Palliative Therapy of Bone Metastases

Abstract

This chapter overviews palliative treatment modalities for patients with bone metastases. In the introduction section, the origin of bone metastases and complication of metastatic patients have been discussed. Then, the main body explains treatment modalities including pain relievers, bisphosphonates, surgery, external beam radiotherapy, and targeted radionuclide therapy for pain palliation of patients with bone metastases.

1. Introduction

1.1 Bone metastasis

Bone is one of the most common sites of metastasis in cancer patients [1]. Bone tissue consists of living cells located in an extracellular matrix composed of minerals (Figure 1). This extracellular matrix is ​​composed of organic matter, mainly type 1 collagen, and inorganic matter, including calcium and phosphate. Calcium and phosphate combine to form hydroxyapatite crystals in bone tissue [3]. Bone cells include three types of cells: osteoblasts, osteoclasts, and osteocytes. Osteoblasts, known as bone-forming cells, are located along the surface of the bone and play a role in bone formation. Osteoclasts, also known as bone-eating cells, contain multinucleated cells that are formed from hematopoietic stem cells under the influence of several factors and play the role of bone resorption. The location of these cells is also on the surface of the bone. Osteocytes contain 90–95% of bone cells derived from osteoblast cells that are surrounded by extracellular matrix and play a structural role [2, 4].

Figure 1.

Cells located in the bone matrix (B): Osteoblast (Ob), osteoclast (Oc), and osteocyte (Ot) cells [2].

Bone metastasis occurs due to a complex pathophysiological process between cancer cells and bone cells that stimulates bone formation or resorption activity. Bone metastasis occurs in people with cancer that started outside the bone. In this case, the cancer cells are isolated from the original site and reach the peripheral areas mainly through venous blood flow, and if the conditions are provided for the growth and proliferation of these cells in the target tissue, they metastasize there [5].

Communication between tumor cells and hematopoietic stem cells is essential for the formation of bone metastases. Bone is the third most common tissue that hosts cancer cells from other tissues. Liver and lung metastases usually do not cause symptoms until the patient is advanced. However, bone metastases in patients are very painful and are usually diagnosed earlier. The source of most bone metastases is breast, prostate, lung, thyroid, and kidney cancers [6, 7, 8].

The risk of bone metastasis varies in different cancers. For example, 70% of patients with breast and prostate cancer develop bone metastases, while the rate of bone metastases in patients with gastrointestinal cancer is between 3 and 15% [4]. Also, the most common sites of bone metastasis include the bones of the spine, pelvic, ribs, humerus, and femur [9].

1.2 Bone remodeling

Bone tissue is normally constantly renewed and replaced, meaning that osteoclasts absorb old bone and osteoblasts build new bone. This process is called bone remodeling. Normally, these two processes are in balance with each other. Any abnormality in the function of osteoblast and osteoclast cells can cause this balance to be lost, resulting in a change in the resorption or formation of bone by these cells. Bone metastasis is one of the factors that upset this balance. Bone metastases are divided into three types: osteoblastic, osteolytic, or a combination of both [10, 11, 12].

1.3 Osteoblastic and osteolytic metastases

The origin of various osteoblastic and osteolytic metastases is not yet well understood. Osteoblastic metastasis occurs when, under certain factors, the bone formation activity of osteoblast cells exceeds the bone-eating activity of osteoclast cells, and bone formation becomes greater than bone resorption. Osteolytic metastasis also occurs when the activity of osteoclasts exceeds that of osteoblasts and bone resorption becomes greater than bone formation [11, 12].

Most metastases are osteolytic. Patients with primary prostate cancer develop osteoblastic metastases. Also, most of the metastases that are the primary source of breast, thyroid, and kidney cancers are osteolytic. Although patients with breast cancer are more likely to develop osteolytic metastases, between 15% and 20% of patients develop osteoblastic metastases or a combination of both.

1.4 Complications of bone metastases

Patients with bone metastases are at risk for bone symptoms and complications such as severe pain, hypercalcemia, bone fractures, pressure, and damage to nerve structures such as the spinal cord [13, 14].

Many bone metastases are asymptomatic and are often discovered accidentally on initial examination or follow-up. In symptomatic cases, pain is the most common symptom. The quality of pain varies from point pain to shooting pain. Involvement or invasion, stretching, or pressure on pain-sensitive structures such as nerves, arteries, and small fractures can lead to pain. Pain due to bone metastases can also be due to mechanical instability in the weakened bone or high intraosseous pressure [15]. Although many factors can cause pain in bone metastases, the major part of the pain is related to bone resorption by osteoclast cells in osteolytic metastases. The pain often intensifies at night and during activity, but direct local invasion and fractures cause persistent pain. Pathological fractures are often seen in osteolytic metastases. Hypercalcemia occurs in 10% of patients and is more common in breast and lung cancers [16].

2. Palliative therapy of bone metastases

2.1 Treatment modalities of bone metastases

Because people with bone metastases live longer than other visceral metastases, finding the right treatment and dealing with the complications of bone metastases are very important in oncology. The goals of treatment for bone metastases include maximizing pain control, maintaining limb function, maintaining bone stability, and local control of the tumor. There are several treatments for bone metastasis and its associated effects, including the use of pain relievers, bisphosphonates, surgery, external beam radiotherapy, and targeted radionuclide therapy [13, 17].

2.2 Pain relievers

Treatment with pain relievers is the first line of treatment for bone metastases. Common medications for pain relief from bone metastases are based on World Health Organization (WHO) guidelines. If the pain is mild, the main treatment is nonsteroidal anti-inflammatory drugs or acetaminophen. Tramadol can be used in the second line of treatment in cases of moderate pain, and in the next step, if the pain is not controlled, drugs can be used. Drugs relieve pain with short-term effects such as oxycodone and hydromorphone [18].

2.3 Surgery

Another treatment for bone metastases is surgery. Most people with bone metastases without bone fractures do not need surgery. If a pathological fracture occurs, the first step in surgery is to fix the fracture site. Preventive surgery is mostly used in metastases with a high probability of fracture in tall bones that support the weight of the body. Vertebroplasty is another method of reducing pain for those patients with vertebral fractures that do not put pressure on the spinal cord but have severe pain [19].

The affected bone should be radiographed and scanned with radionuclides before surgery. Radiotherapy is used to treat every other metastatic lesion that may develop into a pathological fracture after these measures are taken. If methylmethacrylate is used to fix a plate or nail in the bone, a pathological fracture will be more difficult to treat than if there were no implant.

Usually, radiotherapy is the only modality likely to restore mobility and relieve pain in pathological fractures of long bones. For primary internal stabilization of long bones, radiotherapy is the treatment of choice. Even though radiotherapy might control local tumors, it is unlikely that a pathological fracture will heal without treatment. A large area of bone destruction could result in an insufficient matrix for adequate fracture healing, as radiotherapy inhibits chondrogenesis.

2.4 Bisphosphonates

Another treatment is the use of bisphosphonates. Bisphosphonates prevent bone destruction by causing apoptosis in osteoclast cells and inhibiting the activity of these cells in osteolytic metastases. In patients with bone metastases with increased blood calcium, the use of bisphosphonates with adequate hydration is standard treatment. Bisphosphonates are excreted by the kidneys and should not be used by kidney patients [20, 21]. The bisphosphonate zoledronic acid induces apoptosis of osteoclasts and reduces the risk of skeletal-related events. As a result of large randomized controlled trials, bisphosphonates have become the standard of care for treating and preventing skeletal complications associated with bone metastases in patients with solid tumors or multiple myeloma [22]. In these studies, the primary endpoint was how bone-targeted treatment affected the number of patients experiencing skeletal-related events (SREs), the rate of SREs, and the time before the first SRE.

Patients with malignant bone diseases can benefit significantly from early-generation bisphosphonates, such as sodium clodronate and disodium etidronate. The bisphosphonates are metabolized by osteoclasts into non-hydrolyzable, cytotoxic ATP analogs, which have the effect of directly inducing apoptosis and impair mitochondrial function.

Bisphosphonates containing nitrogen inhibit the enzyme farnesyl diphosphate synthase, in contrast to the early-generation bisphosphonates. As a result, osteoclasts cannot function properly and are less able to resorb bone. There are several nitrogen-containing bisphosphonates, including disodium pamidronate, alendronic acid, ibandronate sodium, risedronate sodium, and zoledronic acid. As a result of their introduction in clinical trials, these agents showed dramatic improvements in therapeutic activity [23, 24].

2.5 External radiotherapy

In relieving painful bone metastases, external beam radiotherapy is the most common palliative method used among oncology treatments and provides a very effective treatment to reduce the symptoms of local pain. Radiation therapy helps control pain by destroying tumor cells and eliminating existing inflammation, as well as increasing the ossification of osteolytic lesions. However, the most important disadvantage of external radiotherapy is the exposure of healthy tissues to radiation and unnecessary absorbed dose in these tissues, which can lead to acute complications [25]. In terms of relieving bone pain, local irradiation is without doubt effective. Approximately 85% of patients report complete relief of pain, with half reporting complete relief. Within 1–2 weeks, more than half of responders experience pain relief. Improvement in pain is unlikely to occur if it hasn't been achieved by 6 weeks or more after treatment [26]. It is common to use single treatments or short fractionation schedules in Canada and Europe rather than prolonged fractionated treatments in the United States. Treatment techniques and doses have varied considerably throughout history, with prolonged fractionated treatments preferred in the United States. Fractionation schedules have been compared in a number of randomized trials. The pain relief offered by each approach was not superior. According to several studies, fractionated vs. single treatments do not differ in toxicity, pain response, analgesic consumption, adverse effects, or quality of life when compared with single treatments, including a large Dutch study of 1157 patients with painful bone metastases. 76 No statistically significant differences were found for pain response, analgesic consumption, treatment adverse effects, or quality of life [27].

After a meta-analysis comparing single fraction versus multiple fractions, it was revealed that both single fraction and multiple fractions achieved similar symptomatic responses; 1011 of 1391 (73%) receiving a single fraction and 958 of 1321 (73%) receiving multiple fractions. thus, for many patients suffering from painful bone lesions, single-fraction radiotherapy is a viable treatment option [28].

2.6 Targeted radionuclide therapy

Systemic therapy with appropriate radionuclide has been accepted as a common treatment modality for patients with various bone metastases [29]. In this treatment, radionuclides are combined with targeted agents with the aim of specific uptake into bone tissue. Radiopharmaceuticals have several advantages over local radiotherapy over topical radiation therapy: they can be administered intravenously, they can target very small metastases (micro-metastases), they can treat several separate affected areas at the same time, and they have fewer side effects, including they cause nausea, vomiting, diarrhea, and tissue damage [30]. However, in this type of treatment, the bone marrow as a critical organ receives a dose, and the absorbed dose of the bone marrow needs to be considered as a limiting factor in treatment [31, 32].

Beta-emitters were found to have a response rate of 70% in a systematic review that included 57 studies. Not only does radionuclide-targeted therapy alleviate pain, but it reduces or defers the incidence of skeletal-related events (SRE). Ionizing radiation is delivered to areas with increased osteoblast activity using these agents, which substitute calcium or bind to hydroxyapatite in bones. Radiation should be targeted at metastatic foci while sparing non-affected tissues to the maximum extent possible. In order to achieve the best results, many radiopharmaceuticals have been studied.

Physicians choose appropriate radiopharmaceuticals based on a number of factors, such as metastatic disease extent, renal function, bone marrow reserve, and availability.

2.7 Radionuclides used to relieve bone metastases

Common radionuclides for the treatment and relief of pain from diffuse bone metastases include Phosphorus-32, Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Lutetium-177, and Radium-233. The first radionuclide used for this purpose was Phosphorus-32, which is currently rarely used due to the high energy and consequent high range of emitted beta-particles and the unacceptable absorbed dose in the bone marrow. Rhenium-186 has been approved in Europe, while Rhenium-188 and Luteinium-177 are still being studied as promising radionuclides [33, 34]. Currently, Cerium-141 is being studied as a new promising beta-emitter radionuclide [35, 36].

Radium-223 has also recently been approved by the Food and Drug Administration (FDA) as an alpha radionuclide for those patients with bone metastases without visceral metastases [37, 38]. Patients treated with Ra-223 survived 3.6 months longer and experienced reduced skeletal morbidity compared with those treated with a bisphosphonate. There were no significant side effects associated with Ra-223, which improved QOL. Ra-223 is now being investigated in both endocrine and cytotoxic combinations, after it was approved for use in late-stage disease [39, 40]. Today, Samarium-153 and Strontium-89 are the most widely used radionuclides for bone metastases that are approved by the Food and Drug Administration and have decades of clinical use [41, 42].

Radionuclides are routinely administered in clinical practice as monotherapies. However, radionuclides have been studied in conjunction with other therapies, specifically for prostate cancer. An early study reported an 11-month increase in survival rates if Strontium-89 was added to chemotherapy with doxorubicin [43]. A follow-up study combined beta-emitting bone agents with chemotherapy made in response to this encouraging result. Cancer patients who are castrate-resistant to chemotherapy may benefit from docetaxel because it relieves their pain and improves their quality of life [44]. Strontium-89 combined with docetaxel was found to be a safe combination for concomitant administration in a phase I study [45]. According to Fizazi et al. [46], Sm-153-EDTMP was studied in combination with docetaxel in a single-arm phase II trial. Comparing this study with reference data, the authors reported that the treatment was well tolerated and resulted in an improved overall survival rate. Monoclonal antibodies are used to treat osteoclastic diseases including denusomab. The combination of denusomab with Ra-223 was found to be more effective than Ra-223 alone in reducing symptoms of skeletal events [47].

2.8 New targeted agents for palliative therapy of bone metastases

A number of new targeted agents are being developed as we gain a deeper understanding of the signaling mechanisms between bone cells and tumor cells. The agents include cathepsin K inhibitors (an osteoclast-derived enzyme that is involved in bone resorption), an antibody against PTHrP, Src kinase inhibitors (a key molecule in osteoclastogenesis), and various anabolic agents. As time goes on, it will be possible to learn how these agents can be used to prevent and treat bone metastases.

3. Conclusions

Patients' quality of life is greatly affected by bone metastases. Therefore, prevention and treatment of skeletal metastases require new strategies. New therapeutic strategies can be expected as our understanding of bone metastases evolves. It is possible to further reduce the clinical burden of metastatic bone disease by combining bone-targeted therapies.

Conflict of interest

The author declares no conflict of interest.