Cancer Chemotherapy Update: Mesna,Doxorubicin,Ifosfamide,and Dacarbazine (MAID) Regimen for Sarcomas

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

MAID Acronym for the medications in the regimen

Indications

The MAID regimen is used as adjuvant or neoadjuvant therapy of operable soft tissue sarcoma^1-3 and primary therapy of metastatic or inoperable soft tissue sarcoma.^1,4-9 MAID has also been used as primary therapy of metastatic or inoperable sarcomas of bone^5,6,9 and Ewing sarcoma.⁹

Drug Preparation

Mesna 1.

Follow institutional policies for preparation of hazardous medication when preparing mesna.

Use mesna injection, 100 mg/mL.

Mesna is also available as 400 mg tablets for oral use.

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

Mesna may be mixed in the same bag with ifosfamide.^5,6

Doxorubicin 1.

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

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

Dilute the powder for injection with 0.9% sodium chloride to a concentration of 2 mg/mL.

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

Doxorubicin may be mixed in the same bag with dacarbazine.^5,6

Since dacarbazine is light-sensitive, bags containing doxorubicin and dacarbazine should be protected from light immediately following preparation.

Ifosfamide 1.

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

Use ifosfamide powder for reconstitution or ifosfamide injection.

Reconstitute powder for injection with sterile water for injection, 0.9% sodium chloride, or 5% dextrose in water to a concentration of 50 mg/mL.

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

Ifosfamide may be mixed in the same bag with mesna.^5,6

Dacarbazine 1.

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

Reconstitute to a concentration of 10 to 20 mg/mL with sterile water for injection, 5% dextrose in water, or 0.9% sodium chloride.

Dilute with 250 to 1,000 mL 5% dextrose in water or 0.9% sodium chloride.

Dacarbazine may be mixed in the same bag as doxorubicin.^5,6

Dacarbazine is light-sensitive and should be protected from light immediately following preparation.

Drug Administration

In the MAID regimen, all four drugs are administered by continuous intravenous (IV) infusion.

Supportive Care

Acute Emesis Prophylaxis: The MAID regimen is predicted to cause acute emesis in greater than 90% of patients.^10-13 The studies reviewed reported nausea or vomiting in 81% to 100%^2,9 and severe (grade 3 or 4) nausea or vomiting in 9% to 19%^2,3,5,6,9 of patients. Appropriate acute emesis prophylaxis includes a serotonin antagonist, a neurokinin-1 (NK-1) receptor antagonist, and a corticosteroid.^11-13 One of the following regimens is suggested: 1.

Ondansetron 16 to 24 mg orally and dexamethasone 12 mg orally, given 30 minutes before MAID on days 1 through 4; aprepitant 125 mg orally, given 30 minutes before MAID on day 1; and aprepitant 80 mg orally, given 30 minutes before MAID on days 2 and 3.

Granisetron 2 mg orally and dexamethasone 12 mg orally, given 30 minutes before MAID on days 1 through 4; aprepitant 125 mg orally, given 30 minutes before MAID on day 1; and aprepitant 80 mg orally, given 30 minutes before MAID on days 2 and 3.

Dolasetron 100 to 200 mg orally and dexamethasone 12 mg orally, given 30 minutes before MAID on days 1 through 4; aprepitant 125 mg orally, given 30 minutes before MAID on day 1; and aprepitant 80 mg orally, given 30 minutes before MAID on days 2 and 3.

Palonosetron 0.25 mg IV, given 30 minutes before MAID on day 1; dexamethasone 12 mg orally, given 30 minutes before MAID on days 1 through 4; aprepitant 125 mg orally, given 30 minutes before MAID on day 1; and aprepitant 80 mg orally, given 30 minutes before MAID on days 2 and 3.

The antiemetic therapy should continue for at least 3 days after the completion of MAID to prevent prolonged nausea and vomiting. A meta-analysis of several trials of serotonin antagonists recommends against prolonged (greater than 24 hours after completion of chemotherapy) use of these agents¹⁴; making a steroid, or steroid and dopamine antagonist combination, most appropriate for follow-up therapy. One of the following regimens is suggested: 1.

Dexamethasone 4 mg orally twice a day for 3 days ± metoclopramide 0.5 to 2 mg/kg orally every 4 to 6 hours ± diphenhydramine 25 to 50 mg orally every 6 hours if needed for restlessness, starting on day 5 of MAID.

Dexamethasone 4 mg orally twice a day for 3 days, ± prochlorperazine 10 mg orally every 4 to 6 hours ± diphenhydramine 25 to 50 mg orally every 6 hours if needed for restlessness, starting on day 5 of MAID.

Dexamethasone 4 mg orally twice a day for 3 days ± promethazine 25 to 50 mg orally every 4 to 6 hours ± diphenhydramine 25 to 50 mg orally every 6 hours if needed for restlessness, starting on day 5 of MAID. Patients who do experience significant nausea or vomiting with one of these regimens should receive an agent from a different pharmacologic category.^14-16 A few small studies suggest substituting granisetron for ondansetron in subsequent treatment cycles; however none of these reports found the improvement to be statistically significant.^15-19

Breakthrough Nausea and Vomiting^11-13: 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 orally every 4 to 6 hours if needed ± diphenhydramine 25 to 50 mg orally every 6 hours if needed for restlessness.

Prochlorperazine 10 mg orally every 4 to 6 hours if needed ± diphenhydramine 25 to 50 mg orally every 6 hours if needed for restlessness.

Prochlorperazine 25 mg rectally every 4 to 6 hours if needed ± diphenhydramine 25 to 50 mg orally every 4 to 6 hours if needed for restlessness.

Promethazine 25 to 50 mg orally every 4 to 6 hours if needed ± diphenhydramine 25 to 50 mg orally every 4 to 6 hours if needed for restlessness.

A few small studies suggest that higher doses of granisetron (3 mg or 40 to 240 mcg/kg IV)^15-19 may be effective in treating breakthrough nausea; however, none of these reports found the improvement to be statistically significant.

Hemorrhagic Cystitis: Ifosfamide can cause urotoxicity, consisting of hemorrhagic cystitis, dysuria, urinary frequency, and other symptoms of bladder irritation. Prophylaxis consists of vigorous oral and/or IV hydration and uroprotection with mesna. Urine output of 75 to 100 mL/h should be maintained during administration of ifosfamide.⁵ The mesna regimens used in the trials of MAID reviewed are listed in Table 1.

Table 1.

Mesna, Doxorubicin, Ifosfamide, and Dacarbazine (MAID) Regimens^2,5,6,9

Drug	Dose	Route of Administration	Administered on Day(s)	Total Dose/Cycle
Mesna	2,500 mg/m²	CIVI	1,2,3,4	10,000 mg/m²
Doxorubicin	20 mg/m² 15 mg/m²	CIVI	1,2,3 1,2,3,4	60 mg/m²
Ifosfamide	2,000 to 2,500 mg/m²	CIVI	1,2,3	6,000 to 7,500 mg/m²
Dacarbazine	250 mg/m² 300 mg/m²	CIVI	1,2,3,4 1,2,3	1,000 mg/m² 900 mg/m²
Cycle repeats: Every 21 days.
Variations
1. Bui, et al administered mesna 3,000 mg/m²/day CIVI days 1,2,3; doxorubicin 20 mg/m²/day CIVI days 1,2,3; ifosfamide 2,500 mg/m² IV over 3 hours days 1,2,3; dacarbazine 300 mg/m² IV over 1 hour days 1,2,3; and lenograstim 5 mcg/kg/day subcutaneous days 4 to 13, or days 4 to 16 if ANC less than 1,000 cells/mcL on day 13.⁷
2. Kraybill, et al administered mesna 2,500 mg/m²/day CIVI days 1,2,3; doxorubicin 20 mg/m²/day CIVI days 1,2,3; ifosfamide 2,500 mg/m²/day CIVI days 1,2,3; dacarbazine 225 mg/m²/day CIVI days 1,2,3; and filgrastim 5 mcg/kg/day subcutaneous starting on day 5 and continuing daily until absolute granulocyte count greater than 1,500 cells/mcL.³

ANC = absolute neutrophil count; CIVI = continuous (24-hour) IV infusion; IV = intravenous infusion.

Hypersensitivity Precautions^20-22: 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 infused vein. 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.

Hematopoietic Growth Factors: Accepted practice guidelines and pharmacoeconomic analysis suggest that an antineoplastic regimen has 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.^23,24

Since febrile neutropenia was reported in 25% to 59% of patients in the trials of MAID reviewed, prophylactic use of colony-stimulating factors is recommended.^2,5,7

Extravasation: Doxorubicin is a potent vesicant, and extravasation should be avoided. If extravasation occurs, stop the infusion immediately and aspirate as much of the extravasat-ed solution as possible before withdrawing the needle. The limb should be elevated and cooled intermittently (ice packs for 15 to 20 minutes four times a day for 3 days).^25-27

Major Toxicities

Most of the following toxicities 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 (available at 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: Any (grade 3 or 4) 2%,³ vascular (grade 3 or 4) 3%.³

Dermatologic: Alopecia (all grades) 94%.⁷

Gastrointestinal: Diarrhea (grade 1 or 2) 14%,⁹ (grade 3 or 4) 4% to 5%^3,6; mucositis (grade 1 or 2) 26%,⁹ (grade 3 or 4) 2% to 9%^3,5-7,9; nausea (grade 1 or 2) 72% to 83%,^2,9 (grade 3 or 4) 17%²; nausea or vomiting (grade 3 or 4) 9% to 19%^2,3,5,6,9; vomiting (grade 1 or 2) 83%,² (grade 3 or 4) 10%.²

Hematologic: Anemia (grade 1 or 2) 42% to 52%,^2,9 (grade 3 or 4) 22% to 55%^2,3,6,9; febrile neutropenia 25% to 59%^2,5,7; granulocytopenia (grade 1 or 2) 1%,⁹ (grade 3 or 4) 79% to 80%^6,9; hematocrit (grade 3 or 4) 3%³; leukopenia (grade 1 or 2) 7% to 27%,^2,9 (grade 3 or 4) 58% to 89%^2,3,5-7; neutropenia (grade 3 or 4) 78%³; thrombocytopenia (grade 1 or 2) 14% to 68%,^2,5,9 (grade 3 or 4) 26% to 66%.^2,3,5,6,9

Infection: Any (grade 3 or 4) 33%³; neutropenic sepsis 13%.⁵

Neurologic: Any (grade 3 or 4) 3%³; hallucinations, confusion, or stupor (grade 1, 2, or 3) 2% to 3%^5,6; pain (grade 3 or 4) 3%³; peripheral neuropathy (grade 3 or 4) 2%³; somnolence (grade 1 or 2) 9%⁹; somnolence (grade 2 or 3) 4%⁵; (grade 3 or 4) 1% to 6%.^6,9

Pulmonary: Any (grade 3 or 4) 5%.³

Renal: Acute renal failure (serum creatinine greater than 4 mg/dL) 1%⁵; hematuria (grade 1) 58%,² (grade 2) 4%⁵; hematuria (grade 1 or 2) 4% to 9%^6,9; reversible proximal renal tubular acidosis (1%).⁵

Treatment Related Deaths: Encephalopathy (0.5%)⁶; infection (1%)⁹; infections associated with grade 4 myelosuppression (4%)⁶; leukopenic sepsis with respiratory failure (2%)³; myelodysplasia (2%)²; septic shock (1%).⁵

Pretreatment Studies Needed

Baseline 1.

Aspartame aminotransferase/alanine aminotransferase (AST/ALT)

Total bilirubin

Serum creatinine

Complete blood cell (CBC) count with differential

Cardiac ejection fraction with multigated acquisition scan or echocardiogram

Prior to each treatment 1.

AST/ALT.

Total bilirubin.

Serum creatinine.

CBC count with differential.

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

White blood cell count (WBC): greater than or equal to 3,000 cells/mcL.^4-6,9

Absolute neutrophil count (ANC): greater than 1,500 cells/mcL.^7,8

Platelet count: greater than or equal to 100,000 cells/mcL.^4-9

Serum creatinine: less than 1.5-fold institutional normal value.^7-9

Serum bilirubin: Less than 1.5 mg/dL⁴; less than 1.5 to 2-fold institutional normal value (less than 4-fold if sarcoma metastatic to liver).^7-9

AST/ALT: less than 1.5 to 2-fold institutional normal value (less than 4-fold if sarcoma metastatic to liver).^7-9

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

Dosage Modifications

Renal Function 1.

Ifosfamide: a.

Hold dose for serum creatinine greater than 2 mg/dL.^4-6,9

Reduce dose by 20% for creatinine clearance (CrCl) 46 to 60 mL/min.²⁸

Reduce dose by 25% for CrCl 31 to 45 mL/min.²⁸

Reduce dose by 30% for CrCl less than or equal to 30 mL/min.²⁸

Dacarbazine: a.

Reduce dose by 20% for CrCl 46 to 60 mL/min.²⁸

Reduce dose by 25% for CrCl 31 to 45 mL/min.²⁸

Reduce dose by 30% for CrCl less than or equal 30 mL/min.²⁸

Liver Function 1.

Doxorubicin: a.

Reduce dose by 25% for AST/ALT greater than two to three times upper limit of normal (ULN).²⁹

Reduce dose by 50% for total bilirubin 1.2 or 1.5 to 2.9 mg/dL or for AST/ALT greater than three times ULN.^4,29

Reduce dose by 75% for total bilirubin 3 to 5 mg/dL.⁴

Hold dose for total bilirubin greater than 5 mg/dL.^4,29

Ifosfamide²⁹: a.

Reduce dose by 50% for total bilirubin 1.5 to 2.9 mg/dL.⁴

Reduce dose by 75% for total bilirubin 3 to 5 mg/dL⁴ or for total bilirubin greater than 3 mg/dL.²⁹

Hold dose for total bilirubin greater than 5 mg/dL.⁴

Myelosuppression 1.

Hold MAID for 1 week for WBC less than 3,000 cells/mcL or platelets less than 100,000 cells/mcL.^4,5 Restart MAID only when WBC reaches 3,000 cells/mcL and platelets reach 100,000 cells/mcL.^6,9

For WBC nadir less than 500 cells/mcL or neutropenic fever, reduce ifosfamide and mesna doses by 500 mg/m²/day.⁵

For platelet nadir less than 50,000 cells/mcL, reduce dacarbazine dose by 50%.⁵

Other 1.

Hold ifosfamide for urinary red blood cell count of greater than 50 cells/high-powered field.^5,6,9

Hold ifosfamide for any significant neurologic abnormality.^6,9

References

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology – Soft Tissue Sarcoma. V.2.2007. http://www.nccn.org. Accessed July 14, 2007.

Delaney

T.F.

, Spiro

I.J.

, Suit

H.D.

Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys. 2003; 56(4): 1117–1127.

Kraybill

W.G.

, Harris

, Spiro

I.J.

Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, highgrade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol. 2006; 24(4): 619–625.

Elias

A.D.

, Antman

K.H.

Doxorubicin, ifosfamide, and dacarbazine (AID) with mesna uroprotection for advanced untreated sarcoma: a phase I study. Cancer Treat Rep. 1986; 70(7): 827–833.

Elias

, Ryan

, Sulkes

, Collins

, Aisner

, Antman

K.H.

Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989; 7(9): 1208–1216.

Antman

, Crowley

, Balcerzak

S.P.

An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993; 11(7): 1276–1285.

Bui

B.N.

, Chevallier

, Chevreau

Efficacy of lenograstim on hematologic tolerance to MAID chemotherapy in patients with advanced soft tissue sarcoma and consequences on treatment dose-intensity. J Clin Oncol. 1995; 13(10): 2629–2636.

Chevreau

, Bui

B.N.

, Chevallier

Phase I-II trial of intensification of the MAID regimen with support of lenograstim (rHuG-CSF) in patients with advanced soft-tissue sarcoma (STS). Am J Clin Oncol. 1999; 22(3): 267–272.

Antman

, Crowley

, Balcerzak

S.P.

A Southwest Oncology Group and Cancer and Leukemia Group B phase II study of doxorubicin, dacarbazine, ifosfamide, and mesna in adults with advanced osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. Cancer. 1998; 82(7): 1288–1295.

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 in Oncology - Antiemesis. V.1.2007. http://www.nccn.org. Accessed July 14, 2007.

12.

Multinational Association for Supportive Care in Cancer. Antiemetic Guidelines. 2007. http://www.mascc.org. Accessed July 19, 2007.

13.

Kris

M.G.

, Hesketh

P.J.

, Somerfield

M.R.

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

14.

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.

15.

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.

16.

Carmichael

, Keizer

H.J.

, Cupissol

, Milliez

, Scheidel

, Schindler

A.E.

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

17.

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; 85(8): 1099–1101.

18.

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.

19.

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.

20.

Weiss

R.B.

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

21.

Zanotti

K.M.

, Markham

Prevention and management of antineoplastic-induced hypersensitivity reactions. Drug Safety. 2001; 24(10): 767–779.

22.

Shepherd

G.M.

Hypersensitivity reactions to chemotherapeutic drugs. Clin Rev Allergy Immunol. 2003; 24(3): 253–262.

23.

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.

24.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology - Myeloid Growth Factors. V.1.2006. http://www.nccn.org. Accessed July 14, 2007.

25.

Larson

D.L.

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

26.

Larson

D.L.

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

Plast Reconstr Surgery. 1985; 75(3): 397–402.

27.

Mullin

, Beckwith

M.C.

, Tyler

L.S.

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

28.

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.

29.

Floyd

, Mirza

, Sachs , Perry

M.C.

Hepatotoxicity of chemotherapy. Semin Oncol. 2006; 33(1): 50–67.