Systemic Therapy

Endocrine Therapies

The choice of endocrine therapy depends mostly on the menopausal state of the patient.

Post-Menopausal Women

Post menopausal patients (the majority) receive the most benefit from an aromatase inhibitor. These agents prevent the production of oestrogen in the peripheral tissues of the body, reducing the production of oestrogen in the body to virtually nil. They have significant side effects, including loss of bone mineral, hot flushes, and joint pains. Some women are unable to tolerate this therapy and may perform better with tamoxifen, which has a slightly lower efficacy. Tamoxifen side effects include hot flushes, mood changes, and an increased risk of thromboembolic events and uterine malignancy; there is increase in bone mineral density and joint pains are less common.
Regardless of choice of agent, therapy should be continued for 5 years, and further studies are looking into longer term treatment with aromatase inhibitors.

Pre-Menopausal Women

Pre-menopausal patients represent a more difficult challenge. Tamoxifen, as an antagonist to the oestrogen receptor, is the preferred choice as it prevents binding of ovary-derived oestrogens. Ovarian ablation may be considered but there is insufficient evidence for its benefit over tamoxifen. Ablation of ovarian function would allow the use of aromatase inhibitors which have proven superior tamoxifen in the post-menopausal setting.

  • Tamoxifen should continue for 3 years at which time menopausal status should be reassessed
    • If post-menopausal, patients are converted to an aromatase inhibitor for a further 5 years of therapy
    • If pre-menopausal, patients continue on tamoxifen for a total of 5 years
    • At the end of this period, if the patient has become menopausal, 5 additional years of therapy with an aromatase inhibitor in instigated
  • If patients resume menstruation, aromatase inhibitors should be ceased and tamoxifen restarted.

Special Issues with Tamoxifen

Tamoxifen is metabolised to endoxifen, and certain selective serotonin reuptake inhibitors (SSRIs) have been shown to impact on this conversion. They are best avoided; alternatively an aromatase inhibitor can be used.

Special Issues with Aromatase Inhibitors

No aromatase inhibitor has proven benefit over others. It is important to check bone density prior to starting therapy and regularly monitor this throughout the treatment course.

Cytotoxic Systemic Therapy

Non-Trastuzumab Regimens

Addition of a taxane to an anthracycline regimen improves survival outcomes.

For non-ERBB2 positive malignancies, the following regimens are typically employed:

  • TAC - docetaxal (a taxane), doxorubicin (an anthracycline), cyclophosphomade
  • AC followed by T
  • FEC followed by T (5-fluorouracil, epirubicin, cyclophosphamide)
  • TC
  • AC

TAC is preferred for younger women or for more aggressive malignancies. Women unable to tolerate the intense treatment may need to be treated with one of the less intense regimens instead (which have slight inferiority). TAC includes 6 cycles, spaced 21 days apart:

  • Docetaxal 75 mg/m^2
  • Doxorubicin 50 mg/m^2
  • Cyclophosphamide 500 mg/m^2

FEC followed by T is common in my home city. This involves 3 cycles of:

  • 5-fluorouracil 500 mg/m^2
  • Epirubicin 100 mg/m^2
  • Cyclophosphamide 600 mg/m^2

Then three cycles of:

  • Docetaxal 100 mg/m^2

Older regimens include:

  • FAC (5-fluorouracil/doxorubicin/cyclophosphamide) or FEC (epirubicin)
  • CMF (cyclophosphamide/methotrexate/5-fluorouracil)

Trastuzumab Regimens

These regimens include trastuzumab; this has been shown to lead to significant cardiotoxicity when given in combination with an anthracycline, and therefore regimens either deliver the trastuzumab separately or omit the anthracycline altogether; this is controversial as some retrospective data supports including of anthracyclines in HER2 positive disease. Note that when formed into an acronym, trastuzumab is represented by a H to signify its action agains the HER2 receptor (ERBB2) as well as the trade name Herceptin:

  • AC followed by TH (docetaxal/trastuzumab)
  • TCH (docetaxal/cisplatin/trastuzumab)

Some centres may use FEC followed by TH.
In Australia the PBS restricts the use of trastuzumab to in combination with a taxane. Trastuzumab should be continued for one year from commencement of chemotherapy, and is usually given as a single agent after the main course of systemic treatment has concluded.