|SYMPOSIUM - METASTATIC SPINAL TUMORS
|Year : 2022 | Volume
| Issue : 2 | Page : 145-149
Systemic therapies for the management of cancers with spinal metastases
Mohan Menon1, Gautam R Zaveri2
1 Department of Oncology, Lilavati Hospital, Mumbai, Maharashtra, India; Reliance Foundation Hospital, Mumbai, Maharashtra, India
2 Reliance Foundation Hospital, Mumbai, Maharashtra, India; Jaslok Hospital & Research Centre, Mumbai, Maharashtra, India
|Date of Submission||12-Aug-2021|
|Date of Decision||18-Sep-2021|
|Date of Acceptance||03-Jan-2022|
|Date of Web Publication||08-Jun-2022|
Gautam R Zaveri
Jaslok Hospital & Research Centre, 302 Bhaveshwar Kutir, 4th Road, Rajawadi, Ghatkopar East, Mumbai 400077, Maharashtra
Source of Support: None, Conflict of Interest: None
Management of spinal metastatic disease aims to improve the quality of remaining life in patients who have potentially limited survival. The treatment strategy necessitates multimodality, multidisciplinary involvement. Systemic therapies primarily aim to control systemic spread of the primary cancer. The armamentarium of systemic therapies includes traditional chemotherapy, bone-modifying agents, hormonal therapy, targeted molecular therapy, immunotherapy, and radioisotopes. The newer systemic therapies have resulted in a significant increase in overall survival of patients with metastatic disease. Consequently, treatment strategies must aim to achieve lasting local control of the spinal metastasis. The overall treatment strategy for an individual patient is planned based on a careful consideration of the anticipated survival, medical comorbidities, and the general condition of the patient.
Keywords: Overall survival, spinal metastases, systemic therapies
|How to cite this article:|
Menon M, Zaveri GR. Systemic therapies for the management of cancers with spinal metastases. Indian Spine J 2022;5:145-9
| Introduction|| |
Incremental developments in the management of primary cancer have led to prolongation of patient survival. Most cancers will eventually metastasize. After the lungs and liver, bones are the third most common site to develop metastases. The risk of bony metastases varies based on the site of origin of cancer. About two-third to three-fourths of advanced breast and prostate cancers develop bone metastasis. Similarly, about 30–40% of lung, thyroid, and kidney cancers also metastasize to bone. Bone involvement in the metastatic process is characterized by skeleton-related events (SREs) that include pathologic fractures, spinal cord compression, hypercalcemia, necessity for radiation or surgery to bone, and requirement for opiates. Within the skeletal system, the spine is the most common site for metastasis.
Mean overall survival varies from less than a year for those with bone metastases from lung carcinoma to several years for those with bone metastases from prostate, thyroid, or breast carcinoma. Patients who present exclusively with skeletal metastases have on an average a longer survival than those with visceral metastasis. Management requires a multidisciplinary team including orthopedic and spine surgeons, radiation oncologists, medical oncologists, and palliative care specialists. Communication between the team members especially regarding the expected response to systemic treatment, prognosis, and available surgical options will help arrive at optimal outcomes.
This review aims to provide an overview of current trends in systemic therapies for cancer and their influence on survival in patients with cancers.
| Systemic Treatments|| |
Systemic treatments can be broadly divided into agents that act only on the bone, and those that work on both osseous and non-osseous metastasis [Table 1]. Bone-modifying agents specifically reduce destruction of bone by inactivating osteoclasts. Agents that work on both osseous and non-osseous sites include modalities such as chemotherapy, targeted therapies, immunotherapy, and hormone therapy. These therapies aim to establish control of metastatic disease in the bone as well as the rest of the body, thereby improving progression-free survival and often overall survival. Additionally, these modalities can effectively contribute to palliation and pain relief by reducing tumor bulk and/or by modulating pain signaling pathways.
|Table 1: Modalities of treatments for bony metastasis classified by their foci of activity, viz, bone-specific vs systemic therapy that is not bone specific|
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Important considerations for choosing the modality of treatment are primary tumor type, disease extent, likelihood of response, its duration and treatment-related toxicity, and the presence or absence of biomarkers. Biomarkers are genes, proteins, or other substances that can provide information about the cancer. Each cancer has a unique pattern of biomarkers that may affect the choice of systemic treatment. For example, people with a cancer that has certain genetic changes in the epidermal growth factor receptor (EGFR) gene can be detected using biomarker testing. These patients are then targeted with an EGFR inhibitor. Biomarker testing for solid tumors is performed on tumor tissue, whereas testing for hematologic malignancies is done from blood or bone marrow samples.
Irrespective of the tissue of origin of the primary tumor, osteoclast activation is a key step in the establishment and growth of bone metastases. Biochemical data indicate that osteoclast-induced bone resorption is of importance not only in classic osteolytic diseases such as myeloma and breast cancer but also in osteoblastic lesions like prostate cancer. As a result, the osteoclast is a key therapeutic target for the prevention of skeletal metastases.
Bisphosphonates, which are analogues of pyrophosphate, are internalized by the osteoclast during bone resorption and subsequently cause apoptotic cell death of the osteoclast. Bisphosphonates bind avidly to exposed bone mineral and are subsequently retained there for months or years. Additionally, bisphosphonates have been shown to effectively alleviate localized bone pain in patients with spinal metastasis. Bisphosphonates have been shown to reduce the incidence of morbid SREs such as pathological fracture, spinal cord compression, and future bony metastases by 25–40%.
Orally administered bisphosphonates must be taken on an empty stomach and have poor bioavailability. Oral clodronate and ibandronate have been shown in randomized trials to have useful efficacy in breast cancer. Intravenous bisphosphonates such as zoledronic acid, pamidronate, and ibandronate show useful clinical activity against bony metastasis. In advanced breast cancer, zoledronic acid reduced the risk of SREs by an additional 20% as compared to pamidronate. Ibandronate is licensed in Europe for the treatment of metastatic bone cancer as monthly infusions to reduce SREs. Similarly, intravenous bisphosphonates have become routine clinical management for multiple myeloma, castrate-resistant prostate cancer, and bone metastases from solid tumors other than breast or prostate cancer.
Denosumab is a fully human monoclonal antibody that binds and neutralizes receptor activator of nuclear factor-kB ligand with a high affinity and specificity to inhibit osteoclast function and bone resorption. Denosumab causes rapid and sustained suppression of bone turnover in patients with multiple myeloma and breast cancer. Based on a randomized dose-finding study, a subcutaneous dose of 120 mg every 4 weeks is recommended.
Denosumab was shown to be significantly superior to zoledronic acid in the time to first SRE in trials encompassing a broad range of solid tumors. However, no differences in overall survival or investigator-reported disease progression were found between the two treatment groups in any of the studies.
The safety profiles of denosumab and zoledronic acid are different. Denosumab does not adversely affect renal function, eliminating the need for routine monitoring of renal function. Acute-phase reactions are also less common with denosumab, but hypocalcemia is more frequent. As a result, vitamin D deficiency should be corrected, and all patients should be encouraged to take calcium and vitamin D supplements throughout the course of their treatment.
Optimal use of bone-modifying agents
Despite the presence of metastatic bone disease, some patients do not experience a skeletal event, nor do bone modifying agents prevent every SRE. It is currently impossible to predict whether an individual patient needs or will benefit from treatment with a bisphosphonate. Because of the cost of delivering monthly treatments to all patients with metastatic bone disease and the side effects, certain empiric recommendations on who should receive treatment are needed. These include the underlying disease type and extent, the life expectancy of the patient, the probability of the patient experiencing an SRE, and the ease with which the patient can attend for treatment. The development of an SRE is not a sign of treatment failure or a signal to stop treatment. Bone-targeted treatments delay second and subsequent complications, not just the first event. Bone resorption markers such as N-telopeptide of type 1 collagen may be useful to identify patients at a high risk for skeletal complications. In addition, normalization of bone resorption is associated with improved clinical outcomes including fewer SREs and sometimes prolonged survival. The most important adverse event associated with denosumab and intravenous bisphosphonates in the oncology setting is osteonecrosis of the jaw. This occurs with similar frequency in patients treated with denosumab or zoledronic acid, affecting 0.5–1% of patients per year on treatment.
Traditional chemotherapy is cytocidal. It works by killing rapidly multiplying and growing cancer cells. This may result in destruction/slowing/stopping of cancer growth and spread. Additionally, shrinking of the tumor may provide alleviation of pain and relief of neural compression. Chemotherapy may be used prior to surgery or radiation (neoadjuvant chemotherapy) to reduce the size of the tumor or after surgery/radiotherapy (RT) (adjuvant) to destroy the remaining cancer cells.
The action of chemotherapeutic drugs is not specific to cancer cells alone. They also kill or slow the growth of healthy cells that divide rapidly, resulting in side effects such as mouth sores, nausea, and hair loss.
Chemotherapy regimens for metastatic disease are chosen based on the site of the primary cancer. Chemotherapy treatment of metastatic cancer to the bone usually mirrors treatment of other metastatic sites. Likelihood of a response to chemotherapy depends on the primary site. Cancers such as lymphomas respond well to chemotherapy, whereas others such as melanomas are relatively chemotherapy resistant both at the bone site and systemically.
Unlike chemotherapy that works by simply interfering with all rapidly dividing cells, targeted therapy blocks growth of the cancer by interfering with specific targeted molecules within cancer cells that are necessary for carcinogenesis and tumor growth. While chemotherapy is cytocidal, targeted therapy is cytostatic. Hence, the effect of targeted therapy lasts only until the treatment is continued or until the time when cancer cells develop resistance to the drug.
Targeted therapy can be either small molecules or monoclonal antibodies. Small molecules can easily enter the cancer cells and target molecules inside the cells. On the other hand, monoclonal antibodies get attached to specific targets found on cancer cells, making the cancer cells more visible to the immune system for destruction. Monoclonal antibodies act either by directly stopping the growth of cancer cells or by carrying toxins to the cancer cells, resulting in their destruction. Targeted therapies are used for systemic treatment of many cancers. They are usually combined with other systemic therapies.
Drugs that block the EGFR may be effective for stopping or slowing the growth of non-small cell lung cancer (NSCLC) when the cancer cells have EGFR mutations. Colorectal cancers too produce large quantities of EGFR, making them susceptible to targeted therapy. Another drug used for colorectal cancer blocks the vascular endothelial growth factor, the protein that stimulates angiogenesis within the tumor. Similarly, human epidermal growth factor receptor 2 (HER2)-positive breast cancers produce a protein called HER2, making them eminently suitable for targeted therapy.
Hormonal therapy is used to slow or even stop the growth and spread of cancers that depend on hormones for their growth. It functions by blocking the body’s ability to produce hormones or by interfering with the hormone function within the body.
Metastatic breast and prostate cancer are sensitive to hormonal suppression. Treatment with agents such as tamoxifen, aromatase inhibitors, and several newer agents helps to achieve disease control and palliation in breast cancer. Similar benefits are seen with suppression of testosterone in prostate cancer. In patients with breast cancer that has metastasized only to the bones, hormonal therapy is often the treatment of choice. This disease control can sometimes last many years. However, for many patients presenting with unfavorable features such as extensive disease burden with visceral as well as bone metastases, pain relief is usually not swiftly achieved with hormonal therapy. Such patients with a sufficient performance status may do better with chemotherapy alone or other systemic or local treatments in addition to the hormonal therapy.
Side effects of hormonal therapy include hot flashes, nausea, diarrhea, loss of interest in sex, mood swings, osteoporosis, fatigue, vaginal dryness, and enlarged, tender breasts in men.
Immunotherapy is a type of biological therapy that uses substances made from living organisms to bolster the immune system. An efficient immune system detects and destroys abnormal cancer cells, thereby curbing growth of the cancer. Different types of immunotherapies used for cancer treatment include immune checkpoint inhibitors, T-cell transfer therapy, monoclonal antibodies, immune system modulators, and treatment vaccines.
Agents targeting the programmed death-1 receptor/programmed death ligand-1 (PD-L1) pathway, also named immune checkpoint inhibitors (ICIs), have emerged as a powerful therapeutic strategy for the management of metastases secondary to several different cancers. Long-term survival had been reported in a group of patients with metastatic melanoma and NSCLC treated with ICIs., Although ICIs have shown significant efficacy in controlling visceral metastases, their specific efficacy in patients with bone metastases is not well understood. Among cancers most likely to have bony metastasis, ICIs have been approved for use in prostate, lung, and kidney cancers and triple-negative breast cancers. Likelihood of response to these agents can often be predicted by the level of PD-L1 expression in the cancer tissue, tumor mutation burden, and the presence of microsatellite instability.
The limitation of immunotherapy is that cancer cells can develop resistance to these medications over time. Additionally, side effects of immunotherapy may limit their usage. The common adverse effects include allergic reactions, skin reactions at the site of needle insertion, flu-like symptoms, fluid retention, diarrhea, and an increased risk of infections.
Systemic radioisotope therapy
Diffuse bone-only disease is seen in many patients with metastatic cancer. Systemic administration of a radioisotope can simultaneously target all bony lesions. Moreover, it can be administered as a single dose on an outpatient basis. Radium-223 is a calcium mimetic that preferentially targets bone metastases and emits high-energy alpha particles, resulting in highly localized cytotoxic effects with minimal myelosuppression. In a phase 3 trial of patients with symptomatic bone metastases from castrate-resistant prostate cancer, administration of radium-223 improved median overall survival by 3.6 months and significantly delayed the time to first symptomatic skeletal event. Strontium 89 and samarium 153 are other commonly used agents.
Steroids at appropriate doses are active components of chemotherapy regimens for treatment of lymphomas and myelomas. Steroids are also frequently utilized for palliation and short-term relief of biologic bone pain. They can be given parenterally and act within 24–48 h. A dose of 4–16 mg of dexamethasone is typically used in palliative pain management. In addition, glucocorticoids are helpful adjuncts for patients with somatic pain from bone metastases whose pain is incompletely resolved with opioids with or without nonsteroidal anti inflammatory drugs (NSAIDS) or for whom side effects are limiting. It is preferable to administer doses in the morning to avoid insomnia. After pain control is achieved, doses should be rapidly titrated down to avoid the numerous side effects of long-term steroids.
Systemic therapies and overall survival—The interplay with surgery
The improved overall survival among selected cancer patients with metastatic disease necessitates treatment strategies for more robust and lasting control of local spinal metastasis. Traditional paradigms for estimating anticipated survival and planning treatment strategies among patients with metastatic disease may no longer be uniformly applicable. Hence, it is vital to plan multimodality treatment strategies based on multidisciplinary consensus.
Systemic therapy for cancer is rapidly evolving. Newer drugs for controlling systemic spread of cancer are rapidly being introduced into the market. The newer therapies have resulted in a significant improvement in overall survival, disease-free survival, and progression-free survival among selected cancer types that possess a molecular target and are amenable to targeted therapy, immunotherapy, or hormonal therapy. Notable improvements in the systemic control of disease have been reported over the last decade among selected cancers arising from breast, prostate, kidney, lung, melanoma, colon, etc.
The impact of newer systemic therapy agents is classically highlighted by the improved survival of patients with advanced NSCLC. In the USA, patients diagnosed with NSCLC between 2010 and 2016 had a median survival of 7–11 months, with median survival of NSCLC that had metastasized to bone being only 150 days. The 5-year survival of stage 4 NSCLC was 7%. However, a dramatic improvement in median overall survival (22.3 months) and 5-year survival (23.2%) was reported in July 2019 by the KEYNOTE-1 trial using an immunotherapy agent, pembrolizumab, in treatment-naïve patients with locally advanced or metastatic NSCLC. These results were replicated in the phase 3 KEYNOTE-024 trial. The researchers reported a median overall survival of 26.3 months with a single agent pembrolizumab compared to 13.4 months with standard chemotherapy for patients with previously untreated metastatic PD-L1-positive NSCLC. The 5-year overall survival rate was estimated to be 31.9% in the immunotherapy group vs 16.3% with standard chemotherapy.
Similarly, significantly improved outcomes were seen in the phase 3 FLAURA trial with the use of targeted therapy for EGFR-positive NSCLC. Median overall survival of 38.6 months was reported with osimertinib, a targeted therapy agent, compared to 31.8 months with first-generation EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR mutation positive and previously untreated advanced NSCLC. The ALEX trial reported a clinically meaningful improvement in overall survival for stage 3 or 4, anaplastic lymphoma kinase (ALK)-positive NSCLC using a next generation ALK–TKI (alectinib). The median overall survival was 48.2 months and the 5-year overall survival was 62.5%. The above data reveal that median overall survival has possibly tripled or quadrupled in patients with stage 3 or 4 NSCLC, if amenable to targeted therapy.
Despite an ever-increasing armamentarium of effective treatments, control of metastatic disease is not always long lasting. Strategies include switching to a different treatment regimen or giving the patient a drug holiday. Under these circumstances, management of spinal metastasis becomes challenging. For patients presenting with spinal instability or epidural spinal cord compression, surgery may be indicated. However, the decision to operate must be tempered by the awareness that the perioperative morbidity and mortality are high in sick patients whose medical systems are failing. Also, the risk of local recurrence in the short term is higher and the overall survival is poorer for patients in whom systemic therapies are not effective. In these circumstances, an honest appraisal of the patient’s status and the possible success and failure of surgery must be discussed with the patient before making further treatment decisions.
| Conclusions|| |
SREs such as pain, pathological fractures, spinal instability, and spinal cord compression represent a major source of morbidity in patients with spinal metastases. Optimal management of SREs requires a multidisciplinary approach with effective communication between several specialties.
Advances in systemic therapy have allowed improved systemic control of the cancer, resulting in prolongation of overall survival. The proposed treatment strategy must therefore aim for durable (longer lasting) local control of the spinal metastasis using RT, surgery, or both.
On the other hand, patients in whom the systemic disease is not adequately controlled with systemic therapies have poorer long-term survival. This must be considered when planning a treatment strategy for local control of the spinal metastasis.
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Conflicts of interest
There are no conflicts of interest.
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