What is the role of chemotherapy in the treatment of metastatic breast cancer?

Updated: Dec 27, 2019
  • Author: Pavani Chalasani, MD, MPH; Chief Editor: John V Kiluk, MD, FACS  more...
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Answer

Cytotoxic chemotherapy for metastatic breast cancer initially consisted of single-agent regimens. Combination therapy is currently considered up front, depending on the patient's performance status, because of higher response rates. However, in the setting of advanced disease, the goal in determining a treatment regimen should be to prolong survival while maintaining a good quality of life.

When the patient has life-threatening disease and/or severe symptoms that require quick relief, combinations of cytotoxic agents may be preferable because of their high response rate and early onset of clinical benefit. Randomized trials have shown a survival advantage for the use of a two-drug combination versus a single agent, but this practice has not been widely adopted, because the combination is more toxic and the study designs were flawed in that patients randomized to receive a single agent initially were not crossed over to the other drug component of the initial therapy at the time of relapse.

A second situation, which is becoming increasingly common, is when a cytotoxic chemotherapeutic agent is combined with a targeted agent other than hormone therapy. These targeted agents often have very low response rates when given as monotherapy, but they provide added benefit when given in combination with cytotoxic chemotherapy. A list of targeted chemotherapeutic agents is provided in Table 6, below, followed by Table 7, showing combination regimens for breast cancer.

Table 6. Targeted Chemotherapy for Metastatic Breast Cancer (Open Table in a new window)

Drug

Class

Dose/Schedule

Overall Response Rate (ORR)

Toxicity

Abemaciclib CDK inhibitor

200 mg PO BID continue until disease progression

19.7% Diarrhea, fatigue, neutropenia and nausea

Capecitabine

Oral fluoro-pyrimidine

1250 mg/m²/d PO for 2 weeks with 1 wk off

30%

Rash, hand-foot syndrome,

diarrhea, mucositis

Docetaxel

Antimicrotubule

75-100 mg/m² IV q3wk

or

40 mg/m²/wk X IV for 6 wk with 2 wk off

30-68%

Myelosuppression, alopecia,

skin reaction, mucositis,

and fluid retention

Doxorubicin

Anthracycline

(antitumor antibiotic)

45-60 mg/m² IV q3wk

or

20 mg/m² IV qwk (not to

exceed a cumulative dose

of 450-500 mg/m²)

35-50%

Myelosuppression, nausea/

vomiting, mucositis, diarrhea

cardiotoxicity, alopecia

Doxil (liposomal

encapsulated

doxorubicin)

Anthracycline

20 mg/m² IV q2wk

or

35-40 mg/m² IV q4wk

 

Less cardiotoxicity, neutropenia, alopecia, stomatitis, hand-foot

syndrome

Epirubicin

Anthracycline

90 mg/m² IV q3wk (not

to exceed cumulative dose

of 900 mg/m²)

35-50%

Myelosuppression, mucositis, nausea, vomiting, cardiotoxicity

Gemcitabine

Antimetabolite

725 mg/m²/wk IV for 3 wk

then 1 wk off

or

1 g/m²/wk

IV X 2 then 1 wk off

 

Myelosuppression, nausea/

vomiting, flulike syndrome,

elevated LFTs

Nab-paclitaxel

Antimicrotubule

80-100 mg/m²/wk IV X 3 then 1 wk off

or

260 mg/m² IV q3wk

58-62%

33%

Less neuropathy, and allergic reaction

Olaparib PARP inhibitor 300 mg PO BID 59.9% Anemia, fatigue, nausea, and vomiting

Paclitaxel

Antimicrotubule

80 mg/m²/wk IV

or

175 mg/m² IV over 3 hours q3wk

25-50%

Myelosuppression, alopecia,

neuropathy, allergic reaction

Pertuzumab

Monoclonal antibody

840 mg IV loading dose,

then 420 mg q3wk

Give with trastuzumab and docetaxel

80.2% (objective response rate)

Fever, allergic reaction,

cardiotoxicity/congestive heart failure

Palbociclib

CDK inhibitor

125 mg/day PO for 3 weeks with 1 wk off

Give with letrozole

Data are not available for ORR

Mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole group

Neutropenia, leukopenia, thrombocytopenia, anemia, stomatitis

Ribociclib CDK inhibitor

600 mg/day PO for 3 weeks with 1 wk off

Give with letrozole

Mean PFS was 16 months in the letrozole group and 25.3 months for ribociclib QT prolongation, hepatobiliary toxicity, neutropenia, alopecia, diarrhea, vomiting, constipation, fatigue, anorexia
Talazoparib PARP inhibitor 1 mg PO qDay 62.6% Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite

Trastuzumab

or biosimilars of trastuzumab
Monoclonal antibody

Combination therapy: 4 mg/kg IV once, then 2 mg/kg weekly for 12-18 weeks, then 6 mg/kg q3weeks to total 52 weeks

Single agent: 8 mg/kg IV once, then 6 mg/kg q3weeks to total 52 weeks
10-15% Fever, allergic reaction, cardiotoxicity/congestive heart failure
Trastuzumab deruxtecan [216] Monoclonal antibody conjugate 5.4 mg/kg IV q3weeks 60.3% Interstitial lung disease and pneumonitis; neutropenia; LVEF

Vinorelbine

Vinca alkaloid

20 mg/m²/wk IV

35-45%

Myelosuppression, nausea/

vomiting, constipation, fatigue,

stomatitis, anorexia

 

Table 7. Combination Regimens for Metastatic Breast Cancer (Open Table in a new window)

Chemotherapy

Dose and Schedule

Cycle

XT

Capecitabine

Docetaxel

1250 mg/m² bid days 1-14

75 mg/m² day 1

Repeat cycle every 21 days

May decrease capecitabine dose

to 850-1000 mg/m² to reduce

toxicity risk

XP

Capecitabine

Paclitaxel

825 mg/m² bid days 1-14

175 mg/m² day 1

Repeat cycle every 21 days

XN

Capecitabine

Navelbine

1000 mg/m² bid days 1-14

25 mg/m² days 1 and 8

Repeat cycle every 21 days

     

Gemcitabine [144]

Paclitaxel

1250 mg/m² days 1 and 8

175 mg/m² day 1

Repeat cycle every 21 days

Carboplatin [145]

Paclitaxel

AUC of 6 day 1

200 mg/m² day 1

Repeat cycle every 21 days

Carboplatin [146]

Docetaxel

AUC of 6 day 1

75 mg/m² day 1

Repeat cycle every 21 days

Palbociclib [147]

Letrozole

125 mg PO once daily days 1-21

2.5 mg PO once daily 

days 1-28

Repeat cycle every 28 days

Palbociclib

Fulvestrant

125 mg PO once daily days 1-21

500 mg IM on days 1, 15, 29 and once monthly thereafter 

Repeat cycle every 28 days

Ribociclib [148]

Letrozole

600 mg PO once daily days 1-21

2.5 mg PO once daily days 1-28

Repeat cycle every 28 days

Paclitaxel [149]

90 mg/m² day 1, 8, and 15

Repeat cycle every 28 days

Abemaciclib

Fulvestrant [143]

150 mg PO BID

500 mg IM on Days 1, 15 and 29 and once monthly thereafter

Repeat cycle every 28 days

Ribociclib [150]

Fulvestrant

600 mg PO once daily days 1-21

500 mg IM on Days 1, 15 and 29 and once monthly thereafter
Repeat cycle every 28 days

HER2-positive metastatic breast cancer regimens

Trastuzumab

Paclitaxel

4 mg/kg loading dose then

2 mg/kg weekly

80 mg/m² IV weekly

 

Trastuzumab

Docetaxel

8 mg/kg loading dose then

6 mg/kg day 1

100 mg/m² IV day 1

Repeat cycle every 21 days

Trastuzumab

Vinorelbine

4 mg/kg loading dose then

2 mg/kg weekly

25 mg/m² day 1 weekly

 

Lapatinib

Capecitabine

1250 mg PO daily

2000 mg/m² daily days 1-14

Repeat cycle every 21 days

Paclitaxel

Lapatinib

175 mg/m2

1500 mg/d

Repeat cycle every 3 weeks

AUC = area under the curve (systemic exposure)

References for chemotherapy regimens: XT, [151] XP, [152] XN, [152] HER2-positive metastatic breast cancer regimens [153, 154, 155, 156]

 

The initial choice of chemotherapy is highly influenced by the patient's personal history of previous drug exposure. For example, if doxorubicin was a component of previous adjuvant therapy, the tumor cells have a higher risk of developing resistance, and there is a relationship between cumulative lifetime total dose of doxorubicin and the risk of potentially fatal cardiomyopathy.

It is important to realize that if 1 year or more has elapsed since completion of adjuvant therapy, a patient's tumor is likely to respond to a previously given drug or combination as though that drug or combination had never been given. Most patients have been exposed to both an anthracycline (ie, doxorubicin) and a taxane (docetaxel or paclitaxel) in the adjuvant setting.

Treatment of breast cancer with a taxane in the metastatic setting after treatment in the adjuvant setting may be difficult because of residual toxicity. Although taxanes are not cardiotoxic, they can produce lingering neuropathy (especially paclitaxel) or problems with edema (docetaxel especially), which makes further administration problematic. Substitution of one taxane for another is possible, depending on the nature of the chronic toxicity.

If the tumor has recurred quickly after administration of adjuvant chemotherapy containing a taxane, then changing the schedule of administration can be effective. At least one third of breast cancer patients with taxane resistance due to administration of every-3-week paclitaxel show a response when the same drug is administered on a weekly schedule at a lower dose.

The Cancer and Leukemia Group B (CALGB) 9840 trial reported an improved overall response rate (ORR) in patients receiving weekly dosing of paclitaxel (40%) compared with every-3-week paclitaxel (28%), as well as improved median time to progression (9 mo vs 5 mo). However, care should be taken in watching for progression of adverse effects, especially neuropathy.


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