is predicted to cause acute emesis in 60% to 90% of patients.¹⁰ However, the studies reviewed reported mild nausea or vomiting ranging from 6% to 86% of patients^2,3 in 5% of cycles.¹ Recommendations for acute emesis prophylaxis include a serotonin antagonist and a corticosteroid; some experts recommend use of a neurokinin inhibitor as well.^11-13 Aggressive prophylactic antiemetic therapy with a serotonin antagonist and steroid combination may not be necessary. A regimen for mildly emetogenic regimens may be adequate. Since prednisone is 1 of the components of the EPOCH regimen, additional corticosteroids as part of the antiemetic regimen are not necessary.

If a serotonin antagonist and steroid combination is used on the days when doxorubicin, vincristine, and etoposide are given, 1 of the following regimens is suggested: 1.

Ondansetron 16 to 24 mg PO, given 30 minutes before etoposide, doxorubicin, and vincristine.

Granisetron 2 mg PO, given 30 minutes before etoposide, doxorubicin, and vincristine.

Dolasetron 100 to 200 mg PO, given 30 minutes before etoposide, doxorubicin, and vincristine.

Palonosetron 0.25 mg IV on day 1 only, given 30 minutes before etoposide, doxorubicin, and vincristine.

If a neurokinin antagonist is also used, 1 of the following regimens is suggested: 1.

Ondansetron 16 to 24 mg PO and aprepitant 125 mg PO, given 30 minutes before etoposide, doxorubicin, and vincristine.

Granisetron 2 mg PO and aprepitant 125 mg PO, given 30 minutes before etoposide, doxorubicin, and vincristine.

Dolasetron 100 to 200 mg PO and aprepitant 125 mg PO, given 30 minutes before etoposide, doxorubicin, and vincristine.

Palonosetron 0.25 mg, on day 1 only, and aprepitant 125 mg PO, given 30 minutes before etoposide, doxorubicin, and vincristine.

If a mildly-emetogenic regimen is used, 1 of the following regimens should be used: 1.

Give the first prednisone dose 30 minutes before starting the etoposide, doxorubicin, and vincristine infusion.

Prochlorperazine 10 mg PO or IV ± diphenhydramine 25 to 50 mg PO if needed, given 30 minutes before etoposide, doxorubicin, and vincristine infusion.

Metoclopramide 0.5 to 2 mg/kg PO or IV ± diphenhydramine 25 to 50 mg PO if needed, given 30 minutes before etoposide, doxorubicin, and vincristine infusion.

Promethazine 25 to 50 mg PO, or 12.5 to 25 mg IV ± diphenhydramine 25 to 50 mg PO if needed, given 30 minutes before etoposide, doxorubicin, and vincristine infusion.

Patients who experience significant nausea or vomiting with 1 of these regimens should receive an agent from a different pharmacologic category added to the previous prophylactic antiemetic regimen.^11-13 The following regimens are recommended: 1.

Patients who received a steroid only—add a dopamine antagonist.

Patients who received a dopamine antagonist only— add a steroid.

Patients who received a steroid and dopamine antagonist—substitute a serotonin antagonist for the dopamine antagonist.

If a steroid and dopamine antagonist combination is not effective, a serotonin antagonist and steroid combination may be required.

Wilson et al. (1993) reported mild nausea, adequately managed without antiemetics, following cyclophosphamide administration.¹ When it does occur, onset of cyclophos-phamide-induced emesis is often delayed for up to 12 hours after drug administration and may persist for up to 120 hours.^14,15 Although not well documented in the literature, some clinicians divide the daily antiemetic dose into 2 doses on days when cyclophosphamide is administered. Use of 1 of the aforementioned regimens for prevention of mild emesis is recommended.

Prophylactic therapy should continue for 2 to 3 days. A meta-analysis of several trials of serotonin antagonists recommends against prolonged (greater than 24 hours) use of these agents; making a steroid, or steroid and dopamine antagonist combination most appropriate for follow-up therapy.¹⁶

For most patients, prophylactic antiemetic therapy, particularly with a serotonin antagonist, is not generally required.^11-13 If needed, 1 of the following regimens may be given 30 minutes prior to therapy: 1.

The prednisone 60 mg/m² PO days 1 through 6 of EPOCH may provide adequate control of nausea and vomiting without use of another antiemetic agent.

Prochlorperazine 10 mg PO or IV ± diphenhydramine 25 to 50 mg PO if needed, given 30 minutes before days 1 through 6.

Metoclopramide 0.5 to 2 mg/kg PO or IV ± diphenhydramine 25 to 50 mg PO if needed, given 30 minutes before days 1 through 6.

Promethazine 25 to 50 mg PO or 12.5 to 25 mg IV ± diphenhydramine 25 to 50 mg PO if needed, given 30 minutes before days 1 through 6.

Breakthrough Nausea and Vomiting^10-13: Patients should receive an antiemetic prescription to treat breakthrough nausea. One of the following regimens is suggested: 1.

Metoclopramide 0.5 to 2 mg/kg PO every 4 to 6 hours if needed ± diphenhydramine 25 to 50 mg PO every 6 hours if needed.

Prochlorperazine 10 mg PO every 4 to 6 hours if needed ± diphenhydramine 25 to 50 mg PO every 6 hours if needed.

Prochlorperazine 25 mg rectally every 4 to 6 hours if needed ± diphenhydramine 25 to 50 mg PO every 4 to 6 hours if needed.

Promethazine 25 to 50 mg PO every 4 to 6 hours if needed ± diphenhydramine 25 to 50 mg PO every 4 to 6 hours if needed.

A few small studies suggest that higher doses of granisetron (3 mg or 40 to 240 mcg/kg IV)^17-21 may be effective in treating breakthrough nausea; however, none of these reports found the improvement to be statistically significant.

Hydration: Patients receiving cyclophosphamide must be adequately hydrated to reduce the risk of hemorrhagic cystitis secondary to cyclophosphamide. Patients should be encouraged to frequently void their bladder. This can be accomplished by encouraging liberal fluid consumption (3 to 4 L/day) during each day of treatment with cyclophosphamide and for at least 24 hours after the last cyclophosphamide dose. No hemorrhagic cystitis was reported in the studies reviewed; however, Stillwell (1988) reports it may occur following a single IV dose.²² The risk of hemorrhagic cystitis increases with higher total doses of cyclophosphamide and may be further increased by radiation therapy.²²

Hypersensitivity Precautions: Doxorubicin can induce acute hypersensitivity reactions. However, such reactions are very rare and require no specific precautions. Doxorubicin may also cause a “flare reaction,” manifested by erythema, pruritus, and urticaria surrounding the injection site or extending along the vein being infused. Although sometimes confused with an extravasation or allergic reaction, generally it is self-limiting and resolves at the end of the infusion. Additional doses of the drug can be administered without concern.²³

Hematopoietic Growth Factors: Accepted practice guidelines and pharmacoeconomic analysis suggest that an antineoplastic regimen have a greater than 20% incidence of febrile neutropenia before prophylactic use of colony stimulating factors is warranted. For regimens with an incidence of febrile neutropenia between 10% and 20%, use of colony stimulating factors should be considered. For regimens with an incidence of febrile neutropenia less than 10%, routine prophylactic use of colony stimulating factors is not recommended.^24,25

Since severe (grade 3 or 4) neutropenia was reported in up to 26% of patients in the 3 trials reviewed, and febrile neutropenia was reported in 11% to 17% of patients,^1-3 prophylactic use of colony stimulating factors may be appropriate with the EPOCH regimen.^24,25

Extravasation: Doxorubicin is a potent vesicant, and extravasation should be avoided. If extravasation occurs, stop the infusion immediately, and aspirate as much of the extravasated solution as possible before withdrawing the needle. The limb should be elevated and cooled intermittently (ice packs for 15 to 20 minutes, 4 times a day, for 3 days).^26-28

Vincristine is a moderate vesicant, and extravasation should be avoided. If extravasation occurs, stop the infusion immediately, and aspirate as much of the extravasated solution as possible before withdrawing the needle. The limb should be elevated and cooled intermittently (ice packs for 15 to 20 minutes, 4 times a day, for 3 days).^26,27

Although Larson (1982 and 1985) reported applying ice to all extravasations,^26,27 most other groups suggest dry heat for 30 minutes, 4 times a day, for 3 days²⁸ and hyaluronidase 150 units/mL injected intradermally at the extravasation site has been recommended for treatment of vinca alkaloid extravasations.²⁸

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 Terminology Criteria for Adverse Events (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. Incidence values are rounded to the nearest whole percent unless incidence was less than or equal to 0.5%.

Cardiovascular: Decreased ejection fraction 25%¹; subclavian vein thrombosis 7%¹; atrial fibrillation 3%.²

Dermatologic: Alopecia (grade 3 or 4) 74%.²

Gastrointestinal: Nausea or vomiting 5% to 21% of cycles,^1,3 (grade 3 or 4) 6%²; mucositis 14%,³ (grade 1) 9%,¹ (grade 3 or 4) 3% to 8%^1,2; constipation (moderate) 7%¹; diarrhea 21%.³

Hematologic: Anemia (grade 3 or 4) 13%²; neutropenia (grade 3) 5%,³ (grade 4) 14%,³ (grade 3 or 4) 26%²; febrile neutropenia 11% to 17%^1,3; thrombocytopenia 19% to 25%.^1,3

Neurologic: Neuropathy 7%,³ (mild) 79%,¹ (moderate) 10%,¹ (grade 3 or 4) 3%.²

Infections: Infection 11% to 21%^2,3; fungal 7%¹; viral 14% to 19%.^1,3

Treatment-related deaths: Disseminated fungal infections 3%.¹

Pretreatment Laboratory Studies Needed

Baseline 1.

Aspartame aminotransferase/alanine aminotransferase (AST/ALT)

Total bilirubin

Serum creatinine

Complete blood (cell) count CBC with differential

Cardiac ejection fraction

Prior to each treatment 1.

CBC with differential

Serum creatinine

Recommended pretreatment values: The minimally acceptable pretreatment CBC values required to begin a cycle with full-dose therapy in the protocols reviewed were: 1.

Cardiac ejection fraction (EF): greater than or equal to 40%.¹

Absolute neutrophil count (ANC): greater than or equal to 1,000 cells/mcL.¹

Platelet count: greater than or equal to 100,000 cells/mcL.¹

Serum creatinine: less than 1.5 mg/dL.¹

Creatinine clearance (CrCl): greater than or equal to 40 mL/min.¹

Serum bilirubin: less than 2.5 mg/dL.¹

In clinical practice, a pretreatment ANC of 1,000 cells/mcL and platelets of 75,000 cells/mcL are usually considered acceptable.

Dosage Modifications

Renal Function 1.

Etoposide^29,30: (a)

Reduce dose by 15% for CrCl 46 to 60 mL/min.

(b)

Reduce dose by 20% for CrCl 30 to 45 mL/min.

(c)

Reduce dose by 25% for CrCl no more than 29 mL/min.

Doxorubicin: no adjustment required.²⁹

Vincristine: no adjustment required.²⁹

Cyclophosphamide: (a)

Kintzel and Dorr (1995) report no dosage modification is required for decreased renal function.²⁹

(b)

Patterson and Reams (2001) recommend a 50% dose reduction for a CrCl less than 10 mL/min.³⁰

(c)

Arnoff et al. (1999) recommend a 25% dose reduction for a CrCl less than 10 mL/min.³¹

Prednisone: no adjustment required.³¹

Hepatic Function 1.

Etoposide: reduce dose by 50% if total bilirubin 1.5 to 3 mg/dL.³²

Doxorubicin: (a)

Reduce dose by 25% for ALT or AST 2 to 3 times the upper limit of normal (ULN).^32,33

(b)

Reduce dose by 50% for total bilirubin greater than 1.2 mg/dL, and less than 3 mg/dL or ALT or AST greater than 3 times and less than or equal to 5 times the ULN.³²

(c)

Reduce dose by 50% for total bilirubin greater than 1.2 mg/dL, and less than 3 mg/dL and ALT or AST greater than 3 times and less than or equal to 5 times the ULN.³³

(d)

Reduce dose by 75% for total bilirubin greater than or equal to 3 mg/dL and less than or equal to 5 mg/dL or ALT or AST greater than 3 times and less than or equal to 5 times the ULN.³²

(e)

Reduce dose by 75% for total bilirubin greater than or equal to 3 mg/dL and less than or equal to 5 mg/dL.³³

(f)

Omit dose for total bilirubin greater than 5 mg/dL.^32,33

(g)

Omit dose for ALT or AST greater then 5 times the ULN.³²

Vincristine: reduce dose by 50% for the following^32,33: (a)

Bilirubin greater than or equal to 1.5 mg/dL and less than or equal to 3 mg/dL, or;

(b)

ALT or AST greater than or equal to 2 times the ULN and less than or equal to 3 times the ULN, or;

(c)

Any elevation of alkaline phosphates above the ULN.

Cyclophosphamide³²: (a)

Reduce dose 25% for bilirubin greater than 3.1 gm/dL or ALT or AST greater than 3 times the ULN.

(b)

Do not give the drug for bilirubin greater than 5 mg/dL.

Neutropenia 1.

ANC 1,000 to 1,500— reduce cyclophosphamide dose by 25%.^1,3

ANC less than 500—reduce cyclophosphamide dose by additional 25%.¹

Neurotoxicity 1.

Moderate to severe paresthesias affecting patients' ability to use his or her hands—vincristine dose should not exceed 2 mg per cycle.^1,3

Severe obstipation or inability to walk on heels—reduce vincristine dose by 50%.^1-3

Cardiotoxicity: EF decreased to less than 40% to 50%—do not give doxorubicin.^1,2

References

Wilson

W.H.

, Bryant

, Bates

EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory nonhodgkin's lymphoma. J Clin Oncol. 1993; 11(8): 1573–1582.

Khaled

H.M.

, Zekri

Z.K.

, Mokhtar

A randomized EPOCH vs. CHOP front-line therapy for aggressive non-Hodgkin's lymphoma patients: long-term results. Ann Oncol. 1999; 10(12): 1489–1492.

Stokoe

C.T.

, Ogden

, Jain

V.K.

Activity of infusional etoposide, vincristine, and doxorubicin with bolus cyclophosphamide (EPOCH) in relapsed Hodgkin's disease. Oncologist. 2001; 6(5): 428–434.

Gutierrez

, Chabner

B.A.

, Pearson

Role of a doxorubicin-containing regimen in relapsed and resistant lymphomas: an 8-year follow-up study of EPOCH. J Clin Oncol. 2000; 18(21): 3633–3642.

Wilder

D.D.

, Ogden

J.L.

, Jain

V.K.

A multicenter trial of infusional etoposide, doxorubicin, and vincristine with cyclophosphamide and prednisone (EPOCH) in patients with relapsed non-Hodgkin's lymphoma. Clin Lymphoma. 2001; 1(4): 285–292.

Wilson

W.H.

, Grossbard

M.L.

, Pittaluga

Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002; 99(8): 2685–2693.

Jermann

, Jost

L.M.

, Taverna

C.H.

Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Ann Oncol. 2004; 15(3): 511–516.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines - Non-Hodgkin's Lymphoma. V.2.2007. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed July 30, 2007.

Trissel

L.A.

Handbook on Injectable Drugs, 14th ed. ASHP; Bethesda. MD; 2007. p. 580, 651, 1628.

10.

Hesketh

P.J.

, Kris

M.G.

, Grunberg

S.M.

Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997; 15(1): 103–109.

11.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines - Antiemesis. V.1.2007. http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. Accessed August 10, 2007.

12.

Kris

M.G.

, Hesketh

P.J.

, Somerfield

M.R.

American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006; 24(18): 2932–2947.

13.

Multinational Association for Supportive Care in Cancer. Antiemetic Guidelines. 2007 http://www.mascc.org/media/Resource_centers/MASCC_Guidelines_Update.pdf. Accessed August 10, 2007.

14.

Martin

The severity and pattern of emesis following different cytotoxic agents. Oncology. 1996; 53(Suppl 1): 26–31.

15.

Beck

T.M.

The pattern of emesis following high-dose cyclophosphamide and the anti-emetic efficacy of ondansetron. Anticancer Drugs. 1995; 6(2): 237–242.

16.

Geling

, Eichler

H.G.

Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol. 2005; 23(6): 1289–1294.

17.

Terrey

J.P.

, Aapro

M.S.

The activity of granisetron in patients who had previously failed ondansetron antiemetic therapy. Eur J Clin Res. 1996; 8: 281–288.

18.

Carmichael

, Keizer

H.J.

, Cupissol

, Milliez

, Scheidel

, Schindler

A.E.

Use of granisetron in patients refractory to previous treatment with antiemetics. Anti-cancer Drugs. 1998; 9(5): 381–385.

19.

de Wit

, de Boer

A.C.

, vd Linden

G.H.

, Stoter

, Sparreboom

, Verweij

Effective cross-over to granisetron after failure to ondansetron, a randomized double blind study in patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy. Br J Cancer. 2001; 19: 85(8): 1099–1101.

20.

Smith

I.E.

A dose-finding study of granisetron, a novel antiemetic, in patients receiving cytostatic chemotherapy. The Granisetron Study Group. J Cancer Res Clin Oncol. 1993; 119(6): 350–354.

21.

Soukop

A dose-finding study of granisetron, a novel antiemetic, in patients receiving high-dose cisplatin. Granisetron Study Group. Support Care Cancer. 1994; 2(3): 177–183.

22.

Stillwell

T.J.

, Benson

R.C.

Jr. Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer. 1988; 61(3): 451–457.

23.

Weiss

R.B.

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

24.

Smith

T.J.

, Khatcheressian

, Lyman

G.H.

2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006; 24(19): 3187–3205.

25.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology - Myeloid Growth Factors. V.1.2006. http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf. Accessed August 10, 2007.

26.

Larson

D.L.

Treatment of tissue extravasation by antitumor agents. Cancer. 1982; 49(9): 1796–1799.

27.

Larson

D.L.

What is the appropriate management of tissue extravasation by antitumor agents?

Plast Reconstr Surg. 1985; 75(3): 397–405.

28.

Mullin

, Beckwith

M.C.

, Tyler

L.S.

Prevention and management of antineoplastic extravasation injury. Hosp Pharm. 2000; 35(1): 57–74.

29.

Kintzel

P.E.

, Dorr

R.T.

Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev. 1995; 21(1): 33–64.

30.

Patterson

W.P.

, Reams

G.P.

Renal and electrolyte abnormalities due to chemotherapy. In: The Chemotherapy Sourcebook. 3rd ed. Perry

M.C.

, ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001: 494–504.

31.

Aronoff

G.R.

, Berns

J.S.

, Brier

Mem

, eds. Drug Prescribing in Renal Failure. 4th ed. Phildelphia, PA: American College of Physicians; 1999: 73.

32.

Floyd

, Mirza

, Sachs

, Perry

M.C.

Hepatotoxicity of chemotherapy. Semin Oncol. 2006; 33: 50–67.

33.

King

P.D.

, Perry

M.C.

Hepatotoxicity of chemotherapy. Oncologist. 2001; 6(2): 162–176.