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Treatment of Metastatic/Advanced Breast Cancer


Medical editor Bjørn Naume MD
Oncologist
Oslo University Hospital
Norway

General

The introduction of modern systemic treatment appears to increase survival in patients with metastatic disease. Many patients can benefit from multiple treatment options. The treatment course for each individual patient, depends on both tumor characteristics, the effect of each treatment, toxicity, and the patient’s general condition. An oncologist (or specialist with broad medical oncology competence) should be responsible for all cytostatic treatment and all sequential endocrine treatment of advanced breast cancer disease.

For potentially endocrine-sensitive metastatic disease, endocrine treatment is primarily chosen before chemotherapy. Despite chemotherapy may give a higher response rate, there is no survival benefit by starting chemotherapy before endocrine treatment. Also, endocrine treatment causes less side effects. The choice of treatment strategy should primarily be based on: to what degree the disease appears to be endocrine sensitive, extent of the disease (especially visceral), and how quickly the disease progresses (aggressiveness). Patients with rapid progression should be given chemotherapy initially. In most instances this applies to patients with liver involvement and patients with dyspnea from lung carcinomatosis.

The antiestrogen tamoxifen was previously the initial treatment choice for hormone receptor positive metastatic disease because of its efficacy and low toxicity. This changed after the introduction of specific aromatase inhibitors. Anti-aromatase drugs (non-steroidal or steroidal) are now considered to be the first treatment choice in postmenopausal women whether they have previously used adjuvant tamoxifen or not. Of new medications, the antiestrogen fulvestrant has shown efficacy for metastatic breast cancer, also subsequent to use of aromatase inhibitors. Megestrol acetate was used routinely after progression on tamoxifen before aromatase inhibitors were introduced. Today, megestrol acetate is sometimes used after treatment with the above mentioned drugs. There are multiple studies showing effect of using steroidal aromatase inhibitors (exemestane) after non-steroidal (letrozole, anastrozole) while there is less documentation for use of non-steroidal after steroidal. There are also studies showing efficacy of estrogen therapy.

Everolimus in combination with exesmestane is a possible choise after progression on letrozole/anastrozole, usually for 2. or 3. line. Everolimus in combination with tamoxifen may be an alternative when eksmestan has previously been given (applied for through paragraph 3 a).

The two most effective single groups of cystostatic drugs for metastatic breast cancer are athracycline and taxanes. It is uncertain whether their order of sequence is of importance. There may be differences with regard to rate of response and time to progression (TTP), but this will seldom lead to prolonged total survival.

In Norway, as in many other countries, anthracycline containing regimens have been applied as first line treatment since the eighties, so also today.

Cytostatic treatment is relevant as first-line treatment for metastatic breast cancer when the tumor is estrogen and progesterone receptor negative. If the tumor initially is hormone receptor positive, then cytostatic treatment is appropriate after the endocrine regimens are no longer effective. For HER2 positive tumors, trastuzumab should be administered in combination with cytostatic treatment. It is now more usual that HER2 positive patients are given trastuzumab in combination with a non-anthracycline regimen as first-line treatment. Lapatinib can be used in combination with chemotherapy for patients who have progressed on trastuzumab. 

The treatment of metastatic disease is palliative. However, in many cases, remission can be achieved for several years. Current chemotherapeutic regimens have less side effects  than previous ones.

Brain and bone metastases respond very well to radiation treatment. Bone metastases often also respond well to endocrine treatment.

Indications

Hormone treatment

  • ER and/or PgR positive tumor. When disease development permits to await endocrine response (6-8 weeks) and disease is considered to be endocrine sensitive.

Cytostatic treatment

  • ER and PgR negative tumor
  • Rapid disease development regardless of ER/PgR status
  • ER and/or PgR positive tumor which is not considered to be endocrine sensitive

Bisphosphonates

  • Osteolytic metastases, with or without joint pain (given in addition to cytostatic treatment or hormone treatment)

Goal

  • To control the disease over time
  • Suppress symptoms with as little toxicity as possible
  • Prolong survival if possible

Treatment Plan

Hormone treatment

The treatment plan depends on previously completed adjuvant treatment, relapse time, and menopausal status.

When menopausal status is uncertain FSH and LH should be monitored. If the estrogen level has declined well ahead of the presence of metastases, hormone treatment should be given as for first line treatment in postmenopausal patients.

Treatment of pre- and perimenopausal

First-line treatment

  • LHRH analogue (for instance goserelin (Zoladex® 3.6 mg s.c. every 4 week). If effective LHRH analogue should be substituted with ovarial irradiation or oophorectomy.
  • If the estrogen level has declined well ahead of the detection of metastases hormone treatment should be added as for first line treatment in postmenopausal patients.

Second-line and further treatment (from first-line)

Treatment of postmenopausal

There are few results suggesting that one particular sequence of treatment ( within the treatment lines) of endocrine medication for metastatic disease give better results.The oncologist is therefore free to decide within the lines according to the stage of the disease, expected effect and grade of side effects.

Survey of recommended endocrine treatment for metastatic breast cancer

Several recommended treatment options are referred to in the treatment lines. There is no definite data indicating that a particular treatment sequence should be followed.

In some cases it may be appropriate to initiate treatment in accordance with 2nd- and 3rd line treatment below.


Medication Specification Comment
First-line treatment (1s line) Aromatase inhibitors/inactivators Not relevant when there is a short disease-free interval after treatment with adjuvant AI The effect of fulvestrant is comparable to AI. Tamoxifen is a secondary option, but seems to have less effect compared to AI

Fulvestrant (500mg/dose)

Not primary choise for short disease-free interval after previous adjuvant tamoxifen treatment
Second-line (2nd line) and third-line (3rd line treatment)
Eksemestane + everolimus If previous progression during letrozole/anastrole treatment

2nd and 3rd line treatment choice may depend on individual assessment of the beneficial effect for each patient (including stage of disease, expected effect and side-effects of the treatment).

*If progression occur during treatment on non-steroidal AI, steroidal AI can be used (or vice versa)

Tamoxifen + everolimus If previous progression during AI treatment and exemestane is not current treatment option
Aromatase inhibitors/inactivators* If previously not used or if only one type of AI is used before, and everolimus is not the preferred treatment
Fulvestrant (or tamoxifen)

If previously not used

Fourth-line treatment (4rth line treatment) and further A treatment choice not previously used

Megestrol Acetate
Estrogen therapy   If applicable, an oncologist with expertise in endocrine therapy should be in charge.

Special conditions for HER2 positive

Studies support a shortlasting / modest effect of endocrine treatment for HER2 positive. As long as the progression of the disease permits to wait for an endocrine response endocrine treatment should be tried. An effect on progression free survival by combining endocrine treatment with HER2 rettet treatment, compared to endocrine treatment alone ( HR respectively 0.63 and 0.71). The studies are lacking an arm with singel HER2 treatment, leaving an uncertainty with regard to the effect of the combination regimen. In addition we have no data judging sequential treatment versus combination treatment. The results of the studies still support the use of HERB2 specific treatment in combination with endocrine treatment. This is considered a separate treatment option,

Chemotherapy

Cardiotoxicity and anthracycline treatment

Caution is recommended with regard to heart toxicity during long-term use of anthracycline. The threshold for using MUGA/echocardiography in the treatment follow-up should therefore be low. The maximum treatment dosage is 900 mg/m² of epirubicin (550 mg/m² doxorubicin). Clinically the de facto limit can depend on other factors, for instance age and predisposition for cardiac disease.

Recommended treatment

These recommendations are separated according to whether the disease is HER2 negative or positive.

FLOW CHART FOR CHEMOTHERAPY

HER2 negative patients

First-line treatment

Anthracycline containing regimens are relevant when:

  • The patient has not received adjuvant chemotherapy.
  • The patient has received adjuvant chemotherapy which did not contain anthracycline (for example CMF).
  • It's been ≥ 24 months since completed adjuvant/neoadjuvant chemotherapy containing anthracycline (for example FEC, epirubicin).

The Norwegian Breast Cancer Group has decided on the following anthracycline-containing regimens as appropriate:

  • FEC
  • FAC
  • Epirubicin monotherapy
  • Low-dose Adriamycin® (doxorubicin)
  • Pegylated liposomal doxorubicin (PLD). In the treatment of metastatic breast cancer, PLD shows comparable efficacy to doxorubicin, but with reduced risk of heart toxicity. (O’Brien et al. Annals of Oncology 15: 440-449, 2004). Data exists showing that PLD can be used with satisfactory safety above the dose limit used today for anthracycline (Safra et al. Annals of Oncology. 11: 1029-1033, 2000). PLD is beneficial in cases where heart toxicity is a concern due to age, predisposition for heart disease, high cumulative doses, and HER2-positive disease.

Patients who have received anthracycline containing adjuvant/neoadjuvant treatment < 24 months previously are recommended to use taxanes. 

NBCG has decided on the following taxane regimens to be appropriate depending on the condition of the patient, toxicity, age or other factors:   

  • Docetaxel monotherapy 100 mg/m² every 3 weeks has in two phase III studies documented better TTP than other second line chemotherapy.
  • Paclitaxel 80-90 mg/m² weekly. Weekly paclitaxel in doses of 80-100 mg/m² have in multiple phase II studies shown higher response rates, but type 1 evidence is not available. A Norwegian phase II study with weekly dose paclitaxel as first line has shown a response rate of 39.4% and clinical benefit of 66.7%.
  • Docetaxel 75 mg/m² every 3 weeks + capecitabine 1000 mg/m² x 2 day 1-14 every 21 days. The combination docetaxel/capecitabine is known to be better than docetaxel alone in one phase III study, including overall survival benefit. In the study, docetaxel 75 mg/m² was given every 3 weeks + capecitabine 1250 mg/m² x 2 day 1-14 every 21 days. Many had to reduce the capecitabine dose to 1000 mg/m² due to side effects, and it is recommended to use this dosage as the initial dose. NBCGs experience is that this treatment regimen is more toxic than monotherapy. This combination has not been compared with the same drugs in sequence. 
  • Docetaxel 35 mg/m² weekly (6 out of 8 weeks). Response rates between 30 and 40% have been shown for weekly docetaxel in multiple phase II studies. Type 1 evidence is not available. This is not considered to be advantageous with regard to side effects compared to docetaxel every 3 weeks.
  • Albumin-bound paclitaxel. Studies show equal or better efficacy using albumin-bound paclitaxel (Abraxane) compared to docetaxel.

Second-line treatment

After an anthracycline containing regimen as a first-line treatment, the patient should have: 

  • Docetaxel 100 mg/m² every third week (see 1st line treatment)
  • Paclitaxel 80-90 mg/m² weekly (see 1st line treatment)
  • Docetaxel 75 mg/m²  every third week + capecitabine 1000 mg/m² x 2 days 1-14 every 21 days. 
  • Docetaxel 35 mg/m² weekly (6 out of 8 weeks) 
  • Albumin-bound paclitaxel (see 1st line treatment)

If taxanes were used as first-line treatment, but not in combination with capecetabine: 

  • Capecitabine 1000-1250 mg/m²  x 2 days 1-14 every 21 days. Capecitabine has in multiple phase II studies and in a Norwegian study shown response rates of 20-30% after anthracycline and taxanes.
  • Vinorelbine 25-30 mg/m² weekly, or 30-35 mg/m² day 1 and day 8 every three weeks. The documentation is not as good as for capecitabine, This regime is applied in several institutions in Norway where respnses and low grade of side effects are seen.
  • Eribulin 1.23 mg/m² day1 and day 8 (21 days cycle).

If doxetaxel/capecetabine were used as first-line:

  • Vinorelbine 25-30 mg/m2 weekly, or 30-35 mg/m2 day 1 and day 8 every three weeks, or oral vinorelbine (60 mg/m2 weekly the first 3 weeks before increasing to 80 mg/m2 weekly.)
  • Eribulin 1.23 mg/m² day1 and day 8 (21 days cycle).

Third-line treatment

The indication should be assessed carefully. Depending on what were used as second-line treatment, one of the following may be appropriate:

  • Capecitabine 1000-1250 mg/m2 x 2 day 1-14 every 21 days
  • Vinorelbine 25-30 mg/m2 weekly, or 30-35 mg/m2 day 1 and day 8 every third week, or per oral vinorelbine (60 mg/m² weekly the first 3 weeks before increasing to 80 mg/m² weekly)
  • Eribulin 1.23 mg/m² day 1 and day 8 (21 days cycle).
  • Gemcitabine 1000 mg/m2 i.v. day 1,8 and 15 in 28 day cycle.

Other regimens which NBCG has not decided upon can be found in the literature. The regimens discussed here are considered established and are  found applicable for the most important elements of palliative chemotherapy: to prevent progression of the disease by treatment regimens of low toxicity.

New results suggest that Halaven® (eribulin mesylat) is comparable to capecitabine for patients who have previously been treated with anthracycline and taxane

For triple negative, there is internationally an increasing use of cisplatin/carboplatin regimens. Relatively good response data, with response rates about 33%, have been reported on the combination carboplatin/gemcitabine after use of anthracycline/taxane. The Breast Cancer Group of Norway (NBCG) considers this to be a treatment option for triple negative breast cancer.

HER2 positive patients

Even though very good response rates have been shown by combining chemotherapy with trastuzumab, anthracycline regimens (without trastuzumab) have until recently been the first treatment choice in most cases. The most important argument for starting with an anthracycline regimen has been the risk for cardiotoxicity and falling LVEF due to the long half-life of trastuzumab and fear for increased risk of cardiotoxicity in synergy with anthracycline if given after progression on a trastuzumab regimen. Pegylated liposomal doxorubicine reduces the risk for cardiotoxicity in this context. Antracycline, primarily in the form of liposomal anthracycline, can be used when HER2-directed treatment in combination with non-anthracycline chemotherapies is no longer effective. In addition, after progression on trastuzumab several  patients will be offered lapatinib combined with chemotherapy (second- or third-line), which will eliminate trastuzumab before anthracycline is administered.

First-line treatment

If the tumor is HER2 positive, trastuzumab should either be combined with a taxane or alternatively with vinorelbine. Recently, the HERNATA study was published (randomized phase 3 study) showing that time to progression is identical for trastuzumab in combination with vinorelbine as in combination with docetaxel. The effect of vinorelbine in combination with trastuzumab is supported also by phase 2 studies.

One of the following regimens is recommended for HER2 positive patients:

  • Paclitaxel + trastuzumab
  • Docetaxel+ trastuzumab
  • Vinorelbine 30-35 mg/m² day 1 + day 8 every 3 weeks + trastuzumab
  • Docetaxel (75 mg/m²) + trastuzumab + pertuzumab (420 mg after loading dose) every 3 rd week. (The CLEOPATRA study which randomized HER2 positive pasients between docetaxel + trastuzumab +/- pertuzumab in 1st linje, showed considerable improvement in progression free survival in the pertuzumab arm. Pertuzumab is now accepted in Norway but is not evaluated economically. The combination of docetaxel, trastuzumab and  pertuzumab is now considered an option in first-line treatment

If the patients` general condition, age, expected tolerability or patient preference does not allow the use of taxane or vinorelbine, trastuzumab monotherapy can be considered.

Second-line and third-line treatment

Use of trastuzumab in combination with another type of chemotherapy as second-line after progression of first-line treatment (trastuzumab in combination with first-line chemotherapy) provides additional possibility for clinical benefit. A study has shown effect of continuing trastuzumab in combination with capecitabine, compared to capecitabine as monotherapy, – after progression on trastuzumab combined with other kind of chemotherapy.

The combined HER2/HER1 inhibitor lapatinib in combination with capecitabine has shown a doubling of progression-free survival (4 months) compared to capecitabine alone in patients who have previously taken anthracycline, taxane, and trastuzumab. In addition, lapatinib has shown an effect in monotherapy studies after previous use of trastuzumab. Effect has also been reported in patients with brain metastases. NBCG believes the effect of lapatinib is sufficiently documented to recommend use of this in combination with capecitabine.

The following treatment choices are used for second and third-line treatment:

  • Trastuzumab in combination with the chemotherapy drug not used in first-line treatment.
  • Lapatinib (1250 mg orally x 1 daily) in combination with capecitabine (1000 mg/m² orally x 2 daily for 14 of 21 day cycle). Apply for cost coverage of lapatinib according to paragraph 3a. 
  • Trastuzumab in combination with capecitabine (1000 mg/m² x 2 day 1 – 14 every 21 days).
  • Trastuzumad in combination with lapitinib.

Fourth-line (possibly third-line) treatment

The following treatment choices are possible for fourth-line (possibly third-line) treatment: 

  • Pegylated liposomal doxorubicin. Dosage: 40 mg² i.v. every 28 days.

Pegylated liposomal doxorubicin (PLD) has shown comparable effect with doxorubicin in treatment of metastatic breast cancer, but with a reduced risk for cardiotoxicity (O’Brien et al. Annals of Oncology 15: 440-449, 2004). Further, data show that PLD can be used with satisfactory safety in dosage above limit used today for anthracycline (Safra et al. Annals of Oncology. 11: 1029-1033, 2000).

NBCG holds that PLD can be of special benefit when it is important to consider cardiotoxicity due to age, predisposition for heart disease, high cumulative doses, and for HER2 positive disease. 

Bisphosphonates or denosumab

If osteolytic metastases are present, with or without accompanying pain, treatment with bisphosphonates or denosumab is an appropriate supplement to endocrine treatment or chemotherapy.

Denosumab (subcutaneous administration) has been proven to prevent skeletal-related events to a greater extent than Zoledronic acid.

This treatment does not influence life span but can reduce the extent of skeletal complications (pathologic fractures, surgery for potential fractures, required radiation treatment, compression of the spinal cord and hypercalcemia). When bisphosphonate treatment should be initiated depends on the extent and symptoms of the disease.

 

Treatment recommendations

 

Hormone receptor-negative disease

Hormone receptor-positive disease

Patients starting chemotherapy for metastatic disease having both parenchymal metastases and skeletal metastases should be observed for response for 2-3 months before deciding on addition of bisphosphonates or denosumab. This applies especially to first line chemotherapy. With a good response (CR/PR), it is plausible to postpone treatment with bisphosphonates. Patients with assumed endocrine-sensitive disease in the skeleton should await the effect of this treatment (3-4 months) before treatment with bisphosphonates or denosumab is considered.
Patients who have progressing osteolytic metastases but no parenchymal metastases and where chemotherapy is indicated are recommended a supplement of bisphosphonate or denosumab for 12-24 months or until the first skeletal event. An observation period is usually not indicated as it is difficult to assess a response in the skeleton. At first evidence of osteolytic metastasis which appears to be easily observed, bisphosphonates or denosumab can be awaited, unless otherwise indicated by symptoms. If the patient is considerably pain-ridden at the time of endocrine treatment and the pain is not controlled with traditional analgesics, then bisphosphonates or denosumab should be immediately assessed. The treatment continues for 12-24 months or until the first event in the skeleton.   
In second line chemotherapy where the expectation of response is less and the response duration usually is shorter, the observation time may be reduced. In the absence of response to endocrine treatment, perform the same assessments as described under hormone receptor negative disease.
If the patient has considerable pain when starting chemotherapy and the pain is not controlled by traditional analgesics, the use of bisphosphonates or denosumab should be immediately assessed.  

The treatment continues for 12-24 months or until the first event in the bone.

 

An increased frequency of complications from the jaw, including osteonecrosis and infections has been reported after using intravenous bisphosphonate. This also applies to denosumab.

It is recommended to clarify the patient’s dental status before bisphosphonate and denosumab treatment is initiated since tooth extractions and infections pose an increased risk for osteonecrosis and osteomyelitis.

Invasive dental treatment should be avoided, if possible, in patients undergoing bisphosphonate or denosumab treatment. Dental surgery can exacerbate the condition in patients developing osteonecrosis in the jaw during bisphosphonate or denosumab treatment.


Preparation

  • For advanced/metastatic breast cancer, the status of the hormone receptors and HER2 should be monitored. These have significant consequences for choice of treatment.
  • The patient is explained the treatment and its consequences.
  • If menopausal status is uncertain, estradiol, FSH and LH should be measured.

Hormone treatment

  • In conjunction with the start of treatment with aromatase inhibitors/inactivators (AI), bone density measurement (DEXA-scan) should be performed. This can be postponed until later when it is known whether the treatment is to be continued (if the effect of treatment is appropriate).

Chemotherapy

During chemotherapy for metastatic breast cancer, neutropenia is the most common dose-limiting factor.

  • For weekly cycles, neutrophil granulocyte counts should be 1.0 x 109/l before start of treatment.
  • For tri-weekly cycles, neutrophil granulocytes counts should be ≥ 1.5 x 109/l before the start of treatment. If granulocytes are too low, the treatment should be postponed and it can be necessary to reduce the dosage of subsequent courses, especially for tri-weekly treatments.

The patient is offered a customized wig/scarf/hat.


Implementation

Each principle of treatment is continued until there is evidence for progression or intolerable toxicity.

During chemotherapy a pause in treatment may be acceptable in case of side effects (and continued effect of the treatment) or very good effect of the treatment. The patient should then be cautiously followed.


Follow-up

The effect of treatment is most often evaluated in 2-3 month intervals. Some patients need a first evaluation at a shorter interval. Evaluation often includes use of imaging modalities (UL, CT, scintigraphy).

Hormone treatment

The side effects of endocrine treatment are usually moderate. 

The most common side effect is:

  • hot flashes

Other side effects may be:

  • Nausea
  • Abdominal discomfort
  • Joint problems (especially with LAD)
  • Bone density changes with use of aromatase inhibitors

Tamoxifen poses a small increased risk for deep vein thrombosis (DVT), lung embolism (LE), and endometrial cancer. An annual gynecological examination is recommended during tamoxifen treatment.

Cytostatic chemotherapy

 

 Some side effects of chemotherapy for metastatic treatment

(frequent > 1/100, rare <1/1000)

   Doxorubicin Gemcitabine Capecitabine Vinorelbine
Bone marrow depression frequent frequent frequent frequent
Nausea/Vomiting moderate low frequent low
Hair loss frequent frequent frequent frequent/mild
Diarrhea/constipation diarrhea/rare diarrhea/constipation diarrhea/constipation constipation/diarrhea
Mucositis/stomatitis stomatitis/rare stomatitis stomatitis stomatitis/frequent
Allergic reactions rare rare rare rare
Cardiotoxicity yes rare rare not reported
Neurologic symptoms not reported rare rare frequent
Nail changes frequent not reported frequent not reported
Liver involvement not reported frequent frequent frequent/mild
Skin involvement frequent frequent frequent not reported
Respiratory involvement not reported frequent frequent not reported

Some side-effects of chemotherapy for metastatic treatment (cont’d.) 

                                  FEC    
 

Fluorouracil 

Epirubicin

Cyclophosphamide

Paclitaxel

Docetaxel

Bone marrow depression frequent frequent frequent frequent frequent
Nausea/Vomiting low moderate high/moderate low    low 
Hair loss frequent frequent in high doses frequent frequent
Diarrhea/constipation diarrhea diarrhea dose dependent diarrhea diarrhea/constipation
Mucositis/stomatitis stomatitis mucositis dose dependent mucositis stomatitis
Allergic reactions rare rare frequent rare sometimes
Cardiotoxicity rare yes rare rare rare
Neurologic symptoms rare not reported not reported frequent frequent
Nail changes not reported not reported rare frequent frequent/serious
Liver involvement rare not reported frequent rare/serious frequent
Skin involvement frequent frequent rare not reported less frequent

 

  *Cardiac failure in combination with trastuzumab (comprises 2,2 %)(1).


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