This editorial refers to “Analysis the incidence and related risk factors of depression in patients with esophageal cancer combined with bone metastasis” by Shi et al, 2026; https://dx.doi.org/10.5498/wjp.v16.i1.110875.
INTRODUCTION
Esophageal cancer (EC) is one of the deadliest cancers of the gastrointestinal tract, EC ranks as the 11th most prevalent and the 7th major cause of cancer-associated fatalities globally[1]. According to the estimation of GLOBOCAN 2022, EC demonstrated 2.6% of new cancer incidences and 4.6% of cancer-associated fatalities of all cancer cases[1]. Major cross-regional and cross-national variations in EC burdens and increased mortality among populations with inadequate socioeconomic levels are considered a significant complication of global health, despite the fact that the EC burden pattern has been developed and transformed through the shifting landscape of food habits and social interactions regionally and globally[2]. There are two predominant histological subtypes of EC, these are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. These subtypes differ in geographic distribution and share a bleak prognosis. ESCC is more prevalent in East-Asian countries like Japan and China, which account for almost 90% of EC cases, while esophageal adenocarcinoma is more common in Western countries, accounting for almost 70% of EC cases[3]. Despite significant advances in chemotherapy, surgery, and radiotherapy, the overall survival rate is still poor due to rapid prognosis and the five-year survival rate for advanced-stage EC remains around 15%-20%[3]. After the lungs and liver, bone metastasis is the third most prevalent area of metastasis in EC patients. Bone metastatic EC patients often suffer from various bone-related complications, such as pain, pathological fractures, neurological compression syndrome, and hypercalcemia[4]. These physical burdens are not isolated; they directly contribute to a cascade of psychological distress, which is frequently underrecognized and untreated. A recent retrospective study published in World Journal of Psychiatry by Shi et al[5] found that among 100 EC patients with bone metastasis, 42% patients had suffered from clinical depression. Limited education, low socioeconomic condition, inadequate social support, sleep disturbance, and increased high-sensitivity C-reactive protein (hs-CRP) were found as independent risk factors. The results of this study demonstrated that depression in EC is not only a reactive emotional condition but also a pathophysiological outcome of systemic inflammation intertwined with social vulnerability[5]. Depression in EC cancer patients has profound effects, such as affecting immunological function, reducing treatment adherence, and enhancing mortality risk. Especially in low and middle-income countries (LMICs) where the availability of palliative psychiatry and psychosocial approaches is constrained, the interplay of psychological and physical suffering frequently remains undetected and untreated. In these situations, depression is an undetectable comorbidity that elevates suffering, increases disease progression, and affects overall prognosis[6]. Recent studies show that chronic inflammation, which is reflected by increased pro-inflammatory cytokines and hs-CRP, directly affects depression through the alteration of neuroendocrine regulation, serotonergic transmission, and synaptic plasticity. Additionally, hypothalamic-pituitary-adrenal (HPA) axis hyperactivation and elevated levels of cortisol hormone secretion in EC patients develop tumor progression and depressive symptoms[7]. This editorial argues that addressing psychological distress in EC with bone metastasis is not optional but a clinical imperative.
The combination of oncology practice and psychological care is both clinically and ethically efficient. EC patients often experience depression due to longer hospitalization, reduced adherence to chemotherapy and radiotherapy, and higher inflammatory markers. Early detection and treatment processes through screening tools and structured psychological support can increase treatment resilience, improve treatment adherence, quality of life, and overall survival outcomes[8]. In this study, “psychological distress” is used as a wide range of emotional discomfort, including dread, melancholy, irritability, and difficulty coping. Depression refers to a more focused clinical disease that includes somatic symptoms, cognitive abnormalities, loss of interest, and persistent low mood. Excessive worry, hyperarousal, and fear-based reactions are all considered forms of anxiety. Although these states frequently overlap in cancer patients, they remain distinct constructs and ensure clearer interpretation of the mechanisms and psychological pathways. There is an urgent need to incorporate psychological health into cancer care of EC, especially for patients with metastatic disease. Identifying depression as both a driver and marker of adverse cancer effects and understanding bone metastasis as a specific site of elevated vulnerability provides a significant change in perspective by emphasizing that psychological well-being needs the same consideration as biomarkers, imaging, and systemic approaches. This study highlights that psychological distress in metastatic EC, particularly in patients with bone metastasis, results from the integrated effects of tumor growth, inflammation, and vulnerability, and the need for a supportive cancer care model where psychological health is a regular part of treatment.
THE PSYCHONEURO-ONCOLOGICAL DIMENSION OF EC
Cancer-related fatigue can be treated as one of the most common and lethal disorders in cancer patients. The major symptom of cancer-related fatigue is a painful, constant, personal feeling of physical, mental, or emotional fatigue or wear-out linked to cancer and cancer therapy. During the early stage of EC, the majority of the patients demonstrate complications like dysphagia that lead to severe weight loss[9]. Currently, therapeutic surgery persists as the main technique for regulating EC. A number of complications, like diarrhea and reflux, occur due to the alteration of esophageal anatomical position after surgery, and a collection of distressing complications remains after surgery, causing depression, anxiety, and other negative emotions that influence the condition of patients’ lives[10]. Patients who are suffering from EC often deal with depression after surgery and neoadjuvant therapy, a situation that may cause systemic inflammation, modify immune-inflammatory pathways in the microenvironment, and inhibit antitumor immunity, which leads to continual tumor progression and analytically lowers patient prognosis. In EC, chronic systemic inflammation expressed by hs-CRP and elevated cytokines encourages not only tumor progression but also depression via interconnected neuroendocrine and neuroimmune pathways[7]. Pro-inflammatory mediators like interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-αlpha), and IL-1β secreted from tumor-driven inflammation, surgical injury, or psychological stress can cross the blood-brain barrier and trigger corticotropin-releasing factor production, causing hyperactivation of the HPA axis and glut cortisol secretion. Increased cortisol disturbs serotonergic signaling and synaptic plasticity, leading to depressive symptoms, while concurrently promoting a pro-tumorigenic microenvironment through immune suppression and embellished proliferative and invasive capacity[7]. These cytokines further modify the tumor microenvironment through nuclear factor kappaB (NF-κB)/signal transducer and activator of transcription 3 signaling and enlistment of immunosuppressive cells, composing a feedback loop where inflammation drives neuroendocrine dysfunction and psychological stress augments inflammatory signaling, generally escalating EC progression[7]. Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in EC, and clinically, IDO1 expression was negatively inflated in EC and positively coordinated with complete survival. IDO1 is expressed in two ways - functionally in the proliferation and migration of EC cells and mechanically in the arrangement of the expression of chemokine C-X-C ligand 10 through initiating the entrance of NF-κB into the nucleus to associate with the promoter of C-X-C ligand 10. IDO1 frequently promoted EC progression, which is dependent on the presence of C-X-C ligand 10[11]. Beyond its carcinogenic role, IDO1-driven tryptophan deprivation elevates kynurenine accumulation, which disrupts serotonin synthesis and directly causes neurochemical imbalance and enhanced susceptibility to depression. Therefore, through common metabolic-neuroimmune pathways, IDO1 activation links tumor biology with psychological suffering[12]. High mobility group box-1 (HMGB1), a nuclear non-histone protein, and IDO both have a symbiotic effect that can hinder immune function, stimulate tumor progression in ESCC patients, and thereby lead to poor prognosis[13]. Notably, HMGB1 is also a major modulator of neuroinflammation. When it is released during cellular stress triggered by tumors or treatments, it activates microglia and elevates inflammatory cytokine transmission in the central nervous system. Depressive symptoms are exacerbated by this increase in neuroinflammatory tone. HMGB1 acts as an additional connection between tumor-associated inflammation and psychological distress by bringing this inflammatory “spillover” effect to the brain[14]. Programmed cell death protein, another immune-inflammatory protein, was shown on T-cell membranes and bound to programmed cell death ligand 1 (PD-L1) in cancer cells to inhibit immune responses. The PD-1/PD-L1 pathway is again unregulated in individuals with depression, which results in decreased immune inspection and persistence of inflammatory responses. As a result, individuals with EC with elevated PD-L1 levels may experience a poor prognosis[7]. In addition to promoting tumor growth, the immunological fatigue brought on by the PD-1/PD-L1 pathway also maintains systemic inflammation, which is known to disrupt serotonergic signaling and HPA-axis regulation. Therefore, PD-1/PD-L1 activation indirectly encourages psychological distress by maintaining a chronic inflammatory environment that drives anxiety-related and depressive symptoms[15]. Collectively, these pathways (e.g., IDO1-mediated metabolic dysregulation, HMGB1-driven neuroinflammation, and PD-1/PD-L1-induced immune exhaustion) form a molecular network that is interrelated and allows tumor-associated immunological alterations to regulate brain function beyond the periphery.
Different complications may influence an individual’s quality of life, like anxiety, depression, post-traumatic stress disorder, body image issues, sexual dysfunctions, cognitive disorders, and suicidal thoughts. Stress can impair the body’s defense mechanisms, which makes therapy more difficult[6]. Due to its anatomical location and psychological function, the rate of malnutrition in individuals with EC is greater than that in individuals with other cancers. This might be connected to certain psychological actions, anatomical arrangements, cancer-linked factors like obstruction, dysphagia, and therapy-related factors like vomiting caused by medication of chemotherapeutic drugs and gastroesophageal reflux caused by surgery. EC also causes choking, the impact of a foreign body, and pain behind the sternum[16]. A recent study by Shi et al[5] found that patients in EC with bone metastasis exhibit increased hs-CRP, and corresponded with an increased risk of developing depressive complications. Increased hs-CRP levels can stimulate the discharge of inflammatory cytokines, prohibit serotonin production in the hippocampus, and thereby induce depressive actions[5]. Anxiety and depression are both typical psycho-psychological diseases in patients with EC. According to the univariate analysis of the clinical data of patients with depression and anxiety, demonstrated that the symptoms of anxiety and depression in patients with EC were linked to tumor, node, and metastasis stage, tumor size, irritation level, postoperative complications, and surgical techniques[17]. It also showed that patients with tumor, node, and metastasis stage III, tumor size bigger than 3 cm, radical McKeown esophagectomy, postoperative complications, and CRP levels > 10 mg/L led to a greater incidence of anxiety and depression. The current study of bio-psycho-social medicine highlighted the effect of acknowledging the biological, psychological, and social aspects involved in the improvement and therapy of EC. Therefore, integrating CRP levels, the Self-Rating Anxiety Scale, and the Self-Rating Depression Scale can help develop patients’ management[17]. Prophylactic escitalopram treatment, a pharmacologic intervention, has been exhibited to lower the risk of growing depression and support patients manage their quality of life, but it does not upgrade patients’ handling strategies for the threat of cancer and alter the management of negative thoughts[18]. Cisplatin, an antineoplastic agent, involves a modification in Ca2+ balance, the introduction of lipid peroxidation, and the infliction of DNA damage. However, its continued use is limited because of different acute and chronic toxic effects. In cisplatin treatment, some patients encounter depression and nervousness. Cisplatin use is related to elevated lipid peroxidation, reduced activity of mitochondrial complex I, elevated levels of messenger RNA expression in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and N-methyl-D-aspartate receptors, and hippocampal damage through neuroinflammation (NF-κB, TNF-α, IL-6)[19].
A study by Shi et al[5] showed that poor social support, defined as education, low socioeconomic condition, sleep disruption, and systemic inflammation were independent indicator in patients with EC and bone metastasis. Patients with lower income often encounter major psychological stress because of missing optimal treatment procedures and opportunities. The financial burden of the cancer treatment may cause stress and guilt; as a result, these patients get tense about financial problems and turn down, or overlook, psychological interventions for economic problems. In doing so, patients experience worsened psychological distress and elevated depression[5]. Patients with a low level of education may face complications in understanding disease-related insight through different management. They solely depend on the therapeutic team, leading to an elevated likelihood of misunderstanding, a low consideration of the cancer and therapy, and more confusion, whereas patients with higher education levels are prone to have a fair and detached understanding of their state, acquire strong self-regulation capabilities and finally like to have an optimistic and positive mindset while undergoing treatment complications[20]. Patients who get low social support get less concern from family and friends, leading them to be more disposed to feelings of helplessness, loneliness, and gloom during the experience of the cancer and therapy. Therefore, this diminishes treatment confidence and causes negative emotions, a dangerous cycle, and lastly an elevated risk of depression[21]. Long-term sleep disorder with EC can decrease immune surveillance, lower natural killer cell activity, stimulate tumor progression, and alter feelings of helplessness. Moreover, sleep disorders can decrease serotonin release, which precisely develops the onset of depression, silence melatonin release that influences hormone metabolism linked to tumors, and thereby irritate negative feelings in individuals with EC and bone metastasis[5]. Intervention arrangements concerning social support should be prepared, as it helps the cancer patients feel connected and care and understand the importance and meaning of life. Other interventions, such as metacognitive therapy and rumination-based therapy, have been proven successful and might develop psychological growth and aid patients to rebuild the attitude toward annoying experiences[22].
PSYCHOLOGICAL CONSEQUENCES OF BONE METASTASIS
The structure of bone metastatic cancer pain involves abnormal bone metabolism, nociceptive pain, alterations in the microenvironment of neighboring tissues, activation of nociceptors, nerve compression, and illness caused by tumor growth[23]. Bone metastasis in EC most frequently constructs a mixed cancer-induced bone pain symptom - especially nociceptive (bone) pain with a constant neuropathic element and inflammatory donors[24]. The pathophysiology includes complicated cooperation between bone, inflammatory, tumor, and nerve cells reflecting nociceptive and neuropathic pain, with mechanical and inflammatory pain ascending from cytokine release, bone pressure, periosteal irritation, or mass effect[25]. Cancer-induced bone pain is mostly a serious, unplanned, enduring, and complicated pain, usually followed by hyperalgesia. Mechanisms, including inflammatory components released over the osteosarcoma cell injection site in the tibia, cause an acidic local microenvironment leading to tissue damage and also peripheral sensitization at the level of the cell bodies of the primary sensory neurons in the dorsal root ganglia and the nociceptive nerve terminals, along with the central sensitization in the spinal dorsal horn and pain-linked brain regions[25]. A wide range of mediators, like endothelin, bradykinin, epidermal growth factor, histamine, nerve growth factor, prostaglandins, glial cell line-mediated neurotrophic factor, tumor necrosis factor, and vascular endothelial growth factor, formed by immune cells and tumors, activate and sensitize peripheral nociceptive fibers. Serious bone cancer pain takes place because of various mechanisms among inflammatory, nociplastic, and neuropathic elements[26]. Tumor cells can hamper and kill the distal processes of sensory fibers, which usually strengthen the bone. Various reports demonstrated the activation of activated microglial cells in the dorsal horn of the spinal cord, which is linked with chronic pain cases[26]. The secretion of pronociceptive elements through immune and tumor cells, bone degradation, and direct tissue damage by osteoclast activation initiates the activation of nociceptors and the sense of pain[27]. Hypoactivity or hyperactivity of the HPA axis can originate abnormal cortisol secretion arrangements, like increased or flattened diurnal cortisol profiles. These flaws may destroy immune function, raise inflammation, and negatively hamper psychological and cognitive health through elevating the risks of infections, anxiety, and depression. Chronic pain dysfunctions the HPA axis and modifies cortisol arrangements[28]. The basolateral amygdala and infralimbic amygdala are typically related to pain and negative emotions, and they are recognized to bear mutual relations[29]. A study by Shi et al[5] found that inflammatory cytokines keep in control of the onset, evolution, and aftereffect of depression through monitoring neuroendocrine actions, influencing neurotransmitters, modifying neural plasticity, and finally altering emotional regulation. Hs-CRP is a non-specific inflammatory marker in the blood, and its increased levels can suppress serotonin synthesis in the hippocampus, stimulate the secretion of inflammatory cytokines, and promote depressive natures. Furthermore, chronic inflammation not only extremely elevates cortisol levels, triggers the HPA axis, and impairs depressive symptoms but also harms synaptic plasticity through the blood-brain barrier, activates death anxiety due to heightening infection signs, and weakens executive attention and function, thereby elevating the possibility of depression[5]. EC with bone metastasis often originates skeletal-related events (SREs), for example, spinal cord compression, pathological fracture, and hypercalcemia, which eventually lower physical function and quality of life. Bone metastasis is designated based on osteolytic, osteoblastic, morphology mixed, or intertrabecular morphology. Elements released by tumor cells in osteolytic lesions generate osteoclast activation and recruitment, resulting in elevated osteolysis. This phenomenon often reduces bone integrity and originates extreme bone pain, the discharge of minerals from the bone matrix, and a high risk of fracture that leads to hypercalcemia[30]. Patients who are experiencing (SREs) also suffer from functional impairment, extreme pain, mental health problems, and poor diagnosis[31]. Pathological fractures were individually related to worse quality of life, higher anxiety, and depression. This led to elevated pain and disability, and more depression and panic led to overall degradation in health and eventually death anxiety[32]. EC with bone metastasis experience decreased activities of daily living, and SREs complications are also linked with bone metastasis, like pathological fractures, hypercalcemia, bone pain, and spinal cord compression. Pathological fractures could lead patients to worry about fractures and reduce their daily activities. Furthermore, sometimes a doctor suggests irrelevant rest due to the primary site, which can raise these limitations[33]. A recent study showed that the economic burden of metastatic bone disorder not only affects patients’ health but also adds caregiver burden, financial difficulties, lower quality of life, and psychological impact[34]. It also affects both patients and their families and society in the end. Some major impacts on a caregiver while caring for their loved ones are loss of employment, loss of income, loss of savings, reduced work productivity, and taking low-salaried jobs to adjust schedules. These threats make both patients and their caregivers weak. As a result, sometimes caregivers encountered significant psychological morbidity (anxiety and depression)[34]. In addition, a large number of patients adopt societal self-isolation after the disease and avoid social gatherings, mainly social activities associated with eating. A study found that cancer patients easily related to social restraint, self-blame, and self-perceived burden. Direct rejection by others, the acceptance of patient patterns, and injustice in the social system are the main reasons for the creation of societal self-isolation[35].
CURRENT GAPS IN CLINICAL PRACTICE
Even with strong evidence that psychiatric comorbidity reduces treatment adherence, worsens quality of life, and negatively affects oncologic outcomes. The reliable and routine incorporation of psycho-oncology into cancer care is still absent globally; this absence is caused by complex implementation barriers that are extensively studied in both LMICs and high-income countries (HICs). Implementation studies and quality development audits demonstrate that guideline recommendations for routine depression or distress screening often fail to translate into ongoing clinical practice. This occurs due to heterogeneity of screening tools, used improperly (usually only at diagnosis), and unrelated to reliable referral/triage pathways, so positive screens often do not translate into evidence-based approaches. According to studies, in the United States, single-center development work showed how operational limitations (e.g., limited staff time, absence of electronic health record combination, conflicting clinical priorities, and uncertain local responsibility) produced low baseline screening availability (2%), which only barely developed after targeted implementation initiatives (to approximately 12%). This demonstrates how the presence of policies or guidelines alone is inadequate without administrative alteration[36,37]. European regional workforce mappings also reported significant heterogeneity between centers and nations in the availability of expert psychosocial staff and in the consistency of screening throughout the disease phase, underlining that continental or national programs do not ensure consistent delivery at the bedside[38].
These implementation complications are significantly worse in LMICs, where incorporating psycho-oncology is particularly difficult due to a limited workforce, a lack of specialized psychological health expertise, weak referral networks, and funding shortages. Studies showed that many hospitals lack routinely structured psychosocial programs; this also indicates that the ability for psychosocial evaluation and treatment is concentrated in several tertiary urban centers, while smaller hospitals and rural services provide insufficient standardized support[39]. Hospital-based studies from Nigeria and Nepal found high levels of psychological distress among screened cancer patients, with almost 30% to 56% experiencing clinical depression. The majority of the services lacked routine screening and timely referral methods, which made patients with advanced or metastatic disease very susceptible. Multi-country studies about psychological cancer care in LMICs also recognized the same practical complications, such as workforce shortages, absence of culturally adapted approaches, scarce telehealth linkages, and reliance on on-sustained non-governmental organization support; these complications scale-up incorporated models[40-43].
The second global complication is clinician confidence and workforce training. Recent studies found that in HICs, palliative clinicians, oncologists, and nursing teams frequently complain about limited formal training in psychological evaluation and low confidence in managing mild to severe psychiatric comorbidity. In practice, this leads to a reliance on ad hoc referrals to overloaded psychiatry services instead of rapid cancer-related supervision, which prolongs treatment periods[36,42]. The complete absence of psycho-oncology experts in LMICs increases the complication, since identification without any treatment process indicates unmet need without remedy. Therefore, scalable task-sharing approaches like telepsychiatry, nurse-led stepped care, and community health volunteer help under expert supervision are highlighted in implementation science frameworks, but high-quality implementation trials of these interventions in cancer patients are still constrained[44,45].
Conceptual and quantitative gaps further complicate action. Studies link systemic inflammation (e.g., hs-CRP, neutrophil-to-lymphocyte ratio) and sleep disturbance as depressive phenotypes of cancer, identifying an “inflamed” subtype frequent in the terminal stage that may respond differently to treatment. Although routine cancer workflows hardly incorporate psychological screening with laboratory biomarkers or structured sleep evaluation, biologically induced depression may be missed through psychological tools[46,47]. Similarly, even though there are validated tools like the Patient Health Questionnaire-9 (PHQ-9), Beck Depression Inventory-II, and Distress Thermometer (DT), their operational viability and psychometric action differ based on the setting, and their application in the absence of incorporated triage processes results in minimal clinical advantage. This has been repeatedly underscored via implementation research from both multinational and domestic assessments[36,48].
Socioeconomic determinants of need and availability contribute to another anticipated implementation failure. Insufficient social support, limited education, and low income enhance the risk of depression while also reducing the likelihood of receiving psychological care. LMIC studies in countries like India, Nepal, Nigeria, and multi-national research show that socioeconomically disadvantaged patients are less likely to participate or to be referred with approaches due to stigma, wage loss, transportation costs, and conflicting household priorities. On the other hand, HIC studies show persistent within-national disparities like underserved United States communities, where structural complications and dispersed insurance coverage cause similar disparities[40,41].
Studies demonstrate that psychological strategies can develop quality of life and symptom burden, and in some cases contribute to cancer outcomes. This occurs due to the absence of implementation trials, national regulations with operational detail, and funding for persistently incorporated services, particularly in LMICs[49]. Inadequate workforce training, absence of incorporation of sleep-associated and biological markers into psychological risk models, non-repeated or irregular psychological screening, vulnerable or nonexistent referral processes, constrained expert capacity (particularly in LMICs), socioeconomic and availability disparities, and absence of widespread implementation trials to guide wider acceptance are all major challenges that unify all current gaps in clinical practice. Overcoming these interrelated challenges needs investment in electronic health record-based repeated screening with automated screening, workforce improvement via task-sharing and expert training, affordable service delivery through telehealth, subsidized support, and community navigators, and the addition of sleep evaluation and biomarkers in routine risk stratification. These initiatives are feasible but require coordinated funding, policy, and implementation efforts to make psychosocial care a quantifiable and standardized component of cancer care practice across both LMICs and HICs[37,39].
EMERGING APPROACHES AND INTERVENTIONS
EC patients who develop bone metastases face a distinctive psychological phenotype (e.g., fatigue, pain, and sleep disturbance), rapid role impairment, enhanced reliance, and an increased risk of guilt, demoralization, and humiliation. Studies on cancer patients demonstrate that “self-perceived burden”, shame, and survivor’s guilt are frequent, highly related depressive and anxiety symptoms and can remain unrecognized by routine psychological screening until particular questions about reliance, role shift, and legacy are addressed[50-52]. Quantitative and qualitative studies demonstrate that self-perceived strain impacts the relationship between mood symptoms and role-shift in gastrointestinal malignancy dyads, and validated quantification of stigma and shame have been modified for cancer patients (head and neck and other malignancies), ensuring the accuracy and explicitly screening for shame, guilt, and legacy issues in metastatic cohorts[50-52].
Cognitive-behavioral therapy (CBT) is one of the best-established psychotherapeutic interventions for depressive and anxiety symptoms in malignant patients and has strong mechanistic associations with role-shift and remorse in bone metastatic malignancy. Recent studies showed moderate and clinically effective impacts of CBT on depression, anxiety, dependency, and quality of life[53-55]. Internet-based and short manualized CBT methods demonstrate significance and feasibility for cancer populations, like stepped care and remote methods helpful for patients with pain and impaired mobility. Major methods of CBT are cognitive restructuring to address self-blame, behavioral stimulation to sustain desired activities within functional capacity, and problem-solving for role transitions. These are directly applicable to the frequent cognitions of “I am a burden” or “I did not fulfill my role”. These studies also show the long-lasting advantages of CBT when paired with stepwise supervision and tailored delivery (telehealth, group), suitable for patients with skeletal issues[53-55].
Mindfulness-based stress reduction (MBSR) and associated mindfulness interventions offer an evidence-based additional approach to addressing pain catastrophizing, somatic distress, and reflective anxiety. These domains are specifically useful to patients with bone metastases and impaired mobility. According to a study, MBSR decreases depression and anxiety and increases quality of life, and demonstrates clinically effective improvements in mood and dealing with physical alterations associated with cancer. MBSR can particularly reduce hypervigilance and shame about reliance through its focus on present-moment consciousness, acceptance, and a nonjudgmental mindset toward physical sensations. It is often delivered in low-concentration groups or telehealth methods that are suitable for individuals who are unable to travel because of their skeletal morbidity[56,57].
Meaning-centered and existential therapies concentrate on loss of purpose, demoralization, and legacy concerns that are usually prevalent in advanced EC with bone metastases but are overlooked by conventional symptom-focused screening. Recent studies show that meaning-centered psychotherapy (group and individual procedures) improves meaning in life, post-traumatic growth and spiritual well-being and achieves improvements in depressive and existential distress compared to other active therapies, culturally tailored meaning-centered group psychotherapy has demonstrated feasibility and efficacy. Meaning-centered interventions can directly address thoughts like “what matters now” and help to reconstruct valued roles within new functional capacity and decrease the moral-emotional distress that usually leads to treatment denial or distress escalation for patients suffering from legacy anxieties or remorse about reliance and role transition[58-60].
A multidisciplinary team (MDT) model of palliative care, medical oncology, rehabilitation/pain experts, psychology/psychiatry, nursing, social volunteer, and pharmacy is important for the significant implementation of CBT, MBSR, and meaning-centered therapies. Early incorporation of psycho-oncology into general cancer treatment elevates treatment adherence to holistic care processes, increases referral rates, and reduces time to psychosocial approach. Practical MDT approaches have shown improved recognition and management of hidden distress in metastatic cancer, such as incorporation of psychosocial review into cancer board or palliative support meetings, implementation of fast triage procedures, and repeated distress screening (e.g., DT, PHQ-2/9, and generalized anxiety disorder-7) accompanied by targeted questions for self-perceived/remorse burden[42,61,62].
When psychological therapies are inadequate for managing moderate to severe depression and anxiety symptoms, then pharmacologic interventions play a significant role. The prescription of antidepressants in cancer patients needs to be tailored and MDT-guided. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed class due to their favorable tolerance and constrained drug-to-drug reactions compared to tricyclics, yet caution is needed as particular SSRIs (e.g., fluoxetine, paroxetine) may suppress cytochrome P450 2D6, efficiently changing the metabolism of chemotherapeutic agents like tamoxifen and enhancing side effect risk[63]. A study found that antidepressants might decrease depressive symptoms in cancer patients when compared to placebo, although the evidence base is still limited by study quality and heterogeneity[64]. Recent antidepressant assessments and reviews highlight the equivalency of various agents while stressing the requirement to be vigilant for interactions between drugs and side effect profiles. Specific pharmacologic warnings apply to patients with bone metastases, such as benzodiazepines and other sedatives, which enhance the risk of fracture and fall, and should be applied for short, procedural purposes because of the strong evidence that long-lasting benzodiazepine consumption doubles the risk of fall in older patients[63,64]. Similarly, anticholinergic or sedating antidepressants should be ignored or used with caution when fracture vulnerability and fall risk are present. As a result, while determining drug decisions, the MDT (e.g., pharmacy, psychiatry, pain, and oncology) needs to evaluate possible reactions with chemotherapeutic and bone-targeting drugs (e.g., denosumab, bisphosphonates) and carefully monitor for falls, drowsiness, and cognitive consequences[63,64].
The final unifying concept is individualized treatment, which involves choosing and sequencing interventions based on the patient’s profile, cultural norms, functional ability, and symptom description. In order to regain function and decrease the feedback loop between mood and pain, individualized care for bone-metastatic EC effectively entails steps like routine screening for psychological distress and targeted evaluation of shame guilt and legacy issues, focusing on rehabilitative pain management and spine/orthopedic recovery alongside psychologic interventions, providing CBT, MBSR or meaning-centered therapy according to the patient’s profile, administering pharmacologic treatments only after MDT review with specific plans for long-lasting and safety monitoring and alteration of delivery mode (e.g., group, telehealth, nurse-led task-shared methods). According to implementation research and international surveys of psychological cancer services, task sharing, telehealth, and co-location of psychological support within oncology clinics are significant approaches for enhancing availability, which is an essential consideration for centers with limited resources[42,50,56,65].
The psychosocial care of EC and bone metastatic patients should incorporate evidence-based psychotherapies (e.g., CBT, MBSR, and meaning-centered approaches), MDT combination, careful and personalized pharmacologic treatment, and pragmatic service adaptations to detect and treat depression and anxiety and the common hidden distress of existential loss, guilt, and shame. The effectiveness and viability of these interventions increase when integrated into coordinated, personalized care. Incorporating these findings into routine practice requires detailed MDT protocols for screening, triage, and ongoing review with consideration for safety, drug reactions, and the functional challenges induced through skeletal disease[53,56,58,61,63].
TOWARD AN INTEGRATED PSYCHO-ONCOLOGY MODEL
For patients and their families, the diagnosis or suspicion of cancer leads to widespread biopsychological complications. This reality gets worse in malignancies that cause severe symptom burden and functional loss, like EC with bone metastases. According to a qualitative study from China (a nation with one of the highest absolute cases of ESCC), patients fell into three categories like social, physical, and psychological. In the psychological category, patients expressed regret for not seeking help early, widespread anxiety about the outcome, a sense of unfairness due to a previous healthy lifestyle, trouble accepting the diagnosis, remorse over the family’s financial loss, and isolation and enhanced self-isolation from all social activities. These patient narratives highlight how incorporated physical and socioeconomic strains often lead to emotional aftereffects, such as remorse, humiliation, and demoralization[6,35].
Advocacy for routine psychological health screening in cancer care stems from persistent evidence that psychological distress is more frequent and often remains undetected unless initiated. Several studies estimate clinically effective distress in nearly 20% to 50% of cancer patients, and a few representative surveys based on qualitative strategies reveal elevated levels of distress in more than half of patients[66,67]. Instituting routine screening (rather than clinician opinion alone) enhances detection and referral, such as the initiation of standardized distress screening procedures, which has been linked with efficient growth in reported psychological requirements and elevated rates of referral to therapeutic treatments in pragmatic cancer settings[68,69]. For patients with bone metastases, where mobility issues, pain, and reliance increase the psychological distress, early and regular screening at vital points (detect metastasis, recognition of skeletal-associated occurrence, major therapeutic modification) is essential to prevent the progression of untreated psychological distress[70,71]. The DT and a rapid complication checklist are some of the most pragmatic frontline tools for high-volume facilities because they are short, and digital implementations promote instant assessment. The application of DT in conjunction with structured evaluation processes enhances referral concordance with requirements and decreases the period of psychological contact[68,72]. The DT should not be applied in isolation, as incorporating quality of life tools, such as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 with disease-specific models, provides the social, functional, and symptom setting that usually shows distress (e.g., dysphagia leading to social isolation or skeletal pain influencing reliance and remorse). An incorporated DT and quality of life strategy has been shown to develop susceptibility to clinically efficient psychological challenges and to guide interdisciplinary treatment strategy[70,73].
Effective screening is needed, as detection is ineffective without a connected response. Therefore, the primary operational concept is that a responsive assessment procedure is rapidly mapped to screening outcomes. A three-tiered strategy is applied in effective models, such as short psychoeducation/self-management (tier 1), brief psychosocial models (CBT-based, MBSR-based, or meaning-centered group components) delivered through nurses or trained nonprofessionals (tier 2), and expert psychology/psychiatry for severe and complex cases (tier 3). Telehealth models and nurse/nonprofessional worker-delivered short approaches can elevate reach while monitored remotely[74,75].
Incorporation of psychology and psychiatry within the oncology MDT is significant to translate screening to result in better outcomes. Incorporating psychological overviews (e.g., quality of life snapshot, complication list, DT score) into oncology-board or palliative care reviews decreases time to psychological contact, synchronizes pharmacologic or psychotherapeutic decisions with oncologic timing, and confirms symptom management is addressed in tandem with psychological health strategies. Centers with routine MDT psycho-oncology engagement generate higher rates of guideline-concordant psychological support and better patient-reported results than centers depending on ad hoc referral[42,76].
Pharmacologic treatments have a role for moderate to severe diseases, but need to be personalized and reviewed within MDT due to polypharmacy, reaction risks, and functional issues. Recent guidance underscores shared decision-making about drugs, a defined plan for time and monitoring, and collaborative psychiatry-oncology assessment of complex cases[68,77]. Practical modifications are needed for implementation in LMICs. Recent studies have shown systemic gaps, such as the absence of personalized psycho-oncology services, a lack of workforce, stigma, and practical challenges like transportation and cost. Despite an efficient unmet requirement, these challenges lead to poor application of psychological support. For instance, a recent study revealed that efficient survivorship services like distress management are less prevalent in LMICs, where health systems focus on acute therapy over psychological follow-up[42,43]. Evidence-based strategies, such as task-sharing, co-location of psychological support within cancer or palliative support to decrease travel burden for individual or group sessions, and culturally framed psychoeducation to decrease stigma and develop uptake. Adaptations can enhance screening coverage and referral completion in settings with constrained resources[72,74].
Qualitative patient information should guide service design. Patient accounts of remorse, injustice, regret, and social isolation provide strong targets for therapy like meaning-centered work for legacy and acceptance, cognitive restructuring for self-blame, and mindfulness for somatic distress and contemplation. Additionally, they advocate for the adoption of integrated psychological-rehabilitative packages that target both functional recovery and emotional adjustment. Integrating patient narratives into MDT case assessments, quality indicators, and local implementation of screening thresholds helps confirm that programs remain personalized and attentive to the complicated circumstances of patients with EC and bone metastases[6,35].
CONCLUSION
EC with bone metastasis is one of the most urgent yet underrecognized challenges in oncology, where neglecting psychological distress perpetuates suffering, poor treatment adherence, and enhanced disease progression. Approximately 42% of patients develop clinically efficient depression, driven by systemic inflammation, increased hs-CRP and pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β. Systemic inflammation and HPA-axis dysregulation contribute to depression and worsen cancer outcomes. Skeletal-associated occurrences (e.g., hypercalcemia, fractures, spinal cord compression) increase pain and disability and promote social isolation, demoralization, and hopelessness. While mobility loss and treatment expenses hinder availability to psychological and psychiatric therapies, particularly in LMICs, low income, limited education, absence of social support, and sleep disturbances enhance distress.
Despite strong evidence that psychological comorbidity predicts poor treatment adherence, increased symptom burden, and reduced survival, psycho-oncology care is still inconsistently implemented. Barriers span workforce issues, inadequate training in distress evaluation, inconsistent application of validated instruments (e.g., PHQ-9, Beck Depression Inventory-II, DT), lack of referral channels, and absence of incorporation of biological risk markers. While operational fragmentation and clinician ambiguity continue to hinder guideline-concordant treatment in HICs, structural and economic disparities elevate these challenges in LMICs.
Emerging interventions demonstrate promising results in bridging this gap, such as a patient-centered approach in which psychological care is embedded as a core component of EC management. CBT significantly manages reliance, remorse, and anticipatory anxiety, MBSR reduces hyperarousal and somatic distress, and meaning-centered or existential therapy promotes acceptance and purpose in advanced cancer. By modifying serotonergic and inflammatory processes, these therapies improve resilience and assist in sustaining neuroimmune homeostasis when administered in conjunction with SSRIs under cautious prescription. However, in order to decrease negative responses with immunotherapies, chemotherapeutics, and bone-altering drugs like denosumab or bisphosphonates, pharmacologic strategies need to be customized and monitored within MDT frameworks. When psychology, psychiatry, palliative medicine, and oncology medicine are incorporated into MDT care, then psychopharmacologic and psychotherapy interventions stay in line with the overall treatment goals. Early interventions can be facilitated, particularly for immobile patients with skeletal complications, by enhancing availability through telehealth, task sharing with qualified oncology nurses, and incorporating psycho-oncologists into oncology care. In addition to quality of life and biological indicators, routine and persistent distress screening should guide rapid evaluation and dynamic treatment adaptation. To ensure personalized and collaborative care, these strategies need to be informed by patient-reported experiences of remorse, existential anxiety, exhaustion, and social isolation. Addressing psychological distress in EC patients with bone metastasis is not an optional adjunct but a clinical and ethical imperative. By framing mental health as both a driver and marker of disease progression, we highlight that incorporating psychological care with systemic and skeletal therapies is essential for improving quality of life, treatment adherence, and survival. Only through structured, equitable, and multidisciplinary strategies can we transform psycho-oncologic care from a neglected afterthought into a central pillar of modern cancer practice.
