The primary goal of treatment is to control cancer-related symptoms and to enhance survival where possible. The treatment of metastatic breast cancer requires a multidisciplinary approach (medical, radiation, surgical, specialists in pain and symptom management, and psychosocial support). Community home care and palliative support are important in later stages of the disease. There are a number of online websites, which provide a range of resources, from chat lines to information and testimonials about particular treatments for breast cancer patients. Some useful links are listed below:
Most improvements in survival and quality of life for patients with metastatic breast cancer have come from knowledge gained from successfully completed scientifically rigorous clinical trials. Patients should be given the opportunity to participate in clinical trials if available for their stage and type of breast cancer.
Metastatic breast cancer is moderately radiosensitive and worthwhile symptomatic relief can be expected from radiation to several different types of metastases. Radiation can improve quality of life, and possibly extend life, for patients with metastatic breast cancer in the treatment of:
- Bony metastatic lesions
- Spinal cord compression, in conjunction with steroids with or without surgical decompression
- Symptomatic endobronchial or parenchymal lung lesions
- Superior vena cava obstruction
- Cerebral metastatic disease in conjunction with steroids with or without surgery
- Painful bulky or ulcerating soft tissue or chest wall disease
In select patients with limited metastatic disease (oligometastatic disease), high-dose radiotherapy (stereotactic radiotherapy or radiosurgery) may be considered to gain long-term control of metastatic disease. Patients should be referred to radiation oncology in such circumstances.
There are a few well-defined indications for surgery in the palliative setting. These include investigation of a solitary lesion which may be metastatic or a new primary disease, e.g. a solitary lung lesion; treatment of pathologic fracture; prophylactic instrumentation to prevent an impending fracture; surgical decompression for spinal cord compression and/or surgical stabilization of the spine with metal rods; and surgical resection of solitary and oligo brain metastasis. Radiation following surgical intervention to bone and brain is often indicated.
Other Local Therapy
- Ascites: Patients developing symptomatic ascites may benefit from periodic therapeutic paracentesis.
- Pleural Effusions: Symptomatic pleural effusions may be managed with thoracentesis, PleurX catheters, or pleurodesis.
- Leptomeningeal disease is a poor prognostic sign, and is often a terminal event. However some patients achieve moderate duration of disease control with intrathecal methotrexate or ara-C. High dose iv methotrexate can also produce temporary relief of symptoms, as can craniospinal radiation in select cases.
- Bowel Obstruction. Bowel obstruction resulting from peritoneal metastases from breast cancer is infrequently reversible. A trial of chemotherapy with TPN support may be indicated provided there are clear expectations about when futility will be declared and TPN will be withdrawn in the absence of resolution.
- Uveal and periorbital soft tissue metastases. These are very uncommon in breast cancer and can be treated with radiation.
The systemic management of invasive metastatic breast cancer is complex. At present, invasive breast cancer can be thought of as three broad entities that influence systemic treatment decisions: hormone receptor positive/Her2 negative cancers; Her2 positive cancers (regardless of hormone receptor status); and hormone receptor negative and Her2 negative (ie, triple marker negative) cancers. Within each of these entities, treatment recommendations are also influenced by patient age and comorbidities, personal preferences, extent of disease, and other histopathologic features of the cancer. In every case, patients and physicians must always weigh the benefits of treatment, particularly chemotherapy, against the potential risks of giving it.
Hormone Receptor Positive Breast Cancer
Hormonal therapy is generally the preferred initial treatment for metastatic hormone sensitive (ER and/or PR positive) disease, which is:
- Confined to non-visceral sites, or a low burden of visceral metastases (little/no organ dysfunction, low volume of the organ involved, minimal/no symptoms) and
- Relatively indolent disease not likely to progress rapidly over the ensuing 3-4 months (e.g., one or two solitary pulmonary nodules or chest wall recurrence or skin involvement)
The choice of agent for optimal hormonal therapy in a given situation should reflect the best available evidence showing patient benefit, the likelihood of response and the associated side effects. One must also consider whether a patient is pre or postmenopausal, their co-morbidities and current performance status, what hormone therapies she or he was exposed to in the adjuvant setting, and whether the cancer relapsed on or sometime after they were discontinued. The probability of response is highest in patients with long disease-free interval predating relapse. Response to one hormonal agent often predicts for responses to other agents. Treatment with hormone therapy should be continued to progression unless there is significant toxicity.
Patients requiring chemotherapy as initial therapy for hormone receptor positive disease may benefit from the introduction of hormone therapy on completion of chemotherapy, as a means of maintaining longer remissions.
Hormonal therapy options in pre-menopausal women include:
- Selective estrogen receptor modulator: BRAVTAM.
- Ovarian suppression with LHRH agonist, bilateral oophorectomy, or bilateral ovarian radiation.
- Ovarian suppression plus tamoxifen: BRAVLHRHT. Dual hormone inhibition may lead to longer survival than ovarian ablation alone.2,3
- Ovarian suppression plus an aromatase inhibitor is an option for premenopausal women who have a contraindication to tamoxifen, and for premenopausal women whose disease has progressed after tamoxifen. The combination of an LHRH agonist and an aromatase inhibitor requires a CAP approval.
- Premenopausal women who have menopause induced may benefit from the same treatment options that are recommended for menopausal women.
Hormonal therapy options in post-menopausal women include:
- Non-steroidal aromatase inhibitors: BRAVLET, BRAVANAS
- Steroidal aromatase inhibitor: BRAVEXE
- Steroidal AI plus everolimus: not presently funded by BC Cancer.
- Selective estrogen receptor modulator: BRAVTAM.
- Selective estrogen receptor downregulator: fulvestrant: not presently funded by BC Cancer.
- Occasional patients may still have hormone-sensitive disease after treatment with the above therapies and/or may have compelling reasons to avoid chemotherapy. In such cases older hormonal treatments such as megestrol (BRAVMEG) and testosterone enanthate (BRAVTEST) may provide some disease control.
Anastrozole and letrozole (BRAVLET
) are generally the preferred first line hormone agent in menopausal metastatic breast cancer in patients who have not relapsed on either drug from the adjuvant setting. By inhibiting aromatase, they prevent peripheral conversion of androgens to estrogens, thus greatly reducing circulating estrogen levels in menopausal women. They have proven efficacy in both first and second line metastatic hormone receptor positive disease.4,5,6
They should not be used in sequence, as they have the same mechanism of action and very similar chemistry. A switch between letrozole and anastrozole can be considered if there are intolerable side effects, as sometimes there is a preference. They are not effective single agents in premenopausal women.
) is a good first line choice in premenopausal women and in menopausal patients who have relapsed on an adjuvant aromatase inhibitor. It can also be used in second or third line if there was no prior tamoxifen use in the adjuvant setting, and in women with no relapse on or within one year of adjuvant Tamoxifen.
) is an irreversible steroidal aromatase inactivator that has shown some activity after previous therapy with reversible aromatase inhibitors7
, and can be given as second line or third-line, provided the duration of disease control on anastrozole or letrozole is long enough to suggest possible continued hormone responsiveness of the cancer (generally at least 4-6 months). Combination of exemestane and everolimus after exposure to a non-steroidal AI results in longer disease control than exemestane alone, and may be an option for some patients.8
It is unclear at this time whether the addition of everolimus prolongs survival, however it does add some toxicity in the form of mucositis, diarrhea, and possible interstitial pneumonitis.
Fulvestrant is a pure anti-estrogen given by monthly intramuscular injection. It provides equivalent disease control to anastrozole in the first line setting and to exemestane after a non steroidal aromatase inhibitor (second line plus). It may be particularly effective in patients with no prior hormone therapy exposure (hormone therapy naive).9,10
Hormone Refractory Disease
At some point all hormone receptor positive cancers become unresponsive to hormone therapy and chemotherapy must be considered. As well, even among those cancers felt to retain hormone sensitivity, chemotherapy is generally preferred if the disease is locally-advanced (to achieve better local control), affects the function of visceral organs, or is causing the patient a high degree of symptoms. Chemotherapy is described under the “Hormone Receptor and Her2 Negative” section below.
HER2 Positive Breast Cancer
First line therapy
The standard of care first line therapy for metastatic her2+ disease, regardless of hormone receptor status, is anti-her2 therapy combined with chemotherapy.11
Anthracyclines should not be combined with trastuzumab due to synergistic cardiotoxicity. Unless patients are too frail or have prohibitive cardiac co-morbidity, a taxane combined with trastuzumab (BRAVTRAP
) should be the first choice of therapy.11,12,13
The chemotherapy drug(s) may be discontinued after 6-8 cycles to minimize cumulative toxicity, however trastuzumab should be continued (BRAVTR
) until disease progression or prohibitive toxicity. Vinorelbine can be substituted for a taxane combination in patients who are frail due to disease, co-morbidity, or advanced age (BRAVTRVIN
Some patients achieve a very long disease remission with first line therapy.
During the single agent trastuzumab phase, hormone therapy can be added if the cancer is hormone receptor positive.
All patients should have baseline left ventricular ejection fraction assessment with a MUGA scan or echocardiogram prior to initiating trastuzumab. There is no defined schedule for left ventricular ejection monitoring in the metastatic setting. Patients reporting symptoms or exhibiting signs of congestive cardiomyopathy should have anti-her2 therapy interrupted and cardiac assessment performed. Whether trastuzumab can be safely resumed later depends on the degree of recovery of cardiac function following discontinuation. Recommendations are further detailed in the BRAVTR
Relapse after adjuvant trastuzumab
A small fraction of patients receiving chemotherapy and trastuzumab for early breast cancer will experience a metastatic relapse. Patients relapsing 12 or more months after completion of adjuvant trastuzumab should be treated preferentially with chemotherapy / trastuzumab combination in first line, as described above. Patients relapsing on or within 6 months of completing trastuzumab may experience better disease control by substituting a different anti-her2 drug, such as lapatinib. It is unclear whether trastuzumab or lapatinib is better at controlling disease that recurs between 6 and 12 months after completing trastuzumab.
Concurrent ER+ disease
Patients with hormone receptor positive and her2+ disease who refuse chemotherapy may experience a period of disease control with hormone therapy alone, although this is generally of shorter duration than with chemotherapy and trastuzumab, and of shorter duration than is seen in hormone receptor positive disease that is her2 negative.15 As such, it is not the preferred option. In extenuating circumstances where chemotherapy cannot be safely given, the combination of an aromatase inhibitor and lapatinib may provide longer disease control than an aromatase inhibitor alone.16 This requires CAP approval.
Second line therapy
At the time of disease progression, continuation of anti-her2 therapy and addition of chemotherapy is associated with the longest disease control and preservation of quality of life. Options include continuing trastuzumab or switching to lapatinib, and adding either vinorelbine or capecitabine (BRAVTRVIN
Retreatment with a taxane/trastuzumab combination may be appropriate for patients who achieved a long period of disease control with initial treatment. After an appropriate period of combination therapy, the chemotherapy drug can be stopped to minimize toxicity, while the anti-her2 therapy is continued until disease progression.
Third line therapy and beyond
If available, continuation of anti-her2 therapy with chemotherapy in subsequent lines of therapy appears to be beneficial.19 At each time point that treatment change is required due to disease progression, consideration of whether or not to treat with further chemotherapy and which drug(s) to use must take into consideration the patient’s previous treatments, current performance status, extent of disease, likelihood of further disease control, and comorbidities. Options may include cytotoxic chemotherapy as described below, and hormonal therapy for the hormone receptor positive cancers.
The majority (40-60%) of patients with metastatic her2 positive breast cancer develop brain metastases at some point in their disease course. One should maintain a low threshold for imaging the brain if a patient reports any neurologic symptoms, even if subtle. Oligometastases should be considered for surgical excision or radiotactic surgery followed by whole brain radiotherapy. Retreatment of progressive brain metastases with further radiation is sometimes feasible and beneficial, if the disease was controlled for an extended period (generally at least ten months) after initial radiotherapy. Several systemic drugs have some penetration into the blood brain barrier and may enhance control of brain metastases from breast cancer. These include capecitabine, lapatinib, anthracyclines, and cisplatin. While some other drugs have been used to treat primary brain tumors, their ability to control brain metastases of breast cancer origin has been disappointing.
Occasionally the brain may be the first and only apparent site of metastatic relapse. If isolated brain metastases occur during adjuvant therapy, they should be treated as described above and trastuzumab should be continued indefinitely as the chance of systemic metastases developing is high. If isolated brain metastases develop after completion of adjuvant trastuzumab, patients should be followed closely after treating them. Systemic treatment with chemotherapy and trastuzumab should be started at the time of eventual systemic metastases detection.
Hormone Receptor and HER2 Negative (Triple Negative) Breast Cancer
Cytotoxic chemotherapy remains the standard of care for patients who have breast cancer that is negative for ER, PR, and Her2 expression. Patients with hormone receptor positive disease that is hormone refractory or who require chemotherapy, and patients with her2 positive disease that has progressed beyond available lines of anti-her2 therapy/chemotherapy combinations can be treated with chemotherapy using the same principles as for patients with triple negative disease.
There are several chemotherapeutic agents with activity against breast cancer, and choices should take into account the patient’s previous treatments, performance status, extent of disease, and other comorbidities. There is no single correct order for chemotherapy drug delivery. Unlike hormone therapy, chemotherapy has a narrow therapeutic index, requiring careful attention to toxicity. There should be a low threshold for dose modifications to minimize toxicity and patients should be advised to report side effects.
General indications for chemotherapy in patients with metastatic breast cancer:
- Rapidly progressive metastatic disease.
- Threatening metastatic disease e.g. involving the viscera, particularly the liver.
- Estrogen receptor negative primary tumours with symptomatic metastasis.
- Hormone receptor positive tumors pretreated with and failing hormonal maneouvers.
- Reasonable performance status (ECOG 0-2). Patients with ECOG-3-4 are unlikely to benefit and will very likely experience unacceptable toxicity.
Response to chemotherapy should be evaluated after 2 or 3 cycles, and non-responding patients should have treatment changed. In responding patients, the optimal duration of therapy varies by drug and cumulative toxicity. In general, 6-8 cycles of therapy, or treatment for two cycles beyond best response affords optimal disease control. Longer therapy is an option for patients tolerating a drug well and without evidence of progression.
In general terms, anthracyclines, taxanes, and capecitabine should be considered for the first lines of therapy:
- Anthracyclines: there is a maximum safe lifetime cumulative dose of anthracyclines beyond which the risk of cardiac toxicity is unacceptably high.
- Taxanes: the chief cumulative toxicity limiting therapy with taxanes is peripheral neuropathy.
- Capecitabine: palmar-plantar erythrodysesthesia is a cumulative toxicity which may limit duration of therapy or require dose modification over time.
Several chemotherapy combinations have shown modest gains in response rate and overall survival duration compared with single agent therapy, however generally combining several drugs results in increased toxicity.20,21,22 Combination chemotherapy should be considered in young fit patients and in patients in whom maximal disease shrinkage is optimal for symptom resolution.
Other/subsequent chemotherapy regimens include:
- Gemcitabine: activity of gemcitabine is modest as a single agent. Results are better in combination.
- Vinorelbine: BRAVNAV
- Metronomic low-dose oral cyclophosphamide and methotrexate: BRAVCMPO
- CMF regimens: BRAVCMFPO, BRAVCMF. Survival is better with the classic version of CMF (BRAVCMFPO) however toxicity is slightly better with the iv version (BRAVCMF)
Second and subsequent lines of therapy yield less rewarding results than first-line chemotherapy both in terms of degree and duration of tumour response. Toxicity can be greater due to prior therapy and more advanced disease state. The therapeutic gain is modest in many circumstances, but chemotherapy may relieve symptoms and therefore remains an important therapeutic tool. Chemotherapy can be safely and reasonably considered in patients with a performance status of 0-2, anticipated survival >3 months, and a previous response to at least one prior chemotherapy in metastatic disease.
There is great interest in combining classic chemotherapy with target specific drugs. To date, targeting the ER receptor and the her2 receptor has resulted in the best survival and disease control benefit for metastatic breast cancer.
- PARP inhibitors may have a particular role in cancers with BRCA1 or 2 mutations and are being explored in triple negative disease.23
- Targeting the EGFR and ER receptor simultaneously may result in longer disease control among cancers that are both ER and her2 positive, however this approach is not superior to the combination of anti-her2 therapy with chemotherapy.16
- Combining more than one anti-her2 therapy with chemotherapy in early treatment of metastatic her2+ disease appears to provide longer disease control.24
- The combination of mTOR inhibition and modulation of the ER target may restore or prolong hormone sensitivity in some ER+ cancers.
- Although VEGF inhibition has enhanced the disease control achieved with chemotherapy for some metastatic cancers, the appropriate subtype of breast cancer to treat with this combination is not yet clear.25,26
Bone Modifying Agents
Bone modifying drugs should be considered in women with metastatic breast cancer to bone, and/or presenting with hypercalcemia of malignancy. Patients should have necessary dental work done prior to initiating bone modifying agents to minimize the risk of osteonecrosis of the jaw.
Bisphosphonates have been shown to reduce the incidence of skeletal-related events in patients with metastatic breast cancer to bone. They reduce the rate and time to pathologic fracture, palliative radiation to bone, spinal cord compression, and need for surgical intervention, however they have not been shown to increase survival.27
Oral clodronate (BRAVCLOD
) and intravenous pamidronate (BRAVPAM
) are funded by BC Cancer for bone metastases. For hypercalcemia, iv pamidronate is recommended, with zoledronic acid as a second line agent if hypercalcemia is resistant to pamidronate. Zoledronic acid and denosumab (a RANK-ligand inhibitor) are also active in slowing the development of skeletal related events.28,29
The optimal duration of bisphosphonate therapy is not well defined30
, but the Breast Tumour Group recommends a treatment period of two to three years.
Acute pain syndrome
IV pamidronate 90-120 mg iv over 2-4 hours can also provide dramatic pain relief in cases of acute pain syndrome.31 It should be followed by appropriately dosed narcotic analgesics and treatment of underlying disease if possible. Repeat use of pamidronate may be considered if after 1 week there is clear but only partial relief of the pain despite aggressive analgesics.
- Chu KC, Tarone RE, Kessler LG, et al. Recent trends in US breast cancer incidence, survival, and mortality rates. J Natl Cancer Inst 1996;21:1571-1579
- Klijn JG, Beex LV, Mauriac L, et al. Combined treatment with buserelin and tamoixfen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 2000; 92(11):903-11
- Klijn JGM, Blamey RW, Boccardo F, et al. Combined Tamoxifen and Luteinizing Hormone-Releasing Hormone (LHRH) Agnosit versus LHRH Agonist alone in Premenopausal Advanced Breast Cacner: A Meta-Analysis of Four Randomized Trials. J Clin Onco 2001; 19 (2):343-53
- Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is Superior to Tamoxifen as First-Line Therapy for Adavanced Breast Cancer in Postmenopausal Women: Results of a North American Multicenter Randomized Trial. J Clin Oncol 2000; 18:3758-3767
- Mourisden H, Gershanovich M, Sun Y, et al. Superior Efficacy of letrozole verus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596-2606
- Paridaens RJ, Dirix LY, Beex LV et al. Phase III Study Comparing Exemestane With Tamoxifen As First-Line Hormonal Treatment of Metastatic Breast Cancer in Postmenopausal Women : The European Organisation of Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol 2008;26:1-8
- Lonning PE, Bajetta E, Murray R, et al. Activity of exemestane in metastatic breast cancer aftr failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Oncol 2000; 18:2234-2244
- Baselga J, Campone M, Piccart M, et al. Everolimus in Postmenopausal Hormone-receptor-positive Advanced Breast Cancer. NEJM 2012;366:520-9
- Chia S, Gradishar W, Mauriac L, et al. Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Armatase Inhibitor Therapy in Postmenopausal Women with Hormone receptor-Positive, Advanced Breast Cancer: Results From EFECT. J Clin Oncol 2008;26:1664-1670
- Robertson JFR, Llombart-Cussac A, Rolski J, et al. Activity of Fulvestrant 500mg versus Anastrozole 1mg as the first line treatment of Advanced Breast Cancer: Results from the FIRST trial. J Clin Oncol 2009;27: 4530-4535
- Slamon D, Leyland-Jones B, Shak S, et al. Use of Chemotherapy plus a Monoclonal Antibody for Metastatic Breast Cancer That Overexpresses HER2. NEJM 2001;344:783-92
- Marty M, cognetti F, Maraninchi D et al. Efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor recpetor 2 – positive metastatic breast cancer administered as first-line treatment: results of a randomized phase II trial by the M77001 study group. J Clin Oncol 2005;23:1-10
- Robert N, Leyland-Jones B, Asmar L, et al. Phase III comparative study of paclitaxel, trastuzumab and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2006;24:2786-92
- Anderson M, Lidbink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol 2011;29: 264-271
- Kaufman B, Mackey JR, Clemens M, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast caner: results from the randomized phase III TAnDEM study. J Clin Onco 2009;27:5529-5537
- Johnston S, Pippen Jr J, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009;27:5538-5546
- von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer : a German Breast Group 26/Breast International Groups 03-05 study. J Clin Oncol 2009;27:1999-2006
- Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43
- Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol 2012;30:2585-92
- O’Shaughnessy J, Miles D, Vukekja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002;20:2812-2823
- Chan S, Romieu G, Huober J, et al. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol 2009;27:1753-1760
- Albain KS, Nag SM, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2006;25:3950-3957
- Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) plymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer : a proof of concept trial. The Lancet 2010;376:235-244
- Baselga J, Cortes J, Kim S, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-19
- Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666-2676
- Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor 2-negative metastatic breast cancer. J Clin Oncol 2010;28:3239-3247
- Pavlakis N, Schmidt RL, Stocker MR. Bisphosphonates for breast cancer. Cochrane Library online publication 16 Jul 2008
- Rosen LS, Gordon DH, Dugan Jr W, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36-43
- Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized double-blind study. J Clin Oncol 2010;28:5132-5139
- Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline Update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011;29:1221-7
- Portenoy RK, Lesage P. Management of cancer pain. The Lancet 1999;353:1695-1700