Bone metastases represent a significant clinical concern in oncology, affecting a large percentage of cancer patients, particularly those with advanced stages of solid tumors. The most common cancers that metastasize to bones include breast, prostate, lung, and kidney cancers. Bone metastases are associated with a variety of debilitating symptoms, including pain, fractures, and impaired mobility, which can significantly affect a patient's quality of life. Pain is the hallmark symptom of bone metastasis, with a substantial portion of patients requiring palliative treatments to manage it effectively. Radiation therapy has long been recognized as a cornerstone in the treatment of metastatic bone pain, offering symptomatic relief by reducing tumor burden and alleviating pain.1 However, while radiation therapy can be highly effective in providing pain relief, it is not without its challenges. One of the most notable side effects of palliative radiotherapy for bone metastases is the phenomenon known as radiation-induced pain flare (RIPF). This term refers to a transient increase in pain following radiation therapy, typically occurring within 24 to 72 hours after treatment. The mechanism behind RIPF is still not entirely understood, but it is believed to be related to the inflammatory response induced by radiation, which may exacerbate existing pain or trigger new pain pathways in the affected bones. For many patients, RIPF can be a distressing experience, as it can complicate the management of their symptoms and delay the anticipated pain relief from radiation therapy.2 Given the impact of RIPF on patient well-being, various strategies have been explored to prevent or minimize its occurrence. One such approach involves the use of corticosteroids, specifically dexamethasone. Dexamethasone, a synthetic corticosteroid, is widely recognized for its anti-inflammatory and analgesic properties. It has been used in a variety of clinical contexts, including cancer treatment, to reduce inflammation and control symptoms related to swelling and pain. In the case of radiation-induced pain flare, dexamethasone has been proposed as a prophylactic treatment to prevent or attenuate the intensity of pain flare reactions that can occur after palliative radiotherapy for bone metastases. The rationale for using dexamethasone in this context is rooted in its ability to modulate the immune response and reduce inflammation. Radiation therapy, while effective in targeting tumor cells, also causes damage to normal tissues, triggering an inflammatory cascade that can worsen pain. Dexamethasone acts by inhibiting the release of pro-inflammatory cytokines and suppressing immune cell activation, thus potentially mitigating the inflammatory processes that contribute to RIPF. Additionally, dexamethasone’s well-established analgesic properties, likely related to its effects on pain pathways in the nervous system, make it an attractive option for managing pain flare.3 The administration of dexamethasone in the setting of palliative radiotherapy for bone metastases has been the subject of several clinical studies and trials. Research has sought to determine not only the effectiveness of dexamethasone in preventing or reducing RIPF but also the optimal dosing regimen, timing, and duration of treatment. Most studies have focused on the use of dexamethasone in a short-term, high-dose regimen, given prior to, during, or immediately after radiation therapy. The goal is to achieve rapid control over the inflammatory response and minimize the impact of pain flare in the critical period following radiotherapy.4 The potential benefits of dexamethasone in this context are considerable. If proven effective, it could provide a means of improving the overall comfort and quality of life for patients undergoing palliative radiotherapy. Reducing the incidence and severity of RIPF would allow patients to experience more immediate pain relief from radiation therapy, enhancing their overall treatment outcomes. Furthermore, by preventing the transient flare of pain, dexamethasone could reduce the need for additional analgesic interventions, such as opioid medications, which can be associated with side effects and the risk of dependency. Despite the promising potential of dexamethasone, the use of corticosteroids in cancer patients must be approached with caution. While dexamethasone is generally well-tolerated, long-term or high-dose use can be associated with a range of side effects, including immunosuppression, gastrointestinal disturbances, and metabolic changes such as hyperglycemia. Therefore, careful consideration must be given to the balance between the potential benefits of prophylactic dexamethasone use in preventing RIPF and the possible risks associated with its use, especially in patients with pre-existing comorbidities or those on other therapies that may interact with corticosteroids.5In addition to dexamethasone, other strategies have been explored for the prevention and management of RIPF, including the use of nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and other adjuvant analgesics. However, corticosteroids like dexamethasone remain an attractive option due to their dual action of reducing inflammation and providing analgesia, particularly in the context of bone metastases where inflammation plays a significant role in pain generation.6Overall, the role of dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases is a promising area of research. By understanding the mechanisms of RIPF and the potential for corticosteroids to modulate the inflammatory response, clinicians may be able to optimize treatment strategies for patients with bone metastases, improving their quality of life and minimizing unnecessary suffering.

In this study, we conducted a randomized controlled trial to evaluate the effectiveness of dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases. A total of 110 patients with documented bone metastases were enrolled in the trial. Inclusion criteria included adult patients aged 18 years and older who were scheduled to receive palliative radiotherapy for bone metastases. Exclusion criteria involved patients with contraindications to dexamethasone or corticosteroid therapy, those with uncontrolled infections, and individuals with a history of hypersensitivity to steroids. Patients were randomly assigned to one of two groups: the dexamethasone group and the placebo group. The dexamethasone group received oral dexamethasone (4 mg daily) starting one day prior to the initiation of radiotherapy, continuing for seven days following the treatment. The placebo group received a placebo tablet following the same regimen. Both groups underwent palliative radiotherapy to bone metastases according to standard clinical protocols, with a typical dose fractionation of 30 Gy in 10 fractions or 20 Gy in 5 fractions, depending on the patient's clinical condition. Pain levels were assessed using the Visual Analog Scale (VAS) and the Brief Pain Inventory (BPI) before radiotherapy, during the treatment course, and for up to 14 days after the completion of radiotherapy. The occurrence of radiation-induced pain flare, defined as a significant increase in pain intensity within 48-72 hours after radiotherapy, was closely monitored. The primary outcome measure was the incidence of radiation-induced pain flare, while secondary outcomes included the overall pain reduction, opioid consumption, and quality of life during the follow-up period. Statistical analyses were performed using appropriate tests to compare pain flare rates and other outcomes between the two groups, with significance set at a p-value of less than 0.05. This study was approved by the institutional ethics committee, and informed consent was obtained from all participants prior to their inclusion in the trial.

Table 1: Radiation-induced Pain Flare Incidence The data in Table 1 presents the incidence of radiation-induced pain flare in patients treated with dexamethasone versus placebo. In the dexamethasone group, 12 out of 55 patients (21.82%) experienced a pain flare, while in the placebo group, 30 out of 55 patients (54.55%) had a pain flare. The p-value for this comparison is 0.001, which indicates a statistically significant difference between the two groups. This suggests that dexamethasone significantly reduces the incidence of radiation-induced pain flare after palliative radiotherapy for bone metastases. The lower pain flare percentage in the dexamethasone group supports its role in preventing pain flare compared to placebo. Table 2: Pain Reduction (VAS) Table 2 displays the changes in pain scores, measured by the Visual Analog Scale (VAS), before and after treatment. The mean pre-treatment VAS score was 7.80 ± 1.20 for the dexamethasone group and 7.90 ± 1.10 for the placebo group, indicating similar levels of pain at baseline. After treatment, the dexamethasone group reported a significant reduction in pain, with a post-treatment score of 4.20 ± 1.00, leading to a pain reduction of 3.60 ± 0.90. In contrast, the placebo group showed a smaller reduction in pain, with a post-treatment score of 6.50 ± 1.30, resulting in a pain reduction of 1.40 ± 0.80. The p-value for the dexamethasone group is 0.002, which confirms that the pain reduction in this group is statistically significant. This suggests that dexamethasone is more effective in reducing pain compared to placebo. Table 3: Opioid Consumption Reduction Table 3 compares the opioid consumption before and after treatment. The mean pre-treatment opioid consumption was 60.50 ± 15.00 mg in the dexamethasone group and 61.00 ± 14.00 mg in the placebo group, indicating similar usage at baseline. Post-treatment, the dexamethasone group showed a decrease to 45.50 ± 10.50 mg, a reduction of 15.00 ± 8.50 mg. On the other hand, the placebo group had a smaller reduction in opioid consumption, decreasing to 55.00 ± 12.00 mg, with a reduction of 6.00 ± 7.00 mg. The p-value for the dexamethasone group is 0.04, indicating a statistically significant reduction in opioid consumption, which is associated with better pain control in the dexamethasone group. This suggests that dexamethasone not only reduces pain but also helps in reducing the need for opioid analgesics. Table 4: Quality of Life Improvement (BPI) Table 4 presents the improvement in quality of life, measured by the Brief Pain Inventory (BPI), before and after treatment. The mean pre-treatment quality of life score was 6.70 ± 1.50 for the dexamethasone group and 6.90 ± 1.30 for the placebo group. After treatment, the dexamethasone group showed a significant improvement with a post-treatment score of 4.10 ± 1.20, leading to a quality of life improvement of 2.60 ± 0.90. In contrast, the placebo group showed a smaller improvement, with a post-treatment score of 5.30 ± 1.50, and an improvement of 1.60 ± 1.00. The p-value for the dexamethasone group is 0.01, which indicates a statistically significant improvement in quality of life. This suggests that dexamethasone contributes to a more significant enhancement in the overall well-being of patients compared to the placebo. Table 5: Multiple Regression Analysis Table 5 presents the results of a multiple regression analysis where pain flare percentage is the dependent variable, and pain reduction (VAS), opioid reduction (mg), and quality of life improvement (BPI) are the independent variables. The coefficients represent the impact of each independent variable on the dependent variable, with negative coefficients indicating a decrease in pain flare percentage as the independent variable increases. The constant has a coefficient of 41.03 (p-value 0.0001), suggesting that without the effects of the independent variables, the pain flare percentage would be around 41.03%.Pain Reduction (VAS) has a coefficient of -4.38 (p-value 0.0003), indicating that for every unit increase in pain reduction, the pain flare percentage decreases by 4.38%. This is statistically significant, meaning that greater pain reduction is associated with a reduction in pain flare. Opioid Reduction (mg) has a coefficient of -6.74 (p-value 0.005), suggesting that for every unit reduction in opioid consumption, the pain flare percentage decreases by 6.74%. This result highlights that reduced opioid consumption is linked to lower pain flare incidents.Quality of Life Improvement (BPI) has a coefficient of 37.55 (p-value 0.00001), indicating that a higher improvement in quality of life is associated with a significant increase in the pain flare percentage, which may suggest that better quality of life is a confounding factor in this analysis or that it interacts with other variables. Table 1: Radiation-induced Pain Flare Incidence Group Total Patients Patients with Pain Flare Pain Flare Percentage (%) p-value Dexamethasone 55 12 21.82% 0.001 Placebo 55 30 54.55% Table 2: Pain Reduction (VAS) Group Mean Pre-treatment Pain Score (VAS) Mean Post-treatment Pain Score (VAS) Pain Reduction (VAS) p-value Dexamethasone 7.80 ± 1.20 4.20 ± 1.00 3.60 ± 0.90 0.002 Placebo 7.90 ± 1.10 6.50 ± 1.30 1.40 ± 0.80 Table 3: Opioid Consumption Reduction Group Mean Pre-treatment Opioid Consumption (mg) Mean Post-treatment Opioid Consumption (mg) Opioid Reduction (mg) p-value Dexamethasone 60.50 ± 15.00 45.50 ± 10.50 15.00 ± 8.50 0.04 Placebo 61.00 ± 14.00 55.00 ± 12.00 6.00 ± 7.00 Table 4: Quality of Life Improvement (BPI) Group Mean Pre-treatment Quality of Life Score (BPI) Mean Post-treatment Quality of Life Score (BPI) Quality of Life Improvement (BPI) p-value Dexamethasone 6.70 ± 1.50 4.10 ± 1.20 2.60 ± 0.90 0.01 Placebo 6.90 ± 1.30 5.30 ± 1.50 1.60 ± 1.00 Table 5. Multiple Regression Analysis Variable Coefficient Standard Error t-value p-value 95% Confidence Interval (Lower) 95% Confidence Interval (Upper) Constant 41.03 3.45 11.91 0.0001 34.26 47.80 Pain Reduction (VAS) -4.38 1.12 -3.91 0.0003 -6.60 -2.16 Opioid Reduction (mg) -6.74 2.34 -2.87 0.005 -11.35 -2.12 Quality of Life Improvement (BPI) 37.55 6.88 5.46 0.00001 24.60 50.51

The results from Table 1 demonstrate that dexamethasone significantly reduces the incidence of radiation-induced pain flare following palliative radiotherapy for bone metastases. The dexamethasone group experienced a pain flare rate of 21.82%, compared to 54.55% in the placebo group (p-value = 0.001). This finding is consistent with previous studies that have shown the efficacy of corticosteroids, like dexamethasone, in preventing pain flare in patients receiving radiotherapy for bone metastases (Tannock et al., 2006).6 Similarly, a study by Kaasa et al. (2005) found that corticosteroids, including dexamethasone, reduced the occurrence of pain flare in a similar cohort.7 However, some studies, such as those by McDonald et al. (2013), reported less significant results, suggesting that the effect of dexamethasone may vary based on treatment protocols and patient demographics.8 In Table 2, the dexamethasone group exhibited a statistically significant pain reduction with a decrease of 3.60 ± 0.90 on the VAS, compared to 1.40 ± 0.80 in the placebo group (p-value = 0.002). This result is in line with findings from several studies, such as that by Lutz et al. (2015), who reported significant pain relief in patients treated with dexamethasone following palliative radiotherapy.9 A study by Chow et al. (2007) also supported these findings, demonstrating that corticosteroids, particularly dexamethasone, provide substantial pain relief and improve quality of life in patients with bone metastases.10 In contrast, the placebo group showed a much smaller reduction in pain, reinforcing the notion that dexamethasone has a more robust effect on pain management compared to placebo treatments (Gershenwald et al., 2014).11 Table 3 reveals that the dexamethasone group had a significant reduction in opioid consumption, with a decrease of 15.00 ± 8.50 mg, compared to the placebo group, which showed a smaller reduction of 6.00 ± 7.00 mg (p-value = 0.04). These results are consistent with findings from a study by Fenton et al. (2004), who noted that dexamethasone treatment was associated with reduced opioid use in patients undergoing radiotherapy for bone metastases.12 A similar study by Aapro et al. (2009) suggested that corticosteroids could reduce the need for opioids by providing effective pain relief, allowing for lower doses of opioids.13 However, it is important to note that while dexamethasone can reduce opioid consumption, long-term opioid management remains a critical aspect of palliative care, as highlighted by Coyle et al. (2009), who examined the balance between steroid therapy and opioid use in cancer patients.14 The results from Table 4 demonstrate that dexamethasone significantly improves quality of life, with an improvement of 2.60 ± 0.90 on the BPI, compared to 1.60 ± 1.00 in the placebo group (p-value = 0.01). This finding is supported by a number of studies, including the work by Bruera et al. (2003), which reported improvements in quality of life following corticosteroid therapy for cancer-related pain.15 Furthermore, a study by Nixon et al. (2004) found that corticosteroids like dexamethasone contributed to improvements in both pain relief and overall quality of life in cancer patients receiving palliative treatment. 16 The multiple regression analysis in Table 5 provides deeper insights into the factors influencing pain flare incidence. The results show that both pain reduction (VAS) and opioid reduction (mg) significantly predict a reduction in pain flare percentage, with coefficients of -4.38 (p-value = 0.0003) and -6.74 (p-value = 0.005), respectively. These findings are consistent with research by Cheng et al. (2008), who found that reducing opioid use and improving pain control were both associated with lower rates of radiation-induced pain flare.17 Interestingly, the analysis also reveals a positive coefficient for quality of life improvement (BPI) (37.55, p-value = 0.00001), which may suggest that an improved quality of life could be related to higher pain flare, potentially indicating a confounding effect or interaction with other treatment variables. This finding calls for further investigation, as similar studies by O'Rourke et al. (2010) have explored the complexity of quality of life measures in palliative care, showing that these variables can sometimes interact in unpredictable ways.18 Surgical Management in Bone Metastases Surgical intervention plays a complementary role in the multidisciplinary management of bone metastases, particularly in patients experiencing mechanical instability, pathological fractures, or spinal cord compression. While radiotherapy with dexamethasone prophylaxis is effective in reducing pain flare and improving quality of life, surgery offers structural stabilization and functional restoration in carefully selected patients. Orthopedic procedures, such as internal fixation with intramedullary nails, plates, or endoprosthetic replacement, are frequently performed to prevent or treat pathological fractures and to improve mobility. In spinal metastases, surgical decompression combined with stabilization may be considered to relieve neurological compromise and maintain ambulation. The goals of surgery in this palliative setting are not curative but aimed at pain relief, improved mobility, preservation of independence, and enhancement of overall quality of life. Several studies have highlighted the benefit of integrating surgical approaches with radiotherapy. Stabilization of weight-bearing bones followed by palliative radiotherapy has been shown to decrease pain, reduce the risk of further fracture, and allow earlier mobilization. Importantly, prophylactic administration of dexamethasone can be beneficial in patients undergoing postoperative radiotherapy to minimize radiation-induced pain flare, thus supporting multimodal pain control. Surgical decision-making must take into account the patient’s overall prognosis, performance status, tumor biology, and expected survival. For patients with limited life expectancy, minimally invasive stabilization procedures may be preferred over extensive reconstructive surgery. In contrast, patients with a longer anticipated survival may benefit from more durable reconstructive techniques. Overall, surgical management remains an essential adjunct in the palliative care of patients with bone metastases. When combined with systemic therapy, radiotherapy, and dexamethasone prophylaxis, surgery contributes to comprehensive pain control and functional preservation in advanced cancer care.

In conclusion, this study demonstrates that dexamethasone significantly reduces the incidence of radiation-induced pain flare, improves pain control, decreases opioid consumption, and enhances quality of life in patients undergoing palliative radiotherapy for bone metastases. These findings support the clinical use of dexamethasone as an effective adjunctive therapy in managing bone metastasis-related pain. The results are consistent with previous studies highlighting the benefits of corticosteroids in palliative care. Further research with larger sample sizes and long-term follow-up is warranted to confirm these findings and explore the optimal treatment protocols.

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