Vincristine,Doxorubicin,and Cyclophosphamide Alternating with Ifosfamide and Etoposide Regimen for Ewing's Sarcoma and Primitive Neuroectodermal Tumor (PNET) of Bone

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.

Keywords

Vincristine cyclophosphamide ifosfamide etoposide (VAC/IE)

Indication(s)

The VAC/IE regimen has been used as neoadjuvant and adjuvant treatment for Ewing's sarcoma and primitive neuroectodermal tumors (PNET) of bone.^1–5

Drug Preparation

Vincristine: 1.

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

Use vincristine injection (1 mg/mL)

Withdraw the volume required and dispense in a syringe.

Vincristine doses must have the following warning attached to the syringe: “Fatal if given intrathecally. For IV use only.”

Additionally, the syringe must be enclosed in an overwrap bearing the following warning: “Do not remove covering until moment of injection. Fatal if given intrathecally. For IV use only.”

Vincristine may be diluted in 25 or 50 mL of 0.9% sodium chloride injection in polyvinyl chloride bags; or in 20 mL of 0.9% sodium chloride injection in 30 mL polypropylene syringes.⁵

Dispensing diluted vincristine in minibags, rather than undiluted syringes has been recommended to prevent inadvertent intrathecal injection.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 a syringe, or in 50 to 100 mL (bolus infusions), or 250 to 1,000 mL (24-h infusions) of 0.9% sodium chloride, 5% dextrose in water, or a saline/dextrose solution for infusion.

Table 1.

Vincristine, Doxorubicin, Cyclophosphamide Regimen Alternating with Ifosfamide and Etoposide Regimen^1,2

Drug	Dose	Route of Administration	Administered on Day(s)	Total Dose/Cycle
Cycles 1, 2, 3, and 6
Vincristine	0.67 mg/m²	CIVI	1,2,3	2 mg/m²
Doxorubicin	25 mg/m²	CIVI	1,2,3	75 mg/m²
Cyclophosphamide	2,100 mg/m²	IV	1,2	4,200 mg/m²
Cycles 4, 5, and 7
Ifosfamide	1,800 mg/m²	IV	1,2,3,4,5	9,000 mg/m²
Etoposide	100 mg/m²	IV	1,2,3,4,5	500 mg/m²
Mesna	1,800 mg/m²	CIVI	1,2,3,4,5	9,000 mg/m²
Cycle repeats: every 3 weeks
Variations
1. Vincristine 2 mg/m² IV, doxorubicin 75 mg/m² IV (dactinomycin 1.25 mg/m² IV was substituted for doxorubicin once a cumulative doxorubicin dose of 375 mg/m² was reached) and cyclophosphamide 1,200 mg/m² IV alternating every 3 weeks with ifosfamide 1,800 mg/m²/day IV for 5 days and etoposide 100 mg/m²/day IV for 5 days.³
2. Vincristine 2 mg/m² IV, doxorubicin 75 mg/m² IV (as bolus infusion), and cyclophosphamide 1,200 mg/m² IV (dactinomycin 1.25 mg/m² IV was substituted for doxorubicin once a cumulative doxorubicin dose of 375 mg/m² was reached) alternating every 3 weeks with ifosfamide 1,800 mg/m²/day IV for 5 days and etoposide 100 mg/m²/day IV for 5 days. Courses were repeated every 3 weeks for a total of 17 courses.⁴

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

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 0.9% sodium chloride.

Dilute with 500 mL of 0.9% sodium chloride injection, 5% dextrose injection, or a saline/dextrose solution.

Ifosfamide: 1.

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

Use ifosfamide powder for reconstitution or ifosfamide injection 50 mg/mL.

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

Dispense in 100 to 1,000 mL of 0.9% sodium chloride, 5% dextrose in water, or a saline/dextrose solution for infusion.

Etoposide: 1.

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

Use etoposide injection 20 mg/mL.

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

Mesna: 1.

Use mesna injection 100 mg/mL.

Dilute in 50 to 1,000 mL of 0.9% sodium chloride or 5% dextrose in water for infusion.

Drug Administration

Vincristine: In the VAC/IE regimen, vincristine is usually administered as a continuous intravenous (IV) infusion.^1,2

Doxorubicin: In the VAC/IE regimen, doxorubicin is usually administered as a continuous IV infusion.^1,2

Cyclophosphamide: Administer by IV infusion over 10 to 60 minutes. Some institutions allow doses less than 1 g to be given as a slow IV push.

Ifosfamide: Administer by IV infusion over 30 minutes to several hours.

Etoposide: Administer by IV infusion over 45 to 60 minutes. Etoposide should not be given by rapid IV injection or short (less than 45 min) infusion.

Mesna: Administer by IV infusion over 15 to 30 minutes or as a continuous infusion.

Supportive Care

Acute Emesis Prophylaxis: The VAC and IE regimens are predicted to cause acute emesis in greater than 90% of patients on day 1.⁷ The studies reviewed did not report a specific incidence of nausea or vomiting. Appropriate acute-emesis prophylaxis on day 1 of both the VAC and IE portions of the regimen includes a neurokinin inhibitor, a serotonin antagonist, and dexamethasone.^8–10 One of the following regimens may be given 30 minutes prior to therapy:

Ondansetron 8 to 16 mg orally (PO), dexamethasone 12 mg PO, and aprepitant 125 mg PO, given 30 minutes before VAC or IE.

Granisetron 2 mg PO, dexamethasone 12 mg PO, and aprepitant 125 mg PO, given 30 minutes before VAC or IE.

Dolasetron 100 to 200 mg PO, dexamethasone 12 mg PO, and aprepitant 125 mg PO, given 30 minutes before VAC or IE.

Palonosetron 0.25 mg IV, dexamethasone 12 mg PO, and aprepitant 125 mg PO, given 30 minutes before VAC or IE.

Prophylactic antiemetics should continue for 2 to 3 days after completion of the last chemotherapy infusion in each portion of the regimen. The onset of cyclophosphamide-induced emesis is often delayed for up to 12 hours after drug administration and may persist for up to 120 hours.^11,12 A meta-analysis of several trials of serotonin antagonists recommends against prolonged (greater than 24 h) use of these agents, making a steroid and neurokinin antagonist, or steroid, neurokinin antagonist and dopamine antagonist combination most appropriate for follow-up therapy.¹³ One of the following regimens is suggested:

Dexamethasone 4 mg PO twice a day for 3 days, aprepitant 80 mg PO every morning for 2 days, ± metoclopramide 0.5 to 2 mg/kg PO every 4 to 6 hours, ± diphenhydramine 25 to 50 mg PO every 6 hours if needed (PRN), starting the day after VAC or IE is completed.

Dexamethasone 4 mg PO twice a day for 3 days, aprepitant 80 mg PO every morning for 2 days, ± prochlorperazine 10 mg PO every 4 to 6 hours, ± diphenhydramine 25 to 50 mg PO every 6 hours PRN, starting the day after VAC or IE completed.

Dexamethasone 4 mg PO twice a day for 3 days, aprepitant 80 mg PO every morning for 2 days, ± promethazine 25 to 50 mg PO every 4 to 6 hours, ± diphenhydramine 25 to 50 mg PO every 6 hours PRN, starting the day after VAC and IE completed.

Patients who experience significant nausea or vomiting with one of the above regimens should receive an agent from a different pharmacologic category.^8–10

Breakthrough Nausea and Vomiting^8–10: Patients should receive an antiemetic prescription to treat breakthrough nausea. One of the following regimens is suggested:

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

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

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

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

A few small studies suggest that higher doses of granisetron (3 mg IV or 40 to 240 mcg/kg) may be effective in treating breakthrough nausea; however, none of these reports found the improvement to be statistically significant.^14–18

Hydration: Patients receiving cyclophosphamide and ifosfamide 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 or ifosfamide dose. No hemorrhagic cystitis was reported in the studies reviewed; however, Stillwell reports it may occur following a single IV dose.¹⁹

The risk of hemorrhagic cystitis increases with higher total doses of cyclophosphamide and ifosfamide and may be further increased by radiation therapy.¹⁹ The incidence of hemorrhagic cystitis was not reported in the studies reviewed.^1–4

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.²⁰

Hematopoietic Growth Factors: Accepted practice guidelines and pharmacoeconomic analysis suggest that an anti-neoplastic 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.^21,22 The specific incidence of febrile neutropenia was not reported in the trials reviewed^1–4; however, the occurrence of fatal sepsis as well as the incidence of serious infections or episodes of fever and neutropenia was noted to be greater in patients receiving this regimen^1,3,4 and suggests prophylactic use of colony-stimulating factors may be justified. Kolb et al. (2003) reported the use of granulocyte colony-stimulating factors after each cycle of chemotherapy to shorten the duration of neutropenia.¹

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 min, 4 times daily for 3 days).^23–25 Dexrazoxane has been suggested for treatment of anthracycline extravasations.²⁶ The limited data, expense of the marketed product, questions of comparability of generic products and legal issues make the value of dexrazoxane as an antidote for extravasations uncertain.

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 intermittently cooled (ice packs for 15 to 20 min, 4 times daily for 3 days).^23,24 Although Larson (1982, 1985) reported applying ice to all extravasations,^23,24 most other groups suggest dry heat for 30 minutes 4 times daily for 3 days.²⁵ Hyaluronidase 150 units/mL injected intradermally at the extravasation site also has been recommended for treatment of vinca alkaloid extravasations.²⁵

Major Toxicities

In the studies reviewed, the toxicities reported were limited to treatment-related deaths and incidence of secondary neoplasms. Incidence values are rounded to the nearest whole percent unless less than or equal to 0.5%.

Treatment-Related Deaths: Cardiotoxicity 2% to 7%^3,4; infection 1.5% to 3%^1,3,4; hemorrhage 0.5%.⁴

Secondary Neoplasms: Chondroblastic osteosarcoma 2%³; acute myelogenous leukemia (AML) 1%⁴; acute lymphoblastic leukemia (ALL) 0.05% to 2%^3,4; myelodysplastic syndrome (MDS) 0.05%⁴; secondary MDS/AML 4%.¹

Pretreatment Laboratory Studies Needed

Baseline 1.

Aspartate aminotransferase (AST) and alanine transaminase (ALT)

Total bilirubin

Serum creatinine

Complete blood cell count (CBC) with differential

Serum electrolytes (calcium, magnesium, and potassium)

Prior to each treatment 1.

CBC with differential

Total bilirubin

AST/ALT

Serum creatinine

Serum electrolytes (calcium, magnesium, and potassium)

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

Neutrophil count greater than or equal to 500 cells/mcL.¹

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

Serum creatinine: Less than or equal to 1.5 mg/dL.

Normal renal function as judged by creatinine clearance (CrCl).

Serum bilirubin less than or equal to 1.5 mg/dL.

Dosage Modifications

Hepatic²⁷: 1.

Vincristine - Alkaline phosphatase elevated - Reduce dose 50%

Doxorubicin: a.

AST or ALT 2 to 3 times upper limit of normal (ULN) - Reduce dose by 25%.

Total bilirubin 1.2 to 3 mg/dL or AST or ALT greater than 3 times ULN - Reduce dose by 50%.

Total bilirubin 3 to 5 mg/dL - Reduce dose by 75%.

Total bilirubin greater than 5 mg/dL - Do not give drug.

Cyclophosphamide - No adjustment required.

Ifosfamide - No adjustment required.

Etoposide - Total bilirubin 1.5 to 3 mg/dL or AST greater than 180 units/L -Reduce dose by 50%.

Mesna - No adjustment required.

Renal Function²⁸: 1.

Vincristine - No adjustment required.

Doxorubicin - No adjustment required.

Cyclophosphamide - No adjustment required.

Ifosfamide: a.

CrCl less than 60 mL/minute but greater than 45 mL/minute - Reduce dose by 20%.

CrCl less than 45 mL/minute but greater than 30 mL/minute -Reduce dose by 25%.

CrCl less than 30 mL/minute - Reduce dose by 30%.

Etoposide: a.

CrCl less than 60 mL/minute but greater than 45 mL/minute - Reduce dose by 15%.

CrCl less than 45 mL/minute but greater than 30 mL/minute - Reduce dose by 20%.

CrCl less than 30 mL/minute - Reduce dose by 25%.

Mesna - No adjustment required.

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