1.Overview
The incidence of bone metastases from breast cancer is 65% to 75%. Among the distant metastases of breast cancer, the first symptom is bone metastasis in 27%~50%. Bone pain, bone injury, bone-related events (SREs) and reduced quality of life are common complications of breast cancer bone metastases.
Bone related events include: increased bone pain or new bone pain, pathological fracture (vertebral fracture, non-vertebral fracture), vertebral compression, deformation, spinal cord compression, bone radiotherapy (due to bone pain or prevention of pathological fracture or spinal cord compression), progression of bone metastases (emergence of new or multiple bone metastases, expansion of existing bone metastases) and hypercalcemia.
2.Diagnostic methods of bone metastases
Bone radionuclide scan (ECT) is the initial screening diagnosis method for bone metastases. It has the advantages of high sensitivity, early detection and whole-body imaging, and is not easy to be missed. However, it also has the disadvantages of low specificity, not easy to distinguish osteogenic or osteolytic lesions, and cannot show the degree of bone destruction.
Bone ECT is recommended for routine primary screening of breast cancer with bone pain, fracture, elevated alkaline phosphatase, or hypercalcemia, and for further routine staging of breast cancer patients with stage >T3N1M0. Bone ECT is also selectively used for routine staging of breast cancer patients.
Magnetic resonance imaging (MRI), or CT scan, or X-ray is the confirmatory imaging test for bone metastasis. For patients with abnormal bone ECT scans, MR, or CT, or radiographs should be performed for suspected bone metastasis sites to confirm the diagnosis of bone metastasis and to understand the severity of bone destruction.
PET-CT (Positron Emission Computed Tomography) can directly reflect the glucose uptake by tumor cells, and clinical studies have shown that FDG-PET has similar sensitivity and higher specificity than bone scan, and is better than bone scan in the follow-up of breast cancer bone metastases after treatment. However, the expert group believes that the value of PET-CT in bone metastasis diagnosis needs further study and is not routinely recommended.
Therefore, for the clinical diagnosis of bone metastasis, ECT can be used as a primary screening test, while X-ray, CT, and MRI can clarify the presence of bone destruction, and the value of PET-CT needs further study.
For breast cancer patients with confirmed bone metastasis, further routine examinations should be performed: routine blood, creatinine, blood calcium and other liver and kidney functions and blood biochemical indexes; imaging examinations of chest, abdomen and pelvis.
3.Clinical manifestation of breast cancer bone metastasis
Bone metastasis of breast cancer is mostly seen as multiple osteolytic lesions. Some patients can be diagnosed as osteogenic changes after the repair of osteolytic lesions after treatment can be diagnosed as excessive calcification in imaging, and these patients should be traced whether there are osteolytic changes in their X-rays at the first consultation.
Characteristics of breast cancer bone metastasis: bone metastasis with pain seriously affects patients’ quality of life, but bone metastasis itself generally does not constitute a direct life threat; there are many effective treatment means, and patients without combined visceral metastasis have a relatively long survival period.
4.Treatment of bone metastases
4.1 Treatment goals
The main goals of comprehensive treatment for breast cancer bone metastases are
① Relieve pain, restore function and improve quality of life.
②Prevent and treat bone-related events.
③ Control tumor progression and prolong survival.
4.2 Treatment plan
Breast cancer bone metastasis, as recurrent metastatic breast cancer is already a systemic disease, the treatment options are: 1) chemotherapy, endocrine therapy, molecular targeted therapy, etc.; 2) bisphosphonate therapy; 3) surgery; 4) radiation therapy; 5) analgesia and other supportive treatments. An individualized comprehensive treatment plan should be developed according to the specific condition of the patient.
4.3 Treatment principles.
Systemic therapy is the main treatment, among which chemotherapy, endocrine therapy and molecular targeted therapy are used as basic drug therapy for recurrent metastatic breast cancer; bisphosphonates can prevent and treat bone-related events. Reasonable local treatment can better control the symptoms of bone metastasis, among which surgery is an active means to treat single bone metastasis lesion and radiation therapy is an effective local treatment.
The choice of treatment for recurrent metastatic breast cancer takes into account the hormone receptor status of the patient’s tumor tissue (ER/PgR), Her-2 results, age, menstrual status, and whether the disease is progressing slowly. In principle, endocrine therapy is preferred for hormone-responsive breast cancer patients with slow disease progression, chemotherapy is preferred for patients with recurrent metastases with rapid disease progression, while treatment with trastuzumab alone or in combination can be considered for patients with Her-2 overexpression.
Characteristics of recurrent metastatic breast cancer with slow progression: 1. ER-positive and/or PR-positive tumor tissue in primary and/or recurrent metastases; 2. Patients with recurrent metastases with long disease-free survival after surgery (e.g. recurrent metastases after 2 years after surgery); 3. Only soft tissue and bone metastases, or visceral metastases without obvious symptoms (e.g. non-diffuse lung metastases and liver metastases with small tumor load and non-life-threatening Other visceral metastases).
The concept of Hormoneresponsive Breast Cancer (HBC) defines patients who are suitable for endocrine therapy based on their potential benefit from endocrine therapy, and considers that patients who meet one or more of the following conditions are likely to benefit from endocrine therapy: 1. positive ER and/or PR for primary and/or recurrent metastases; 2. elderly patients; 3. Longer interval; 4. Previous benefit from endocrine therapy.
Based on the fact that breast cancer bone metastasis itself generally does not constitute a direct life threat, and patients without combined visceral metastasis have a relatively long survival, unnecessary and intense chemotherapy should be avoided as much as possible. In contrast, long-term disease stabilization after treatment for patients with advanced breast cancer should be considered a clinical benefit, as patients with sustained stability for more than 6 months have the same survival as CR+PR. Based on the fact that endocrine therapy is more suitable for long-term use, the duration of treatment dosing can be maximized to prolong disease control.
In postmenopausal recurrent metastatic breast cancer, the first choice of first-line endocrine therapy is third-generation aromatase inhibitors, including anastrozole, letrozole, and exemestane, because third-generation aromatase inhibitors are more effective than megestrol in the second-line treatment of recurrent metastatic breast cancer that has failed triamcinolone therapy.
In first-line endocrine therapy for recurrent metastatic breast cancer, the next-generation aromatase inhibitors are significantly superior to triamcinolone. Chemotherapy is preferred for premenopausal patients with recurrent metastatic breast cancer, and pharmacologic ovarian function inhibition combined with an aromatase inhibitor is indicated when an aromatase inhibitor is appropriate or needed as endocrine therapy.
Patients with bone metastases from breast cancer should be considered for chemotherapy if they are ER and PR negative, have a short disease-free postoperative interval, have rapidly progressing disease, have combined visceral metastases, and are unresponsive to endocrine therapy. Drugs recommended for chemotherapy of metastatic breast cancer include: anthracyclines, paclitaxel, cabergoline, vincristine, gemcitabine.
The following chemotherapy regimens are available: CMF, CAF, AC, AT, XT, and GT regimens. Patients treated with endocrine therapy only without chemotherapy can choose CMF (CTX/MTX/5-FU) or CAF (CTX/ADM/5-FU)/AC (ADM/CTX) regimens for adjuvant therapy.
The AT regimen (anthracycline combined with paclitaxel) is preferred for patients who have not used anthracycline and paclitaxel chemotherapy for adjuvant therapy, such as patients who have failed adjuvant chemotherapy with CMF; the AT regimen can also be used for some patients who have used anthracycline and/or paclitaxel chemotherapy for adjuvant therapy but have not been clinically determined to be resistant and have failed treatment. For patients who have failed anthracycline adjuvant therapy, the following regimens are available: XT (cabergoline combined with doxorubicin) and GT (gemcitabine combined with paclitaxel) regimens.
For patients who fail paclitaxel therapy, there is no standard regimen recommended, and the drugs that can be considered are cabergoline, vincristine, gemcitabine and platinum, which can be used as single agent or combined chemotherapy, but patients with simple bone metastases should not take combined chemotherapy.
4.4 Radiation therapy
Radiotherapy is an effective method for palliative treatment of breast cancer bone metastases. Bone pain is a common symptom of bone metastasis, and it is also the main reason affecting patients’ quality of life and mobility; the risk of pathological fracture complicating bone metastasis in weight-bearing parts such as spine and femur is about 30%, and pathological fracture will significantly affect patients’ survival quality and survival time.
The main role of radiotherapy in the treatment of breast cancer bone metastases is to relieve bone pain and reduce the risk of pathological fracture. Radiation therapy includes two types of treatment: extracorporeal irradiation and radionuclide therapy.
Extracorporeal irradiation is a common and effective method for palliative treatment of bone metastases. The main indications for extracorporeal irradiation are: symptomatic bone metastases for pain relief and restoration of function; selective prophylactic radiotherapy for weight-bearing bone metastases, such as spine or femoral metastases.
The common doses and segmentation methods of external irradiation for radiation therapy of bone metastases are three protocols: 300 cGy/dose for 10 times; 400 cGy/dose for 5 times; and 800 cGy/dose for a single irradiation. There was no significant difference in the efficacy and tolerability of the three methods of irradiation for the relief of bone pain. The treatment cost of the single-radiation regimen was significantly lower than that of fractionated irradiation, but the incidence of reirradiation and pathological fracture was higher than that of fractionated irradiation. The single-shot irradiation technique for bone metastases is particularly suitable for patients with advanced cancer who have difficulty moving and mobilizing.
Radionuclide therapy is effective in relieving pain in generalized bone metastases, but the high incidence of bone marrow suppression and slow recovery after some radionuclide therapy, which takes about 12 weeks, may affect the delivery of chemotherapy. Therefore, the clinical use of radionuclide therapy should be fully considered to select appropriate cases and proper timing.
The efficiency of radiotherapy for relieving bone pain ranges from 59% to 88%. It is worth noting that it takes some time for radiotherapy to be effective in relieving bone pain, therefore, for patients before radiation therapy is apparently effective, and for patients whose pain cannot be completely controlled by radiation therapy, it is still necessary to use analgesics according to the patient’s pain level, as well as the necessary bisphosphonate therapy, which can be used in loading doses.
4.5 Surgical treatment
The purpose of surgical treatment of bone metastases is to improve patients’ quality of life. The progress of bone surgery technology can enable patients with cancer bone metastases to solve the compression of nerves, reduce pain and restore limb function to the maximum extent, thus improving patients’ quality of life. Close follow-up and observation of patients with bone metastases, early detection of bone metastases, and proper judgment of whether surgery is needed for long bones with potential pathological fractures are important to improve patients’ quality of life.
Surgical treatment of bone metastases from breast cancer includes: fixation of bone injury, replacement and nerve release. Fixation treatment can be considered selectively for patients with pathological fracture or spinal cord compression with breast cancer bone metastases with expected survival time >4 weeks. Prophylactic fixation treatment can be considered electively for patients with bone metastases from breast cancer with femoral metastases >2 or 5 cm in diameter, or femoral neck bone metastases, or bone cortical destruction >50%, and expected survival time >4 weeks.
4.6 Analgesic treatment
Analgesics are the main method to relieve the pain of breast cancer bone metastasis. Analgesic treatment of bone metastasis pain should follow the basic principles of WHO’s three-step cancer pain relief guidelines: preferred oral and non-invasive routes of administration; administration by step; timely administration; individualized administration; and attention to specific details.
Analgesic drugs include NSAIDs, opioid analgesics, and adjuvant medications.
Commonly used NSAIDs include: acetaminophen, ibuprofen, diclofenac sodium, indomethacin, naproxen, celecoxib, cronoxicam, etc.
Commonly used opioid analgesics include: morphine extended-release tablets, fentanyl transdermal patches, oxycodone controlled-release tablets, morphine immediate release tablets, codeine, methadone, etc. Pethidine should not be used for cancer pain treatment.
Adjuvant drugs include tricyclic antidepressants, anticonvulsants, neuroleptics, glucocorticoids, etc.
Non-steroidal anti-inflammatory drugs are the basic drugs for pain management of bone metastases. When the pain relief is not effective, or when moderate to severe pain occurs, the combination of opioid analgesics is recommended. The choice of opioid extended-release agents for timely dosing facilitates sustained relief of bone pain. However, approximately 63% of patients with painful bone metastases have sudden (flare-up) pain in conjunction with persistent chronic pain.
For patients with frequent episodes of sudden pain, pain relief can be achieved by increasing the on-time dose of pain medication. In a minority of patients, pain cannot be controlled by increasing the dose of pain medication on schedule, or even by increasing the dose of medication on schedule because of intolerable adverse drug reactions. The primary method of controlling sudden onset pain is to use a backup of fast-acting or short-acting analgesics. The single dose of short-acting analgesics for sudden pain control is usually 5%-10% of the daily dose.
For patients with refractory sudden-onset pain, the use of patient-controlled drug pumping may be considered. In case of neuropathic pain, adjuvant medication should be selected according to the condition. For example, if burning pain or cramping pain is present, amitriptyline, nortriptyline, or tricyclic antidepressants such as doxepin may be used; if electric shock-like pain or shooting pain is present, anticonvulsants such as gabapentin or carbamazepine may be used. Painkillers can be combined with bisphosphonates and radiotherapy.
5.Expert consensus on the clinical application of bisphosphonates for breast cancer bone metastases
5.1 Commonality and individuality of bisphosphonates
Principle of action: Bisphosphonates are stable analogues of pyrophosphonate molecules. After osteoclasts aggregate in mineralized bone matrix, they lead to bone resorption through enzymatic hydrolysis, and bisphosphonates can inhibit osteoclast-mediated bone resorption.2 Bisphosphonates can inhibit osteoclast maturation, inhibit the function of mature osteoclasts, inhibit the aggregation of osteoclasts at the site of bone resorption, and inhibit the spread, infiltration and adhesion of tumor cells to the bone matrix.
Indications
1) Hypercalcemia;
2)Bone pain;
3) Treatment and prevention of bone-related events (SREs). Bone related events (SREs) have a critical impact on the quality of life of patients with bone metastases from breast cancer and include pathological fractures, spinal cord compression, radiotherapy to relieve bone pain or to prevent and treat pathological fractures or spinal cord compression, skeletal surgery, changes in anti-cancer regimens to treat bone pain, and hypercalcemia from malignancy. The current use of bisphosphonates in breast cancer bone metastases is aimed precisely at reducing the incidence of SREs.
Clinical studies have confirmed the effectiveness of bisphosphonates in the treatment of bone metastases from breast cancer. As recommended by the UK National Institute for Clinical Recommendations for Treatment Options (NICE), these drugs are now being widely used to treat bone complications of advanced breast cancer. And subsequent clinical studies have demonstrated that bisphosphonates can prevent bone-related events (SREs) in patients with bone metastases from breast cancer.
Therefore, breast cancer bone metastases with expected survival ≥ 3 months and creatinine less than 3,0 mg/dL should be promptly treated with bisphosphonates along with the chemotherapy and hormonal therapy required to treat the disease.
The clinical activity and efficacy of bisphosphonates vary depending on the side chain attached to the central carbon atom in the chemical structure of bisphosphonates.
The first generation of bisphosphonates is represented by clodronate, which entered clinical use 30 years ago.
Dosage and Administration: Disodium clodronate, oral 1600 mg/day 3C for 4 weeks; disodium clodronate is mainly cleared by the kidneys; therefore, it is important to maintain adequate water intake during disodium clodronate therapy Disodium clodronate capsules should be swallowed whole. A single daily dose of 1600 mg is recommended; if the daily dose is higher than 1600 mg, the excess is recommended to be administered as a second dose in divided doses. Under no circumstances should clodronate be taken with milk, food or medication containing calcium or other divalent cations as they will reduce the absorption of clodronate.
The second generation are nitrogen-containing bisphosphonates, including disodium pamidronate and alendronate, which have a stronger effect on inhibiting bone resorption than the first generation drugs.
Dosage and administration: pamidronate 60-90mgiv>2h1/3C4 weeks;
The third generation is zoledronic acid, a nitrogen-containing bisphosphonate with a heterocyclic structure, and ibandronate, which does not contain a cyclic structure containing nitrogen, which has further improved than the second generation in terms of strength of action and efficacy.
Dosage and Administration.
Zoledronic acid 4 mgiv>15 min for 1/3-4 weeks.
Ibandronate 6mgiv>15 minutes for 1/3-4 weeks.
1. Ibandronic acid for metastatic bone disease.
Conventional dose: 6mg IV every 3-4 weeks for no shorter than 15 minutes for 1/3-4 weeks.
2. LoadingDose of ibandronate: Loading dose of ibandronate can provide rapid relief to patients with metastatic bone pain with severe pain, use: 6mg/day for 3 consecutive days, then 6mg/time every 3-4 weeks.
Ibandronic acid is currently available in two kinds of formulations, intravenous and oral, and the efficacy of 6mg of Ibandronic acid by intravenous drip and 50mg of Ibandronic acid by oral drip are comparable, and the oral formulation of bisphosphonates can be used conveniently at home or in combination with oral chemotherapy drugs and endocrine drugs.
5.2 Indications for the use of bisphosphonates and timing of administration.
Expert opinion recommends the use of bisphosphonates does not recommend the use of bisphosphonates
Hypercalcemia caused by bone metastases√
Bone pain due to bone metastasis √
Abnormal ECT, X-ray (or CT, or MRI) confirmed bone metastasis √
Abnormal ECT with normal X-rays, but CT or MRI showing bone destruction
Imaging diagnosis of bone destruction, even without symptoms of bone pain √
Abnormal ECT with normal X-rays and no bone destruction on CT or MRI √
Patients at risk of bone metastasis (high lactate dehydrogenase or elevated alkaline phosphatase) √
5.3 Use of bisphosphonates and precautions.
(1) Before using bisphosphonates, patients’ serum electrolyte levels should be tested, focusing on blood creatinine, serum calcium, phosphate, and magnesium.
(2) Clinical studies have shown that first-generation clodronate, second-generation pamidronate and third-generation zoledronic acid and ibandronate, all have the effect of treating bone metastases from breast cancer. All can be used to treat hypercalcemia, bone pain, prevention and treatment of bone metastasis related events. The results of clinical studies have shown that the third-generation bisphosphonates, zoledronic acid and ibandronate, have the advantages of better efficacy, lower toxicity and ease of use.
(3)) The choice of drug therapy should take into account the patient’s general condition and overall disease, and concurrent treatments received. Intravenous use of zoledronic acid and ibandronate has the advantage of shorter infusion times.
(4) Bisphosphonates can be used in combination with radiotherapy, chemotherapy, endocrine therapy, and analgesics.
(5) Long-term use of bisphosphonates should be noted with daily calcium supplementation of 500mg and vitamin D.
(6) No dose adjustment is required in patients with mild to moderate renal insufficiency (creatinine clearance > 30 ml/min), but patients with severe renal insufficiency (creatinine clearance > 30 ml/min) should have dose adjustment reduction or extended infusion time according to the instructions of different products.
(7) In view of the risk of osteonecrosis of the jaw in a few patients after long-term use of bisphosphonates, attention should be paid to oral examination and daily oral cleaning before using bisphosphonates, and oral surgery, including tooth extraction, should be avoided as far as possible during the drug administration.
5.4 Dosing time and discontinuation indications.
(1) Duration of medication: Studies have proven that the median time to bone-related events for bisphosphonates used in breast cancer is 6 to 18 months, so the duration of medication should be at least 6 months.
(2) Indications for discontinuation.
Adverse reactions monitored during use and clearly related to bisphosphonates;
Tumor deterioration during treatment, metastasis to other organs and life-threatening;
When deemed necessary by the clinician ;
But after other treatment bone pain relief is not an indication for discontinuation.
5.5 Biochemical markers.
There are some biochemical markers that may help physicians understand the patient’s response to bisphosphonate therapy – but they are currently limited to the scientific field and are not recommended for clinical use.
5.6 Clinical data and expert opinion.
(1) The role of bisphosphonates in preventing bone metastases
Clinical studies of bisphosphonates for the prevention of bone metastases are still ongoing, although studies have suggested that bisphosphonates may have a role in the prevention of bone metastases and may potentially have a role in the prevention of visceral metastases. Therefore, however, bisphosphonates are not currently recommended for patients without imaging evidence of bone metastases, nor for patients who present with extraosseous metastases but no evidence of bone metastases.
(2) Bisphosphonates as adjuvant therapy after breast cancer surgery
In vitro studies have shown that bisphosphonates have antitumor effects, but clinical studies are still in progress. Although some small sample studies have demonstrated that the risk of bone metastasis and even visceral metastasis can be reduced with the addition of bisphosphonates after standard radiotherapy, chemotherapy and endocrine therapy after breast cancer surgery, large-scale studies have not been completed, therefore, bisphosphonates are not recommended as adjuvant therapy after breast cancer surgery at present.
(3) Antitumor therapy-induced bone loss (CTIBL) in breast cancer patients
CTIBL (CancerTreatment-inducedBoneLoss) is a clinical problem that should be taken seriously and can occur in elderly patients, after chemotherapy, after hormonal therapy, especially ovarian suppression and aromatase inhibitor therapy, and according to ASCO bone health guidelines, bone mineral density (BMD) should be measured and Consider the use of bisphosphonate drugs based on the results.