Paclitaxel and Gemcitabine (PG) for Advanced Breast Cancer

Abstract

The increasing complexity of cancer chemotherapy increases 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, and review various agents, both commercially available and investigational, used to treat malignant diseases.

Regimen name: Paclitaxel and Gemcitabine (PG), also called Gemcitabine and Taxol (GT).

Origin of Name: The regimen is named for the two drugs (paclitaxel and gemcitabine, or gemcitabine and Taxol) it contains.

Indication(S)

The PG regimen is used as first-line and salvage therapy for metastatic breast cancer.^{1

11}

Drug Preparation

Paclitaxel

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

Use paclitaxel injection (6 mg/mL).

Dilute with 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose/0.9% sodium chloride injection, or 5% dextrose in Ringer's injection. The final concentration should be 0.3 to 1.2 mg/mL.

Avoid contact of the undiluted injection with plasticized polyvinyl chloride (PVC) equipment or devices. In order to minimize patient exposure to the plasticizer Di(2-ethylhexyl)phthalate (DEHP), which may be leached from PVC infusion bags, store diluted paclitaxel solutions in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin).

Gemcitabine

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

Use gemcitabine hydrochloride for injection, 200 mg or 1 g vial of lyophilized powder.

Reconstitute the lyophilized powder to yield a concentration of 38 mg/mL.

Note: When reconstituted according to the manufacturer's recommendation, the final concentration is 38 mg/mL, not 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution and should be avoided.

Dilute with 50 to 250 mL 0.9% sodium chloride injection.

Drug Administration

Paclitaxel

In order to minimize patient exposure to the plasticizer DEHP, which may be leached from PVC, administer paclitaxel with polyethylene-lined infusion sets.

Because of paclitaxel's tendency to form microfilaments, infuse the drug through a 0.22 micron filter.

Administer by IV infusion over 3 hours.

Gemcitabine

Administer by IV infusion over 30 minutes.

Sequence of Administration

In vitro data indicate when breast cancer cells are exposed to gemcitabine first and then to paclitaxel, or to both medications simultaneously, gemcitabine antagonizes the cytotoxic effects of paclitaxel. However, when cells are exposed to paclitaxel first and then to gemcitabine, there is a synergistic cytotoxic effect. It is recommended that paclitaxel be administered before gemcitabine in the PG regimen.^12,13 This sequence was used in all of the reviewed studies. To date, no study has compared the three sequences in human subjects.

Table 1.

Paclitaxel and Gemcitabine^{1

6}

Drug	Dose	Route of Administration	Administered on Day(s)	Total Dose/Cycle
Paclitaxel	175 mg/m²	IV	1	175 mg/m²
Gemcitabine	1,000 to 1,250 mg/m²	IV	1, 8	2,000 to 2,500 mg/m²
Cycle repeats: Every 3 weeks
Paclitaxel and Gemcitabine^{7 10}^*
Paclitaxel	130 to 150 mg/m²	IV	1	130 to 150 mg/m²
Gemcitabine	1,500 to 2,500 mg/m²	IV	1	1,500 to 2,500 mg/m²
Cycle repeats: Every 2 weeks.

Some of the references regarding every-2-weeks regimens used prophylactic filgrastim,^8,9 while others did not.^7,10

Supportive Care

Acute Emesis Prophylaxis: The PG regimen is predicted to cause acute emesis in 30% to 60% of patients on treatment days containing both paclitaxel and gemcitabine, and in 10% to 30% of patients on gemcitabine-only treatment days.¹⁴ The reviewed studies reported nausea or vomiting in 50% to 67% of patients,^5,8,9 with severe (grade 3 or 4) nausea or vomiting reported in 3% to 4% of patients.^{5

7} According to current guidelines, appropriate acute emesis prophylaxis for paclitaxel plus gemcitabine treatment days includes a serotonin antagonist and a corticosteroid.^{15

17} One of the following regimens may be given 30 minutes prior to therapy:

Ondansetron 16 to 24 mg and dexamethasone 20 mg, both given orally.

Granisetron 2 mg and dexamethasone 20 mg, both given orally.

Dolasetron 100 mg and dexamethasone 20 mg, both given orally.

Palonosetron 0.25 mg intravenously and dexamethasone 20 mg orally.

The antiemetic therapy should continue for at least 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.¹⁸ One of the following regimens is suggested:

Dexamethasone 8 mg orally once a day or 4 mg orally twice a day for 3 days, plus or minus metoclopramide 0.5 mg/kg or 20 to 40 mg orally every 4 to 6 hours, plus or minus diphenhydramine 25 to 50 mg orally every 6 hours if needed for metoclopramide-induced restlessness, starting the day after paclitaxel plus gemcitabine treatment days.

Dexamethasone 8 mg orally once a day or 4 mg orally twice a day for 3 days, plus or minus prochlorperazine 10 mg orally every 4 to 6 hours, plus or minus diphenhydramine 25 to 50 mg orally every 6 hours if needed for prochlorperazine-induced restlessness, starting the day after paclitaxel plus gemcitabine treatment days.

Patients who experience significant nausea or vomiting with one of these regimens should receive an agent from a different pharmacologic category.^{15

17} 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.^{19

21}

According to current guidelines, appropriate acute emesis prophylaxis for gemcitabine-only treatment days does not include a serotonin antagonist.^{15

17} One of the following regimens may be given 30 minutes prior to therapy:

Dexamethasone 12 mg orally.

Prochlorperazine 10 mg orally.

Metoclopramide 20 to 40 mg orally.

Breakthrough Nausea and Vomiting^{15

17}: Patients should receive an antiemetic prescription to treat breakthrough nausea or vomiting. One of the following regimens is suggested:

Metoclopramide 0.5 mg/kg or 20 to 40 mg orally every 4 to 6 hours if needed, plus or minus diphenhydramine 25 to 50 mg orally every 6 hours if needed for metoclopramide-induced restlessness.

Prochlorperazine 10 mg orally every 4 to 6 hours if needed, plus or minus diphenhydramine 25 to 50 mg orally every 6 hours if needed for prochlorperazine-induced restlessness.

Prochlorperazine 25 mg rectally every 4 to 6 hours if needed, plus or minus diphenhydramine 25 to 50 mg orally every 4 to 6 hours if needed for prochlorperazine-induced restlessness.

A few small studies suggest that higher doses of granisetron (3 mg IV or 40 to 240 mcg/kg)^{19

23} may be effective in treating breakthrough nausea; however, none of these reports found the improvement to be statistically significant.

Hydration: No special precautions are required.

Hypersensitivity Precautions: Paclitaxel injection produces hypersensitivity reactions in about 10% of patients.²⁴ Routine prophylactic premedications should be given prior to paclitaxel administration. The following regimen is suggested²⁵:

Dexamethasone 20 mg (do not repeat dose if already part of antiemetic regimen)

Diphenhydramine 50 mg

Cimetidine 300 mg or ranitidine 50 mg

All given IV over 30 minutes prior to paclitaxel.

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.^26,27 Since febrile neutropenia was reported in 2% to 8%^{5

7} of patients receiving PG, prophylactic use of colony-stimulating factors is not recommended.

Extravasation: No special precautions are required.²⁸

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 (http://ctep.info.nih.gov). Oncologists generally do not adjust doses or change therapy for grade 1 or 2 toxicities; however, dosage reductions or therapy changes should be considered 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: Arrhythmia (grade 3 or 4) 3%⁶; reversible bradycardia (during paclitaxel infusion) 3%¹; tachycardia (grade 3 or 4) 3%.⁶

Dermatologic: Alopecia (grade 1 or 2) 16% to 75%^4,6; skin toxicity (unspecified grade 1 or 2) 15%.⁸

Gastrointestinal: Constipation (grade 3) 4%⁷; diarrhea (grade 1 or 2) 8% to 65%,^4,5 (grade 3 or 4) 4%⁴; mucositis (grade 1 or 2) 10% to 44%,^4,5,8,9 (grade 3 or 4) 3% to 16%^4,9; nausea/vomiting (grade 1 or 2) 50% to 67%,^5,8,9 (grade 3) 4%,⁷ (grade 3 or 4) 3% to 4%.^5,6

Hematologic: Anemia (requiring transfusion) 10%,¹ (grade 1 or 2) 16% to 65%,^4,5,9 (grade 2) 32%,⁸ (grade 3) 3% to 12%,^{8

10} (grade 3 or 4) 4% to 5%,^5–6 (grade 4) 1%²; febrile neutropenia 2% to 8%^{5

7}; leukopenia (grade 1 or 2) 65%,⁴ (grade 3 or 4) 13% to 48%,^4,6 (grade 4) 8%⁷; neutropenia (grade 1 or 2) 58% to 85%,^4,5 (grade 1 or 2, with filgrastim support) 5%,⁹ (grade 3) 13%,¹ (grade 4) 17%,^2,7 (grade 3 or 4) 13% to 85%,^4-6,9,10 (grade 3 or 4, with filgrastim support) 3% to 7%^8,9; thrombocytopenia (grade 1 or 2) 13% to 62%,^4,5,8,9 (grade 3 or 4) 5% to 20%,^4-6,10 (grade 3) 4%,⁷ (grade 4) 0.4%.²

Hepatic: Aspartame aminotransferase/alanine aminotransferase (AST/ALT) elevations (grade 1 or 2) 4% to 26%,^4,9 (grade 3 or 4) 2% to 5%^4,9; AST elevations (grade 3) 8%.⁷

Hypersensitivity: Allergic reaction (grade 1 or 2) 4%.⁵

Infection: (grade 1 or 2) 12%,⁵ (grade 3 or 4) 3%.⁶

Neurologic: Arthralgia/myalgia (grade 1 or 2) 38%⁵; asthenia (grade 1 or 2) 69%⁵; myalgia (grade 1 or 2) 13% to 28%,^1,4 (grade 3 or 4) 2%⁴; neurosensory (unspecified grade 3) 4%⁷; neurotoxicity (unspecified, grade 1 or 2) 62%⁵; peripheral neuropathy (grade 1) 17%,¹ (grade 2) 30%,⁶ (grade 1 or 2) 23% to 38%,^4,8,9,10 (grade 3) 7% to 10%,^1,9 (grade 3 or 4) 2% to 8%.^4,6

Pulmonary: Dyspnea (grade 2) 3%.⁶

Pretreatment Laboratory Studies Needed

Baseline

AST/ALT

Total bilirubin

Serum creatinine

Complete blood (cell) count (CBC) with differential

Prior to each treatment

CBC with differential.

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

Absolute neutrophil count (ANC):

Greater than 1,000 cells/mcL.¹

Greater than 1,500 cells/mcL.^5,6,9

Greater than 2,000 cells/mcL.⁴

Platelet count:

Greater than 100,000 cells/mcL.^4-6,9

Greater than 120,000 cells/mcL.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

Paclitaxel: No adjustment required.²⁹

Gemcitabine: No adjustment required.^29,30

Liver Function

Paclitaxel:

Total bilirubin is within normal limits and AST is greater than two times the upper limit of normal, reduce paclitaxel dose by 25%.³¹

Total bilirubin is 1.6 to 3 mg/dL, reduce paclitaxel dose by 60%.³¹

Total bilirubin is greater than 3 mg/dL, reduce paclitaxel dose by 75%.³¹

Gemcitabine:

Dosage reduction is unnecessary if AST is elevated and total bilirubin is normal.³¹

Reduce dose to 800 mg/m² if total bilirubin is 1.6 to 7 mg/dL.³¹

Increase dose if 800 mg/m² dose is tolerated.³¹

Myelosuppression

Murad delayed treatment (every-3-weeks regimen) for 1 week if ANC was less than 1,000 cells/mcL or platelet count was less than 120,000 cells/mcL. The doses of paclitaxel and gemcitabine were reduced by 50% if febrile neutropenia occurred or if ANC nadir was less than 500 cells/mcL or platelet count nadir was less than 50,000 cells/mcL.¹

Delfino et al. (2004) reduced the day 8 gemcitabine dose (every 3 weeks regimen) by 25% if ANC was between 2,000 and 2,500 cells/mcL or platelet count was between 75,000 and 100,000 cells/mcL, by 50% if the ANC was between 1,000 and 2,000 cells/mcL or platelet count was between 50,000 and 75,000 cells/mcL. For the cycle following any cycle in which hematologic toxicity occurred, Delfino et al. (2004) reduced paclitaxel and gemcitabine doses by 25% for ANC between 1,000 and 1,500 cells/mcL or platelet count between 75,000 and 100,000 cells/mcL and by 50% for ANC between 500 and 1,000 cells/mcL or platelet count between 50,000 and 75,000 cells/mcL. Depending on clinical judgment, treatment was withheld if ANC was less than 1,000 cells/mcL and/or platelet count was less than 50,000 cells/mcL.⁴

Demiray et al. (2005) (every-3-weeks regimen) held treatment 1 week for ANC less than 1,500 cells/mcL or platelet count less than 100,000 cells/mcL. Paclitaxel and gemcitabine doses were reduced by 25% for febrile neutropenia, platelet count less than 25,000 cells/mcL, or a second episode of ANC less than 500 cells/mcL.⁵

Allouache et al. (2005) (every-3-weeks regimen) held day 8 gemcitabine doses for ANC less than 1,000 cells/mcL or platelet count less than 75,000 cells/mcL. After recovery from ANC less than 500 cells/mcL lasting more than 1 week, or platelet count less than 25,000 cells/mcL lasting more than 1 week, or febrile neutropenia, both paclitaxel and gemcitabine doses were reduced by 25%.⁶

Vici et al. (2006) (every-2-weeks regimen) held treatment for a maximum of 2 weeks if ANC was less than 1,500 cells/mcL or platelet count less than 100,000 cells/mcL. Both drugs were reduced by 25% for febrile neutropenia.⁹

Other

Delfino et al. (2004) held or reduced doses of both medications by 50% for grade 3 nonhematologic toxicity, excluding nausea/vomiting or alopecia.⁴

Demiray et al. (2005) reduced the dose of both medications by 25% for any grade 3 or 4 nonhematologic toxicities.⁵

Vici et al. (2006) reduced the dose of both medications by 25% for grade 3 or 4 mucositis, or grade 2 neurotoxicity. Treatment was stopped for persistent transaminitis or grade 3 or 4 neurotoxicity.⁹

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