Chapter 6: Breast Cancer

Epidemiology

Pathology

Work-up

In situ:

1. History and physical

2. Bilateral diagnostic mammogram

3. Pathology review with ER status

4. Genetic counseling if patient is high risk for hereditary breast cancer

Stages I & II:

1. History and physical

2. CBC with platelets

3. LFTs and alkaline phosphatase

4. Diagnostic bilateral mammogram

5. Pathology review with ER/PR/HER-2 status

6. Genetic counseling if the patient is at high risk for hereditary breast cancer

Stage III:

1. History and physical

2. CBC with platelets

3. LFTs and alkaline phosphatase

4. Diagnostic bilateral mammogram

5. Pathology review with ER/PR/HER-2 status

6. Consider bone scan, abdominal ± pelvis CT or US or MRI, and chest imaging

7. Genetic counseling if the patient is at high risk for hereditary breast cancer

Stage IV:

1. History and physical

2. CBC with platelets

3. LFTs and alkaline phosphatase

4. Diagnostic bilateral mammogram

5. Pathology review with ER/PR/HER-2 status

6. Chest imaging

7. Bone scan, X-rays of symptomatic bones and long or weight-bearing bones and bones abnormal on bone scan

8. Consider abdominal ± pelvis CT or MRI

9. Biopsy at first recurrence with pathology review

10. Genetic counseling if the patient is at high risk for hereditary breast cancer

Staging

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010

Systemic Adjuvant Treatment Guidelines

Less-Favorable Histologies: Ductal, Lobular, Mixed, and Metaplastic

1. Hormone receptor-positive–HER2-negative

   pT1, pT2, or pT3 and pN0 or pN1mi:

   Tumor ≤0.5 cm or microinvasive:

   • N0: consider adjuvant endocrine therapy

   • N1mi: Adjuvant endocrine therapy ± adjuvant chemotherapy

   Tumor >0.5 cm (consider 21-gene RT-PCR assay):

   • Assay not done: adjuvant endocrine therapy ± adjuvant chemotherapy

   • Low recurrence score (<18): adjuvant endocrine therapy

   • Intermediate recurrence score (18–30): adjuvant endocrine therapy ± adjuvant chemotherapy

   • High recurrence score (≥31): adjuvant endocrine therapy + adjuvant chemotherapy

   Node positive:

   • Adjuvant endocrine therapy + adjuvant chemotherapy

2. Hormone receptor-positive–HER2-positive

   pT1, pT2, or pT3 and pN0 or pN1mi:

   Tumor ≤0.5 cm or micro-invasive:

   • N0: consider adjuvant endocrine therapy

   • N1mi: adjuvant endocrine therapy ± adjuvant chemotherapy + trastuzumab

   Tumor 0.6–1.0 cm:

   • Adjuvant endocrine therapy ± adjuvant chemotherapy and trastuzumab

   Tumor >1.0 cm:

   • Adjuvant endocrine therapy + adjuvant chemotherapy + trastuzumab

   Node positive:

   • Adjuvant endocrine therapy + adjuvant chemotherapy + trastuzumab

3. Hormone receptor-negative–HER2-positive

   pT1, pT2, or pT3 and pN0 or pN1mi:

   Tumor ≤0.5 cm or micro-invasive:

   • N0: no adjuvant therapy

   • N1mi: consider adjuvant chemotherapy + trastuzumab

   Tumor 0.6–1.0 cm:

   • Consider adjuvant chemotherapy + trastuzumab

   Tumor >1.0 cm:

   • Adjuvant chemotherapy + trastuzumab

   Node positive:

   • Adjuvant chemotherapy + trastuzumab

4. Hormone receptor-negative–HER2-negative:

   pT1, pT2, or pT3 and pN0 or pN1mi:

   Tumor ≤0.5 cm or microinvasive:

   • N0: no adjuvant therapy

   • N1mi: Consider adjuvant chemotherapy

   Tumor 0.6–1.0 cm:

   • Consider adjuvant chemotherapy

   Tumor >1.0 cm:

   • Adjuvant chemotherapy

   Node positive:

   • Adjuvant chemotherapy

Favorable Histologies: Tubular, Colloid

1. ER-positive and/or PR-positive

   pT1, pT2, or pT3 and pN0 or pN1mi:

   Tumor <1.0 cm:

   • No adjuvant therapy

     Tumor 1.0–2.9 cm:

   • Consider adjuvant endocrine therapy

     Tumor ≥3.0 cm:

   • Adjuvant endocrine therapy

     Node positive:

   • Adjuvant endocrine therapy ± adjuvant chemotherapy

2. ER-negative and PR-negative:

   Repeat ER and PR status; if truly negative, treat as usual breast cancer histology

Preferred Adjuvant Chemotherapy Regimens

Non-Trastuzumab Regimens

1. TAC (docetaxel/doxorubicin/cyclophosphamide)

2. Dose-dense AC (doxorubicin and cyclophosphamide) followed by paclitaxel every 2 weeks

3. AC (doxorubicin/cyclophosphamide) followed by weekly paclitaxel

4. TC (docetaxel and cyclophosphamide)

5. AC (doxorubicin/cyclophosphamide)

Other Adjuvant Regimens

1. FEC (fluorouracil/epirubicin/cyclophosphamide)

2. CMF (cyclophosphamide/methotrexate/fluorouracil)

3. AC (doxorubicin/cyclophosphamide) followed by docetaxel every 3 weeks

4. FEC followed by docetaxel

5. FEC followed by weekly paclitaxel

Trastuzumab-Containing Regimens

Preferred adjuvant trastuzumab-containing regimens:

Pertuzumab should be administered to patients receiving neoadjuvant therapy with ≥T2 or ≥N1, HER2-positive, early-stage breast cancer

1. TCH (docetaxel/carboplatin/trastuzumab)

2. AC (doxorubicin/cyclophosphamide) followed by a taxane + concurrent trastuzumab

Other adjuvant trastuzumab-containing regimens:

1. Docetaxel + trastuzumab followed by FEC (fluorouracil/epirubicin/cyclophosphamide)

2. AC (doxorubicin/cyclophosphamide) followed by docetaxel with trastuzumab

Preferred Chemotherapy for Metastatic Breast Cancer (MBC)

Single Agents

Anthracyclines:

1. Doxorubicin

2. Epirubicin

3. Doxorubicin HCl liposomal injection

Taxanes:

1. Paclitaxel (preferred agent with bevacizumab)

2. Docetaxel

3. Paclitaxel protein bound particles for injectable suspension (albumin-bound)

Antimetabolites:

1. Capecitabine

2. Gemcitabine

Other microtubule inhibitors:

1. Vinorelbine

2. Eribulin

Other Single Agents

1. Cyclophosphamide

2. Mitoxantrone

3. Cisplatin

4. Etoposide (oral)

5. Ixabepilone

Preferred Chemotherapy Combinations

1. FEC (fluorouracil/epirubicin/cyclophosphamide)

2. AC (doxorubicin/cyclophosphamide)

3. CMF (cyclophosphamide/methotrexate/fluorouracil)

4. Docetaxel/capecitabine

5. GT (gemcitabine/paclitaxel)

Other Combinations

1. Ixabepilone + capecitabine

Preferred First-line Agents for HER2-Positive Disease

1. Pertuzumab + trastuzumab + docetaxel

2. Pertuzumab + trastuzumab + paclitaxel

Other First-line Agents for HER2-Positive Disease

Trastuzumab alone or in combination with:

1. Paclitaxel + carboplatin

2. Paclitaxel

3. Docetaxel

4. Vinorelbine

5. Capecitabine

Preferred Agents for Trastuzumab-Exposed HER2-Positive Disease

1. ado-Trastuzumab emtansine (TDM-1)

Other Agents for Trastuzumab-exposed HER2-Positive Disease

1. Lapatinib + capecitabine

2. Trastuzumab + capecitabine

3. Trastuzumab + lapatinib

Adjuvant, Metastatic Regimen: Docetaxel + Doxorubicin + Cyclophosphamide (TAC)

Nabholtz JM et al. J Clin Oncol 2001;19:314–321 [Treatment for metastatic disease]

Nabholtz J-M et al. Proc Am Soc Clin Oncol 2002;21:36a [Abstract 141; adjuvant treatment]

Premedication:

Dexamethasone 8 mg/dose; administer orally twice daily for 3 days, starting on the day before docetaxel administration (total dose/cycle = 48 mg)

Hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before starting cyclophosphamide and 500 mL after completing cyclophosphamide

Doxorubicin HCl 50 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 3 weeks for 6 cycles (total dosage/cycle = 50 mg/m²), followed by:

Cyclophosphamide 500 mg/m²; administer intravenously in 100–500 mL 0.9% NS or 5% dextrose injection (D5W), over 15–60 minutes on day 1, every 3 weeks for 6 cycles (total dosage/cycle = 500 mg/m²), followed by:

Docetaxel 75 mg/m²; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a docetaxel concentration within the range 0.3–0.74 mg/mL over 60 minutes on day 1, every 3 weeks for 6 cycles (total dosage/cycle = 75 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

• Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection, or

• Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL, by subcutaneous injection for 1 dose

  • Begin use from 24–72 hours after myelosuppressive chemotherapy is completed

  • Continue daily filgrastim until ANC ≥5000/mm³

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Steroid-associated gastritis

Add a proton pump inhibitor during steroid use to prevent gastritis and duodenitis

Treatment Modifications

Patient Population Studied

Nabholtz JM et al. J Clin Oncol 2001;19:314–321 [Treatment for metastatic disease]

Nabholtz J-M et al. Proc Am Soc Clin Oncol 2002;21:36a [Abstract 141]

Study of 745 patients with node-positive primary breast cancer treated with adjuvant TAC and 54 patients with metastatic breast cancer and no prior chemotherapy for metastatic disease. All patients were anthracycline-naïve

Efficacy

Toxicity (N = 745)

Therapy Monitoring

Before each cycle: CBC with differential and platelet count, LFTs, and serum electrolytes

Adjuvant Regimen: Dose-Dense Doxorubicin + Cyclophosphamide, then Paclitaxel Every 2 Weeks (DDAC → P)

Citron ML et al. J Clin Oncol 2003;21:1431–1439

Note: Doxorubicin and cyclophosphamide (ddAC) are given in combination, followed sequentially by paclitaxel (P). Both ddAC and P are given for 4 complete cycles

Hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before starting cyclophosphamide and 500 mL after completing cyclophosphamide

Doxorubicin HCl 60 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 14 days for 4 cycles (total dosage/cycle = 60 mg/m²)

Cyclophosphamide 600 mg/m²; administer intravenously in 100–500 mL 0.9% NS or 5% dextrose injection (D5W) over 15–60 minutes on day 1, every 14 days for 4 cycles (total dosage/cycle = 600 mg/m²)

Filgrastim 5 mcg/kg per day; administer subcutaneously for 7 consecutive days on days 3–9, every 14 days for 4 cycles

• Calculated doses may be rounded by ±10% to use the most economical combination of commercially available products (containing 300 mcg or 480 mcg)

After 4 cycles, doxorubicin + cyclophosphamide are followed by:

Premedication:

Dexamethasone 10 mg/dose; administer orally for 2 doses 12 hours and 6 hours before paclitaxel (total dose/cycle = 20 mg), or

Dexamethasone 20 mg; administer intravenously over 10–15 minutes, 30–60 minutes before paclitaxel (total dose/cycle = 20 mg)

Note: Dexamethasone doses may be gradually decreased in the absence of hypersensitivity reactions during repeated paclitaxel treatments

Diphenhydramine 50 mg; administer by intravenous injection 30–60 minutes before paclitaxel

Cimetidine 300 mg (or Ranitidine 50 mg, Famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist); administer intravenously over 15–30 minutes, 30–60 minutes before paclitaxel

Paclitaxel 175 mg/m²; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a concentration within the range 0.3–1.2 mg/mL over 3 hours, on day 1, every 14 days for 4 cycles (total dosage/cycle = 175 mg/m²)

Filgrastim 5 mcg/kg per day; administer subcutaneously for 7 consecutive days on days 3–9, every 14 days for 4 cycles

• Calculated doses may be rounded by ±10% to use the most economical combination of commercially available products (containing 300 mcg or 480 mcg)

Supportive Care with Doxorubicin + Cyclophosphamide (AC) Chemotherapy

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis, is indicated as described in the regimens

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Supportive Care with Paclitaxel (P) Chemotherapy

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis, is indicated as described in the regimens

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

Toxicity

Patient Population Studied

Women with node-positive operable breast cancer. Chemotherapy was given adjuvantly after recovery from surgery. A total of 2005 females were randomly assigned to receive one of the following regimens: (1) Sequential A × 4 → P × 4 → C × 4 with doses every 3 weeks; (2) sequential A × 4 → P × 4 → C × 4 every 2 weeks with filgrastim; (3) concurrent AC × 4 → P × 4 every 3 weeks, or (4) concurrent AC × 4 → P × 4 every 2 weeks with filgrastim

Efficacy

Therapy Monitoring

Before each cycle: CBC with differential and platelet count, LFTs, and serum electrolytes

Adjuvant Regimen: Doxorubicin + Cyclophosphamide, then Weekly Paclitaxel (AC → P)

Perez EA et al. J Clin Oncol 2001;19:4216–4223

Seidman AD et al. J Clin Oncol 1998;16:3353–3361

Sparano JA. N Engl J Med 2008;258:1663–1671

Hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before starting cyclophosphamide and 500 mL after completing cyclophosphamide

Doxorubicin HCl 60 mg/m²; administer by intravenous injection over 3–5 minutes on day 1 every 21 days for 4 cycles (total dosage/cycle = 60 mg/m²)

Cyclophosphamide 600 mg/m²; administer intravenously in 100–500 mL 0.9% NS or 5% dextrose injection (D5W) over 30–60 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 600 mg/m²), followed after 4 cycles by:

Premedication:

Dexamethasone 10 mg/dose; administer orally for 2 doses at 12 hours and 6 hours before paclitaxel (total dose/cycle = 20 mg), or

Dexamethasone 20 mg; administer intravenously over 10–15 minutes, 30–60 minutes before starting paclitaxel (total dose/cycle = 20 mg)

Diphenhydramine 50 mg; administer intravenously 30 minutes prior to starting paclitaxel

Cimetidine 300 mg (or ranitidine 50 mg, or famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist); administer intravenously over 15–30 minutes, 30–60 minutes before starting paclitaxel

Paclitaxel 80 mg/m² per dose; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a concentration within the range 0.3–1.2 mg/mL over 60 minutes, weekly for 12 consecutive weeks (total dosage/21-day cycle = 240 mg/m²)

Supportive Care with Doxorubicin + Cyclophosphamide (AC) Chemotherapy

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Supportive Care with Paclitaxel (P) Chemotherapy

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications: AC

Treatment Modifications: Paclitaxel

Patient Population Studied

Sparano JA. N Engl J Med 2008;258:1663–1671

Study of 4950 patients with operable, hormone receptor positive adenocarcinoma of the breast with either (a) histologically involved lymph nodes (tumor stage T1, T2, or T3 and nodal stage N1 or N2) or (b) "high-risk, axillary node-negative disease" (T2 or T3, N0) without distant metastases. Of the study patients, 88% were node-positive and 19% HER2neu+. All patients received 4 cycles of intravenous doxorubicin and cyclophosphamide at 3-week intervals and were assigned to intravenous paclitaxel or docetaxel given at 3-week intervals for 4 cycles or at 1-week intervals for 12 cycles. The primary end point was disease-free survival

Efficacy (N = 4950)

Toxicity of Paclitaxel and Docetaxel

Therapy Monitoring

1. Weekly: CBC with differential and platelet count

2. Monthly: LFTs and serum electrolytes

Adjuvant Regimen: Docetaxel + Cyclophosphamide (TC) Every 3 Weeks × 4 Cycles

Jones S et al. J Clin Oncol 2006;24:5381–5387

Jones S et al. J Clin Oncol 2009;27:1177–1183

Hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before starting cyclophosphamide and 500 mL after completing cyclophosphamide

Premedication:

Dexamethasone 8 mg/dose; administer orally every 12 hours for 3 days starting on the day before docetaxel administration (total dose/cycle = 48 mg)

Docetaxel 75 mg/m²; administer intravenously in a volume of 0.9% NS or 5% dextrose injection (D5W) sufficient to produce a docetaxel concentration within the range 0.3–0.74 mg/mL over 30–60 minutes on day 1 every 21 days for 4 cycles (total dosage/cycle = 75 mg/m²)

Cyclophosphamide 600 mg/m²; administer intravenously in 100–500 mL 0.9% NS or D5W over 30–60 minutes on day 1 every 21 days for 4 cycles (total dosage/cycle = 600 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Steroid-associated gastritis

Add a proton pump inhibitor during steroid use to prevent gastritis and duodenitis

Efficacy

Treatment Modifications

Patients were taken off treatment if administration of any study drug was delayed more than 2 weeks as a result of drug-related toxicities. No dose reductions were permitted. No prophylactic growth factors were used and the use of oral prophylactic antibiotics was at the discretion of the treating physician

Patient Population Studied

Phase III randomized prospective clinical trial comparing 4 cycles of doxorubicin + cyclophosphamide (AC) with 4 cycles of docetaxel + cyclophosphamide (TC) as adjuvant chemotherapy in 1016 women with operable stages I to III invasive breast cancer. Eligible patients had a Karnofsky performance status of ≥80% and no evidence of metastatic disease. Before treatment, a complete surgical excision of the primary tumor (lumpectomy and axillary dissection or modified radical mastectomy) was performed. Neoadjuvant chemotherapy was not permitted. Eligible primary tumor size was ≥1.0 cm and <7.0 cm. Patients were randomly assigned to 4 cycles of either standard-dose AC (60 and 600 mg/m², respectively) or TC (75 and 600 mg/m², respectively) administered on day 1 of each 21-day cycle for 4 cycles as adjuvant treatment after complete surgical excision of the primary tumor. Chemotherapy was administered before radiation therapy (XRT) when XRT was indicated (breast conservation or postoperative XRT for patient with 4 or more involved axillary lymph nodes). On completion of 4 cycles of chemotherapy (±XRT), tamoxifen was administered to all patients with hormone receptor-positive breast cancer for 5 years. The majority (71%) of patients had breast cancer that was estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive. The number of patients with node-negative disease was balanced between groups (47% TC and 49% AC); 12% of TC and 9% of AC patients had ≥4 positive nodes

Toxicity^✫

Therapy Monitoring

1. Baseline: LFTs, serum chemistry, CBC with differential and platelet count

2. Follow-up: CBC with differential and platelet count at start of each cycle

Adjuvant, Neoadjuvant Metastatic Regimen: Doxorubicin + Cyclophosphamide (AC)

Fisher B et al. J Clin Oncol 1997;15:1858–1869

Hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before starting cyclophosphamide and 500 mL after completing cyclophosphamide

Doxorubicin HCl 60 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 60 mg/m²)

Cyclophosphamide 600 mg/m²; administer intravenously in 100–500 mL 0.9% NS or 5% dextrose injection over 15–60 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 600 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

Patient Population Studied

Fisher B et al. J Clin Oncol 1997;15:1858–1869

Study of 764 patients with node-positive primary breast cancer who were treated with AC for adjuvant therapy. This regimen has also been studied in the neoadjuvant and metastatic settings

Toxicity^✫

Therapy Monitoring

Before each cycle: CBC with differential and platelet counts, LFTs, serum electrolytes, BUN, and creatinine

Efficacy

Adjuvant, Metastatic Regimen: Cyclophosphamide + Epirubicin + Fluorouracil (FEC 100)

Bonneterre et al. J Clin Oncol 2004;22:3070–3079

French Adjuvant Study Group. J Clin Oncol 2001;19:602–611

Fluorouracil 500 mg/m²; administer by intravenous injection over 1–3 minutes on day 1, every 21 days for 6 cycles (total dosage/cycle = 500 mg/m²)

Epirubicin HCl 100 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 21 days for 6 cycles (total dosage/cycle = 100 mg/m²)

Hydration with 1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before starting cyclophosphamide and 500 mL after completing cyclophosphamide

Cyclophosphamide 500 mg/m²; administer intravenously in 100–500 mL 0.9% NS or 5% dextrose injection over 15–60 minutes on day 1, every 21 days for 6 cycles (total dosage/cycle = 500 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

  Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection, or

  Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL by subcutaneous injection for 1 dose

• Begin use from 24–72 hours after myelosuppressive chemotherapy is completed

• Continue daily filgrastim until ANC ≥5000/mm³

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Premenopausal and postmenopausal women with histologically proven axillary lymph node involvement (at least 5 axillary nodes resected) with more than 3 positive nodes or between 1 and 3 positive nodes with Scarff-Bloom-Richardson (SBR) grade ≥2 and hormone receptor negativity (both estrogen and progesterone) were enrolled. Postmenopausal status was defined as an amenorrhea for at least 1 year. Main eligibility criteria included a World Health Organization (WHO) performance status ≤2, no cardiac dysfunction (baseline left ventricular ejection fraction [LVEF] ≥50%). Patients were randomized after surgery to receive either fluorouracil 500 mg/m², epirubicin 50 mg/m², and cyclophosphamide 500 mg/m² every 21 days for 6 cycles (FEC 50), or the same regimen except with epirubicin dose of 100 mg/m² (FEC 100). Treatment was begun within 42 days of surgery

Treatment Modifications

Efficacy

Toxicity

Therapy Monitoring

1. Weekly: CBC with differential and platelet count

2. Before each cycle: CBC with differential and platelet count, LFTs, and serum electrolytes

Adjuvant, Metastatic Regimen: Cyclophosphamide + Methotrexate + Fluorouracil (CMF; ORAL)

Amadori D et al. J Clin Oncol 2000;18:3125–3134

Cyclophosphamide 100 mg/m² per day; administer orally for 14 consecutive days on days 1–14, every 4 weeks for 6 cycles, (total dosage/cycle = 1400 mg/m²)

Note: Encourage patients to supplement their usual oral hydration with (extra) non–alcohol-containing fluids, 1000–2000 mL/day, to take cyclophosphamide doses at the beginning of a waking cycle, and to void urine frequently while taking cyclophosphamide

Methotrexate 40 mg/m² per dose; administer by intravenous injection over ≤1 minute for 2 doses on days 1 and 8, every 4 weeks for 6 cycles (total dosage/cycle = 80 mg/m²)

Fluorouracil 600 mg/m² per dose; administer by intravenous injection over 1–3 minutes for 2 doses on days 1 and 8, every 4 weeks for 6 cycles (total dosage/cycle = 1200 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on Days 1–14 is LOW–MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

Patient Population Studied

Amadori D et al. J Clin Oncol 2000;18:3125–3134

Study of 281 women with node-negative resectable breast cancer. CMF was given as adjuvant therapy within 6 weeks of surgery. All patients had rapidly proliferating tumors as determined by thymidine-labeling index

Toxicity

Efficacy

Therapy Monitoring

Before each cycle: CBC with differential and platelet counts

Adjuvant, Neoadjuvant Regimen: Doxorubicin + Cyclophosphamide then Docetaxel Every 3 Weeks (AC → T)

Bear HD et al. J Clin Oncol 2003;21:4165–4174

AC (Doxorubicin + Cyclophosphamide) × 4 cycles

Hydration with 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before and 500 mL after cyclophosphamide

Doxorubicin HCl 60 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 60 mg/m²)

Cyclophosphamide 600 mg/m²; administer intravenously in 100–500 mL 0.9% NS or 5% dextrose injection (D5W), over 15–60 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 600 mg/m²), followed after 4 cycles by:

T (Docetaxel) × 4 cycles

Premedication:

Dexamethasone 8 mg/dose; administer orally twice daily for 3 days, starting on the day before docetaxel administration (total dose/cycle = 48 mg)

Docetaxel 100 mg/m²; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a docetaxel concentration within the range 0.3–0.74 mg/mL over 60 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 100 mg/m²)

Supportive Care for Doxorubicin + Cyclophosphamide (AC) Chemotherapy

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Supportive Care for Docetaxel (T) Chemotherapy

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

• Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection, or

• Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL, by subcutaneous injection for 1 dose

• Begin use from 24–72 hours after myelosuppressive chemotherapy is completed

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Steroid-associated gastritis

Add a proton pump inhibitor during steroid use to prevent gastritis and duodenitis

Patient Population Studied

Study of 1584 women with primary breast cancer with tumor size >1 cm or lymph nodes with clinical evidence of malignant disease. Regimen was given as neoadjuvant therapy in this study, but is also often given as adjuvant therapy in node-positive disease. The regimen is 1 of 3 arms in NSABP B-30

Efficacy (N = 752/1534)

Toxicity (for Docetaxel) (N = 1584)

Therapy Monitoring

Before each cycle: CBC with differential and platelet count, LFTs, and serum electrolyte

Treatment Modifications

Adjuvant Regimen: Cyclophosphamide + Epirubicin + Fluorouracil (FEC) × 3 Cycles → Docetaxel × 3 CYCLES

Roché HJ. Clin Oncol 2006;24:5664–5671

FEC (Cyclophosphamide + Epirubicin + Fluorouracil) × 3 cycles

Hydration before and after cyclophosphamide with 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before starting cyclophosphamide and 500 mL after completing cyclophosphamide

Fluorouracil 500 mg/m²; administer by intravenous injection over 1–3 minutes on day 1, every 21 days for 3 cycles (total dosage/cycle = 500 mg/m²)

Epirubicin HCl 100 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 21 days for 3 cycles (total dosage/cycle = 100 mg/m²)

Cyclophosphamide 500 mg/m²; administer intravenously in 100–500 mL 0.9% NS or 5% dextrose injection (D5W) over 30–60 minutes on day 1, every 21 days for 3 cycles (total dosage/cycle = 500 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Docetaxel × 3 cycles

Premedication:

Dexamethasone 8 mg/dose; administer orally twice daily for 3 days, starting on the day before docetaxel administration (total dose/cycle = 48 mg)

Docetaxel 100 mg/m²; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a final docetaxel concentration of 0.3–0.74 mg/mL over 30–60 minutes on day 1, every 21 days for 3 cycles (total dosage/cycle = 100 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

• Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection, or

• Sargramostim (GM-CSF) 250 mcg/m² per day, by subcutaneous injection

• Begin use from 24–72 h after myelosuppressive chemotherapy is completed

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

Patient Population Studied

Study of 1999 patients with operable node-positive breast cancer who were randomly assigned to receive fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m² (FEC) intravenously on day 1 every 21 days for 6 cycles or the same regimen of FEC for 3 cycles followed by docetaxel 100 mg/m² intravenously on day 1 every 21 days for 3 cycles

Efficacy

Toxicity^✫

Therapy Monitoring

1. Before each cycle: CBC with differential and platelet count, serum total bilirubin

2. Before each cycle with docetaxel: Neurologic examination

Adjuvant Regimen: Cyclophosphamide + Epirubicin + Fluorouracil (FEC) × 4 Cycles → Weekly Paclitaxel × 8 Cycles

Martin et al. J Natl Cancer Inst 2008;100:805–814

FEC × 4 cycles

Hydration with 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before starting cyclophosphamide and 500 mL after completing cyclophosphamide

Fluorouracil 600 mg/m²; administer by intravenous injection over 1–3 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 600 mg/m²)

Epirubicin HCl 90 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 90 mg/m²)

Cyclophosphamide 600 mg/m²; administer intravenously in 100–500 mL 0.9% NS or 5% dextrose injection (D5W) over 30–60 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 600 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Paclitaxel, weekly × 8 weeks

Follows 3 weeks after completing 4 cycles of FEC

Premedication:

Dexamethasone 10 mg/dose; administer orally or intravenously for 2 doses at 12 hours and 6 hours before paclitaxel, or

Dexamethasone 20 mg; administer intravenously 30–60 minutes before paclitaxel (total dose/cycle = 20 mg)

Note: Dexamethasone doses may be gradually decreased in the absence of hypersensitivity reactions during repeated paclitaxel treatments

Diphenhydramine 50 mg; administer by intravenous injection 30–60 minutes before paclitaxel

Cimetidine 300 mg (or ranitidine 50 mg, or famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist); administer intravenously over 15–30 minutes, 30–60 minutes before starting paclitaxel administration

Paclitaxel 100 mg/m²; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a concentration within the range 0.3–1.2 mg/mL over 60 minutes, once weekly for 8 weeks (total dosage/week = 100 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Notes:

On completion of chemotherapy, tamoxifen (20 mg daily; administer orally for 5 years) was mandatory for all patients whose tumors were positive for estrogen receptor, progesterone receptor, or both (according to institutional guidelines). Subsequently an amendment to the study protocol allowed the use of aromatase inhibitors in postmenopausal women

1. Radiotherapy was mandatory after breast-conserving surgery, and was administered after mastectomy according to the guidelines of each participating institution, mostly to women with tumors >5 cm or with ≥4 affected lymph nodes

2. Prophylaxis with filgrastim (granulocyte colony-stimulating factor) was not routine. However, secondary prophylaxis with filgrastim was mandatory among patients who had at least 1 episode of febrile neutropenia or an infection

Treatment Modifications–FEC

Treatment Modifications–Paclitaxel

Patient Population Studied

Study of 1246 women who had undergone primary curative surgery (ie, mastectomy, tumorectomy, or lumpectomy) with axillary lymph node dissection (in which at least 6 lymph nodes were isolated) for operable unilateral carcinoma of the breast (stage T1–T3) and were found to have node-positive breast cancer. All patients had at least 1 axillary lymph node that was positive for cancer on histologic examination. The margins of resected specimens had to be histologically free of invasive carcinoma and ductal carcinoma in situ. A complete staging work-up was carried out within 16 weeks before registration in the study. Criteria for exclusion included advanced disease (ie, stage T4, N2 or N3, or M1) and motor or sensory neuropathy of NCI Common Toxicity Criteria G2 or more

Efficacy

Toxicity^✫

Therapy Monitoring

1. Before each cycle: CBC with differential and platelet count, serum total bilirubin

2. Before each treatment with paclitaxel: Neurologic examination

Adjuvant, Neoadjuvant Regimen: Docetaxel + Carboplatin + Trastuzumab (TCH)

Slamon S et al. N Engl J Med 2011;365:1273–1283

(Third Interim Analysis Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Docetaxel [AC → T] with Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab [AC → TH] with Docetaxel, Carboplatin and Trastuzumab [TCH] in Her2neu Positive Early Breast Cancer Patients: BCIRG 006 Study)

TCH regimen

Premedication:

Dexamethasone 8 mg/dose; administer orally twice daily for 3 days, starting on the day before docetaxel administration (total dose/cycle = 48 mg)

Docetaxel 75 mg/m²; administer intravenously in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) sufficient to produce a final docetaxel concentration of 0.3–0.74 mg/mL over 30–60 minutes on day 1, every 3 weeks for 6 cycles (total dosage/cycle = 75 mg/m²)

Carboplatin target AUC = 6 mg/mL · min; administer intravenously in 250 mL D5W or 0.9% NS over 30–60 minutes on day 1, every 3 weeks for 6 cycles (total dose/cycle calculated to achieve a target AUC = 6 mg/mL · min), concurrently with:

Trastuzumab every 21 days for 6 cycles:

• Loading Dose: Trastuzumab 8 mg/kg; administer intravenously in 250 mL 0.9% NS over 90 minutes as a loading dose on day 1, cycle 1 only (total dosage during the first cycle = 8 mg/kg), followed 3 weeks later by:

• Maintenance Doses: Trastuzumab 6 mg/kg; administer intravenously in 250 mL 0.9% NS over 30 minutes on day 1, every 3 weeks for 5 cycles (total dosage/cycle = 6 mg/kg)

Three weeks after completing combination (TCH) chemotherapy:

Trastuzumab 6 mg/kg; administer intravenously in 250 mL 0.9% NS over 30 minutes every 3 weeks for 11 doses (total dosage/3-week cycle = 6 mg/kg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with TCH combination chemotherapy is HIGH. Potential for delayed symptoms

Emetogenic potential on days with trastuzumab alone is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Trastuzumab infusion reactions:

• A symptom complex most commonly consisting of chills and/or fever may occur in as many as 40% of patients during the first infusion of trastuzumab. These symptoms occur infrequently with subsequent trastuzumab infusions. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, rash, and asthenia. Although the symptoms are usually mild to moderate in severity, infrequently, trastuzumab may need to be discontinued

• When such a symptom complex is observed it can be treated with or without reduction in the rate of trastuzumab infusion, and:

  • Acetaminophen 650 mg; administer orally

  • Diphenhydramine 25–50 mg; administer orally or by intravenous injection, and

  • Meperidine 12.5–25 mg; administer by intravenous injection every 10 minutes if needed for shaking chills (generally, cumulative doses >50 mg are not needed; use with caution in persons with moderate or more severely impaired renal function)

  • With or without reduction in the rate of trastuzumab infusion

Treatment plan notes:

• LVEF assessment (MUGA or echocardiography) every 3 months in patients receiving trastuzumab

• One year of trastuzumab therapy = 51 weeks or 17 total doses (6 doses [cycles] with docetaxel and carboplatin and 11 doses [cycles] of single agent trastuzumab)

Carboplatin dose

Carboplatin dose is based on a formula described by Calvert et al. to achieve a target area under the plasma concentration versus time curve (AUC)

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be estimated from the equation of Cockcroft and Gault, thus:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the U.S. Food and Drug Administration (FDA) identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States will use the standardized isotope dilution mass spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity. Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling. If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommended for patients with normal renal function capping an estimated GFR at 125 mL/min for any targeted AUC value. No greater estimated GFR values should be used U.S. Food and Drug Administration. Carboplatin dosing. May 23, 2013. Available from: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974.htm [accessed February 26, 2014]

Treatment Modifications

Patient Population Studied

Study of 3222 women with HER2+ by FISH, T1–3, N0/N1, M0 breast cancer (AC → T: 1073; AC→TH: 1074; TCH: 1075). Stratified by nodes and hormonal receptor status

Therapy Monitoring

1. Before each cycle: CBC with differential and platelet count, LFTs, serum electrolytes, BUN, and creatinine

2. Assessment of ejection fraction: Every 3 months or as clinically indicated

3. Hearing test: At baseline and as needed

Note

In the neoadjuvant setting, consider adding Pertuzumab to TCH chemotherapy

Give pertuzumab every 21 days for 6 cycles:

• Loading dose: Pertuzumab 840 mg; administer intravenously in 250 mL of 0.9% NS over 90 minutes on day 1 after trastuzumab, cycle 1 only (total dose during the first cycle = 840 mg), followed 3 weeks later by:

• Maintenance doses: Pertuzumab 420 mg; administer intravenously in 250 mL of 0.9% NS over 30–60 minutes on day 1 after trastuzumab, every 3 weeks for 5 cycles (total dose/cycle = 420 mg)

Schneeweiss A et al. Ann Oncol 2013;24:2278–2284

Efficacy

Toxicity

Adjuvant, Neoadjuvant Regimen: Doxorubicin + Cyclophosphamide, then Paclitaxel + Trastuzumab, then Trastuzumab Alone (AC × 4 → TH × 12 Weeks → H × 40 Weeks)

Romond EH et al. N Engl J Med 2005;353:1673–1684

Seidman AD et al. J Clin Oncol 2001;19:2587–2595

AC (doxorubicin + cyclophosphamide) regimen

Hydration with 0.9% sodium chloride injection (0.9% NS); administer intravenously 500 mL before starting cyclophosphamide and 500 mL after completing cyclophosphamide administration

Doxorubicin HCl 60 mg/m²; administer by intravenous injection over 3–5 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 60 mg/m²)

Cyclophosphamide 600 mg/m²; administer intravenously in 100–500 mL 0.9% NS or 5% dextrose injection (D5W) over 15–60 minutes on day 1, every 21 days for 4 cycles (total dosage/cycle = 600 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Weekly TH (paclitaxel + trastuzumab) regimen

Schedule for first week of paclitaxel + trastuzumab

Trastuzumab 4 mg/kg (loading dose); administer intravenously in 250 mL 0.9% NS over at least 90 minutes, 1 day before the first dose of paclitaxel is administered (total trastuzumab dosage during the first treatment week = 4 mg/kg), followed 1 day later by:

Premedication for paclitaxel:

Dexamethasone 10 mg; administer intravenously 30–60 minutes before paclitaxel (total dose/cycle = 10 mg)

Note: Dexamethasone doses may be gradually reduced in 2- to 4-mg increments if a patient has no hypersensitivity reactions during repeated paclitaxel treatments

Diphenhydramine 50 mg; administer intravenously 30–60 minutes before paclitaxel

Cimetidine 300 mg (or ranitidine 50 mg, or famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist); administer intravenously over 15 to 30 minutes, 30 to 60 minutes before starting paclitaxel administration

Paclitaxel 80 mg/m²; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a concentration within the range 0.3–1.2 mg/mL over 60 minutes (total dosage = 80 mg/m²)

Paclitaxel + trastuzumab during the second and subsequent weeks

Premedication for paclitaxel:

Dexamethasone 10 mg; administer intravenously 30–60 minutes before paclitaxel

Note: If a patient does not experience any manifestations of hypersensitivity or an allergic reaction after 8 paclitaxel infusions, the dexamethasone dose may be reduced as follows:

Diphenhydramine 50 mg; administer by intravenous injection 30–60 minutes before paclitaxel

Cimetidine 300 mg (or ranitidine 50 mg, or famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist); administer intravenously over 15–30 minutes, 30–60 minutes before starting paclitaxel administration

Paclitaxel 80 mg/m² per week; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a concentration within the range 0.3–1.2 mg/mL over 60 minutes, weekly, for 11 weeks (total dosage/week = 80 mg/m²), followed immediately afterward by:

Trastuzumab 2 mg/kg per week; administer intravenously in 250 mL 0.9% NS over 30 minutes, weekly, for 11 weeks (total trastuzumab dosage/week during the second and later weeks = 2 mg/kg)

Note: The duration of trastuzumab administration may be decreased from an initial infusion duration of 90 to 30 minutes if administration over longer durations is well tolerated

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Weekly H (trastuzumab) regimen

Trastuzumab 2 mg/kg per week; administer intravenously in 250 mL 0.9% NS over 30 minutes, weekly, for 40 weeks (total trastuzumab dosage/week = 2 mg/kg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

    Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Trastuzumab infusion reactions

• A symptom complex most commonly consisting of chills and/or fever may occur in as many as 40% of patients during the first infusion of trastuzumab. These symptoms occur infrequently with subsequent trastuzumab infusions. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, rash, and asthenia. Although the symptoms are usually mild to moderate in severity, infrequently, trastuzumab may need to be discontinued

• When such a symptom complex is observed it can be treated with or without reduction in the rate of trastuzumab infusion, and:

  • Acetaminophen 650 mg; administer orally

  • Diphenhydramine 25–50 mg; administer orally or by intravenous injection, and

  • Meperidine 12.5–25 mg; administer by intravenous injection every 10 minutes if needed for shaking chills (generally, cumulative doses >50 mg are not needed; use with caution in persons with moderate or more severely impaired renal function)

  • With or without reduction in the rate of trastuzumab infusion

Treatment Plan Notes:

• LVEF assessment (MUGA or echocardiography) every 3 months in patients receiving trastuzumab

Treatment Modifications: Cyclophosphamide + Doxorubicin

Treatment Modifications: Paclitaxel

Patient Population Studied

Romond EH et al. J Clin Oncol 2005;16:1673–1684: Report of two trials that treated 1672 women with a regimen of AC followed by paclitaxel with trastuzumab, followed by trastuzumab alone [AC → P + H → H]. Two studies were combined in one analysis: (a) National Surgical Adjuvant Breast and Bowel Project trial B-31 and (b) North Central Cancer Treatment Group trial N9831. Both trials enrolled women with a pathologic diagnosis of adenocarcinoma of the breast with immunohistochemical staining for HER2 protein of 3+ intensity or amplification of the HER2 gene on fluorescence in situ hybridization. Initially, required patients to have histologically proven, node-positive disease; subsequently, N9831 was amended to include patients with high-risk node-negative disease (defined as a tumor that was more than 2 cm in diameter and positive for estrogen receptors or progesterone receptors or as a tumor that was more than 1 cm in diameter and negative for both estrogen receptors and progesterone receptors). Other requirements included a left ventricular ejection fraction (LVEF) that met or exceeded the lower limit of normal. Complete resection of the primary tumor and axillary-node dissection were required (negative sentinel-node biopsy was allowed in trial N9831). Patients were ineligible if they had one of several cardiac risk factors

Note

In the neoadjuvant setting, consider adding pertuzumab to paclitaxel and trastuzumab

Give pertuzumab every 21 days for 4 cycles:

• Loading dose: Pertuzumab 840 mg; administer intravenously in 250 mL of 0.9% NS over 90 minutes on the same day as trastuzumab, but after completing trastuzumab administration (total dose during the first cycle = 840 mg), followed 3 weeks later by:

• Maintenance doses: Pertuzumab 420 mg; administer intravenously in 250 mL of 0.9% NS over 30–60 minutes after trastuzumab, every 3 weeks for 3 cycles (total dose/3-week cycle = 420 mg)

Schneeweiss A et al. Ann Oncol 2013;24:2278–2284

Efficacy (Combined Analysis of NSABP B-31 and NCCTG N9831)

Toxicity