Abstract
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Renal cell carcinoma (RCC) is a common type of tumor that can develop in the kidney. It is responsible for around one-third of all cases of neoplasms. RCC manifests itself in a variety of distinct subtypes. The most frequent of which is clear cell RCC, followed by papillary and chromophobe RCC.
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RCC has the potential for metastasis to a variety of organs; nevertheless, bone metastases are one of the most common and potentially fatal complications. These bone metastases are characterized by osteolytic lesions that can result in pathological fractures, hypercalcemia, and other complications, which can ultimately lead to a deterioration in quality of life and an increase morbidity.
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While nephrectomy remains a foundational treatment for RCC, emerging evidence suggests that targeted therapies, including tyrosine kinase inhibitors and T cell checkpoint inhibitors, may offer effective alternatives, potentially obviating the need for adjuvant nephrectomy in certain cases of metastatic RCC
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Bone metastases continue to be a difficult complication of RCC, which is why more research is required to enhance patient outcome.
Introduction
Renal cell carcinoma (RCC) is a prevalent cancer contributing notably to global cancer statistics (1, 2). Distinct histologic subtypes, notably clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chrRCC), define this disease (3, 4), each presenting unique genetic and physiological characteristics (5). Metastatic RCC (mRCC) generally has an unfavorable prognosis (6, 7).
In its localized form, nephrectomy – either partial or radical – serves as the primary treatment, offering hope for those with kidney-confined disease (8, 9). However, when RCC invades the bone, complications such as fractures, hypercalcemia, severe pain, and spinal cord compression emerge (10), demanding orthopedic surgical intervention. These interventions aim to alleviate symptoms, especially since RCC bone metastases tend to be osteolytic (11). Even with advancements like T cell checkpoint and tyrosine kinase inhibitors, managing bone metastasis remains challenging (12, 13).
Innovations in surgical techniques have been introduced to improve outcomes and minimize recovery times (14, 15). Successful RCC management mandates a collaborative effort from medical oncologists. radiation oncologists, and orthopedic surgeons (16, 17). Despite some treatments offering limited effects, drugs like soratenib, sunitinib, and cMET inhibitors are showing potential (19, 19, 20, 21, 22).
The osteolytic mechanism of RCC bone metastases is intricate, suggesting an interplay between abnormal bone remodeling and tumor growth. Such metastases usually indicate a bleak prognosis, with factors like elevated alkaline phosphatase levels, C-reactive protein, and the presence of extraosseous metastases impacting outcomes. Personalized treatment strategies, factoring in disease stage and overall health, are paramount. Surgical methods frequently offer symptom relief and a better quality of life. Emerging treatments, including cabozantinib, show promise, but the efficacy of targeted treatments on bone health is still under review (23, 24, 25, 26).
RCC metastasis pathology
RCC has a particular tendency to spread to the bones, causing mainly osteolytic lesions that have a significant impact on the patient’s health and likelihood of survival (27). RCC predominantly stimulates osteoclast activation, resulting in bone resorption and weakening, unlike other cancers that may cause mixed or osteoblastic skeletal metastases. The process is intricately connected to the interaction between tumor cells and the bone microenvironment, which is a characteristic feature of RCC’s metastatic behavior.
The pathophysiology of bone metastases in RCC is marked by the disruption of crucial molecular pathways, particularly the RANK/RANKL/OPG system, which has a central role in bone metabolism (28, 29). Within the framework of RCC, tumor cells manipulate this mechanism to amplify osteoclastogenesis, consequently facilitating the deterioration of bone tissue. More precisely, RCC cells have been discovered to release substances that enhance the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts and stromal cells. This leads to an imbalance favoring bone resorption (30). The release of pro-osteoclastic cytokines like interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) intensifies this interaction, worsening bone loss and promoting tumor growth in the bone marrow environment (31).
Recent studies have emphasized the importance of focusing on the RANKL pathway in patients with RCC who have bone metastases. Denosumab, a monoclonal antibody that targets RANKL, has demonstrated potential in decreasing skeletal-related events and delaying the advancement of bone metastases in RCC. This underscores the therapeutic possibilities of modulating this pathway (32). Additionally, the involvement of the calcium-sensing receptor (CaSR) in the spread of cancer to the bones in RCC is a topic that is gaining attention (33). The participation of CaSR in cellular processes like proliferation and migration indicates its potential as a target for therapy. Initial studies suggest that controlling CaSR activity could impact the behavior of RCC cells in the bone microenvironment (34, 35).
The evolving comprehension of RCC’s metastatic mechanisms to bone emphasizes the necessity for a multidisciplinary approach to management, incorporating targeted therapies that tackle the distinct molecular interactions propelling bone degradation (36). As research progresses in understanding the intricacies of RCC bone metastasis, it is crucial that clinical strategies also advance in parallel. This will provide hope for better outcomes in this difficult aspect of RCC treatment.
Medical care
The management of RCC has experienced substantial transformation, propelled by the formulation of comprehensive clinical guidelines that incorporate the most recent advancements in diagnosis and treatment. These guidelines are essential for providing both localized and advanced RCC care, as they guarantee that patients receive the most efficient and tailored treatment strategies currently available.
The main approach for treating localized RCC is surgical resection, which involves removing the tumor while trying to preserve kidney function as much as possible. This approach is supported by evidence that shows substantial survival advantages from both partial and radical nephrectomy in patients with localized disease (4). In situations where surgery poses a high level of risk for patients or when dealing with small renal masses, alternative approaches such as active surveillance or minimally invasive ablative techniques are taken into account. These strategies reflect a patient-centered approach to treatment.
The shift to systemic therapies represents a crucial stage in the treatment of advanced RCC, focusing on particular molecular pathways that are essential for the growth and spread of cancer. The introduction of tyrosine kinase inhibitors (TKIs) and mTOR inhibitors has significantly enhanced the prognosis for patients with metastatic RCC (4, 9), leading to improved survival rates and quality of life. The treatment of bone metastases, a common complication in advanced stages, has also progressed with the administration of bisphosphonates and denosumab, highlighting the significance of reducing skeletal-related events (5, 7).
Recent research emphasizes the significance of vascular endothelial growth factor (VEGF) inhibitors in extending the amount of time that a patient with RCC remains free from disease progression. This underscores the importance of angiogenesis in the pathological progression of RCC. In addition, the revolutionary implementation of immune checkpoint inhibitors, such as nivolumab, has created new opportunities for treatment, providing optimism for patients who had few alternatives before (13).
Tumor cells activate osteoclasts through the RANKL signaling pathway and other biochemical mechanisms. The goal of medical therapy is to inhibit these signaling pathways and consequently prevent osteoclast activation. It is imperative to acknowledge that treatment guidelines for RCC are subject to change, as they adapt to the swift progress of research and the findings of clinical trials. It is recommended that practitioners regularly refer to these guidelines to ensure that treatment plans are in line with the latest evidence-based recommendations (37).
Bisphosphonates
Bisphosphonates, discovered in the 1960s, are pivotal in treating malignancies like RCC due to their ability to inhibit osteoclasts and slow bone loss. Their safety and efficacy have been supported by clinical trials, showing notable reductions in skeletal-related events (SREs) such as pain. Evidence suggests they can even curtail RCC tumor growth and enhance both overall survival (OS) and progression-free survival (PFS) when used in targeted mRCC therapy (38).
Patients undergoing therapy should he informed of potential side effects. Notably, acute symptoms resembling the flu can be addressed with analgesics, and dosage adjustments can mitigate renal toxicity. Combination treatment carries a rare risk of jaw osteonecrosis, making dental check-ups essential pre- and post-treatment (39, 40, 41).
Zoledronic acid, a third-generation bisphosphonate, excels in treating bone metastases in malignancies, including RCC. Supported by three randomized trials (42), it not only alleviates pain but also extends the time before SREs manifest and reduces their occurrence. Its efficacy surpasses pamidronate in addressing RCC, metastatic lung cancer, among others. Notably, zoledronic acid has shown potential in enhancing the radiation therapy response for RCC bone metastases, with over half the patients witnessing reduced SREs (43, 44).
Combined radiation therapy with supplementary treatments leads to improved response rates and prolonged SRE-free survival. Zoledronic acid can enhance the sensitivity of RCC cells to radiation in bone metastatic locations. Kijima et al. revealed its ability to bolster caspase-3-mediated cell death in RCC cells and diminish STAT I expression post transcription, hinting at STAT1’s potential role (45). The therapeutic potential of combining everolimus and zoledronic acid has been validated, showcasing a progression-free survival increase from 5.4–7.5 months after 12 weeks (20, 46).
Denosumab
Denosumab, similar to zoledronic acid, benefits patients with advanced cancer or bisphosphonate resistance (47). It acts by binding to RANKL, thwarting bone loss and tumor progression. OPG and RANKL are critical in osteoclast-mediated bone remodeling (48, 49). A study revealed denosumab, when compared to zoledronic acid in patients with bone metastases, postponed the initial skeletal-related event (SRE) by 8.21 months and slashed the first SRE risk by 17% (50). Unlike its counterpart, denosumab does not demand renal function checks or dosage tweaks but can cause hypocalcemia Osteonecrosis rates for both drugs, including jaw involvement, are similar (50, 51).
While denosumab edges zoledronic acid in safety and ease for those with advanced cancer and bone metastases, data gaps remain regarding patient drug preference, administration method impact on life quality, and administration duration. Also, denosumab’s efficiency remains untested for patients with creatinine clearances under 30 mL/min. potentially sidelining those with significant renal issues from zoledronic acid use (52).
VEGF inhibitors
Haaker et al. studied metastatic pRCC (m-pRCC) patients starting first-line VEGFR-TKIs. The study measured best response (response evaluation criteria in solid tumors (RECIST)), PFS, and OS from the beginning of VEGFR-TKI treatment. Bone scintigraphy and thoracic CT identified bone metastases (BM), with targeted radiology for specific limb symptoms. Comparisons were made using unpaired t-tests and Fisher’s exact test (8, 51). PFS and OS were evaluated with the Kaplan–Meier method, and factors influencing these were analyzed with Cox models. Lymph nodes were the leading metastasis site (79.6%), followed by lungs (55.1%) and bones (36.9%) (8).
Prognostic indicators are scarce for m-pRCC patients treated with VEGFR-targeted therapies. Biomarkers were identified in m-ccRCC patients treated with angiogenesis inhibitors, but most studies emphasized non-ccRCCs over pRCCs. Existing data suggest BM negatively affects m-pRCC patients on VEGFR-TKIs. m-ccRCC patients treated with first-line VEGFR-TKIs show worsened outcomes with BM. The reasons for poorer prognosis in RCC patients with BM are not entirely clear. Highly aggressive primary kidney tumors might metastasize to bones more frequently. Vrdoljak et al. confirmed poorer outcomes in patients with BM (52).
Sunitinib
Sunitinib, a VEGF receptor tyrosine kinase inhibitor, demonstrated a 39% objective response rate in a phase III trial. Patients’ PFS increased from 5 to 11 months, though interferon-treated patients had a longer lifespan (26.4 vs 21.8 months). Sunitinib is now a favored first-line treatment for metastatic RCC. Maita et al. showed its efficacy in halting renal cell cancer bone metastasis growth in mice. Furthermore, sunitinib reduced para-neoplastic hypercalcemia in metastatic RCC, hinting at a potential positive impact on bones (53).
Sorafenib
Sorafenib inhibits VEGF and its receptors, as well as the intracellular signaling enzyme Raf kinase. It is a generic medication. In a phase III research, individuals with treatment-refractory metastatic RCC survived 5.5 months longer than placebo-controlled patients (54).
mTOR inhibitors
In a phase III trial by Hudes et al., patients with high-risk metastatic RCC were assigned to temsirolimus or IFN monotherapy, or a combination of both. Temsirolimus alone extended OS to 10.9 months compared to IFN’s 7.3 months. However, the combination did not enhance OS (55).
Inhibitors of tyrosine kinases including MET, vascular endothelial growth factor receptors, and AXL
Cabozantinib, an oral pro-oncogenic tyrosine kinase inhibitor, has shown potential in inhibiting prostate tumor growth in bone and positively impacting the bone microenvironment (56, 57). Clinical trials linked cabozantinib to improved bone response and decreased bone-related adverse events in prostate cancer (58). A phase III trial found cabozantinib outperformed everolimus in advanced RCC patients, especially those with bone metastases. Specifically, cabozantinib led to a median OS of 20.1 months and PFS of 7.4 months, in contrast to everolimus’s 12.1 months and 2.7 months, respectively. Recent findings from the CheckMate 025 study suggest nivolumab had a promising OS compared to everolimus (59). Cabozantinib was also linked to shifts in bone biomarkers, like reduced P1NP and increased CTX (60). Common side effects included fatigue, diarrhea, and palmar–plantar erythrodysesthesia with cabozantinib, while everolimus was associated with anemia, hyperglycemia, and lymphocytopenia. Severe hypercalcemia was rare regardless of treatment or bone metastasis presence (61).
Immunotherapy resistance in RCC: molecular mechanisms
Cancer treatment is frequently hindered by drug resistance, both intrinsic and acquired. While intrinsic resistance is due to preexisting resistant tumor cells, acquired resistance develops post-initial treatment remission. Two causes of targeted treatment resistance include the sequestration of Tyrosine kinase inhibitors (TKIs) in lysosomes and changes in gene mutations or expression (62, 63).
A significant factor in clear cell RCC is the deactivation of the von Hippel–Lindau (VHL) gene, leading to the activation of hypoxia inducible factor (HIF) (64). This can cause abnormal AKT/mechanistic target of rapamycin (mTOR) signaling resulting in resistance to some drugs. However, the H1F-2 antagonist PT2399 has demonstrated efficacy in overcoming resistance in some RCC tumors resistant to sunitinib (62, 65).
Medications like sorafenib and axitinib can inhibit the growth of RCC cell lines. High levels of certain interleukins in ccRCC patients might lead to resistance to TKIs (66, 67, 68). Another factor affecting drug resistance is the PTEN tumor suppressor, which generally shows decreased expression in RCC. ccRCC tumors also produce a significant amount of fat which might diminish treatment efficacy. Furthermore, ABC transporters influence drug effectiveness and their interactions (69, 70).
One of the biggest challenges for targeted therapy is intratumoral heterogeneity (ITH) due to the varied genetic and protein expression within a tumor. The tumor microenvironment, which includes the extracellular matrix (ECM), stromal cells, and tumor cells, is vital for tumor growth and resistance to therapies. Specific cells, such as pericytes and myeloid-derived suppressor cells, contribute to treatment resistance (71, 72).
The growth and resistance of cancer stem-like cells depend on notch signaling, but its inhibition can reinstate drug sensitivity. On the other hand, tumor-associated fibroblasts can override the suppression of VEGF-mediated angiogenesis (73). Sequentially applying TKIs with different target profiles has shown promise in advanced RCC patients (74).
Lastly, immune checkpoint inhibitors target mechanisms like PD1-PD-L1/CTLA4, preventing tumor cells from camouflaging from host immunity. However, mRCC cells expressing PD-L1 show aggressive pathology. The checkpoint inhibitor CTLA-4 has potential in combination therapies for various cancers, despite its toxicity (1, 75, 76).
Non-drug treatment
Orthopedic surgery addresses most symptoms of bone metastasis, preventing potential fractures and managing spinal and long bone issues. Osteolytic lesions without periosteal reaction are characteristic of renal cell metastasis (77).
Angioembolization
RCC metastases often display vascularity similar to the primary tumor (Fig. 1) (50). Hypervascular bone metastases have been effectively embolized intra-arterially. Pre-operative embolization reduces post-surgical complications, including pain and blood loss. Chatziioannou et al. highlighted that full embolization reduced blood loss to an average of 535 ± 390 mL compared to 1247 ± 1047 mL in partial embolization (78). The role of local treatments, like metastasectomy or radiation, is debated, with concerns including metastasis accessibility and patient health (79).
The case of a 56-year-old man with a vascularized metastasis from renal cell carcinoma in the proximal humerus. A–C showcase the tumor's rich blood supply, indicating potential surgical bleeding risks. (D) Post-treatment image revealing a significant decrease in vascularization following angiography and embolization, thus confirming the procedure's success and indicating reduced intraoperative bleeding risks.
Citation: EFORT Open Reviews 9, 6; 10.1530/EOR-23-0178
Nephrectomy
Nephrolithotomy is employed in patients with metastatic RCC to relieve symptoms like hypercalcemia and erythrocytosis. On the other hand, cytoreductive nephrectomy, which was used before targeted therapies were available, has been proven to increase survival by 6 months and decrease metastatic lesions in 1–2% of cases. Due to the palliative nature of care in advanced stages, it is crucial to combine these surgical interventions with efficient pain and symptom management.
Eliminating metastases
Solitary metastases from RCC are uncommon, occurring in less than 5% of cases. Nevertheless, in specific cases, the surgical removal of these separate metastases can profoundly influence clinical results. The justification for surgically treating solitary metastases is based on the possibility of not only relieving symptoms but also prolonging survival in a condition that is typically considered palliative once metastasis occurs. This approach is based on meticulous patient selection, taking into account factors such as the patient’s overall health, the absence of other metastatic sites, and the ability to completely remove the metastasis with clear margins. The objective is to attain a state where there is no presence of tumors, which, despite being difficult, may provide a survival advantage and enhanced quality of life (Figs. 2 and 3) (27, 80).
The case of a 62-year-old woman. (A) An unexpected solitary metastasis in the proximal femur discovered due to a fracture after a minor fall. ( B) A transverse CT scan, showing the fracture paths and exact tumor location. (C and D) Sagittal and frontal views of the tumor, illustrating its three-dimensional nature and proximity to nearby structures. (E) Post-surgery image depicting the tumor’s removal and the femur’s reconstruction using a modular prosthesis, emphasizing the surgery’s success in restoring bone structure and function.
Citation: EFORT Open Reviews 9, 6; 10.1530/EOR-23-0178
The case of a 59-year-old male patient with an unremarkable medical history and no previous hospitalizations. The patient arrived at the emergency department with a sudden onset of pain and limited ability to move the right hip. These symptoms occurred while trying to chase after public transportation. Upon initial radiographic examination of the pelvis, a pathological fracture was observed at the specific location of interest (A). Following further medical examinations, which included extensive laboratory tests and a thoracoabdominopelvic CT scan, no abnormalities were found except for a cancerous growth in the left kidney. Due to the metastasis being limited to the upper third of the right femur, it was decided to surgically remove the kidney lesion as a whole, and then reconstruct the upper part of the femur using a modular prosthesis (B).
Citation: EFORT Open Reviews 9, 6; 10.1530/EOR-23-0178
Impending and pathologic fractures
Although there have been improvements in systemic treatments, radiation therapy continues to be a viable choice for alleviating the pain caused by bone metastases, spinal cord compression, and brain metastases. Contemporary methods administer accurate and concentrated amounts of treatment, focusing on specific areas while minimizing any negative effects on nearby healthy tissue (Fig. 4) (81, 82). Historically, non-surgical painful bone metastases have been treated using analgesics and radiation therapy to relieve pain and halt additional bone deterioration (50).
A 69-year-old male with advanced metastases in the proximal femur and sacrum. The image shows significant osteolysis, which is a strong indication of an imminent pathological fracture. (A) Depicts the presence of an osteolytic tumor in the femur, whereas B and C exhibit CT scans that illustrate the magnitude of metastasis in the femur and sacrum. The bone scintigraphy (D) provides additional evidence of the extensive distribution of the disease. Due to the presence of an inoperable tumor in the femur and sacrum, as shown in Fig. 4, the patient received a comprehensive treatment plan aimed at alleviating symptoms and enhancing quality of life. Due to the unavailability of surgical alternatives, the patient underwent a treatment regimen consisting of a combination of radiation therapy and radiofrequency ablation. The objective of this approach was to alleviate pain, decrease the size of the tumor, and stabilize the bone structure in order to prevent fractures. The radiation therapy was carefully designed to optimize the dosage delivered to the tumor while minimizing the impact on nearby healthy tissues, thereby effectively reducing pain and preventing additional deterioration of the bone.
Citation: EFORT Open Reviews 9, 6; 10.1530/EOR-23-0178
Presently, the available treatments for painful bone lesions encompass minimally invasive procedures like ethanol, laser, and radiofrequency ablation. These procedures provide targeted relief and result in shorter recovery periods (83). Furthermore, there have been advancements in the recommendations for preventive fixation to tackle the negative health outcomes and death rates linked to hip fractures. These guidelines prioritize early intervention to avoid fractures in areas with a high risk (50).
Surgical fixation’s purpose is pain relief, improved function, and better nursing care (Figs. 5 and 6). Rapid surgical fixes are essential, relying on internal fixation or PMMA prosthesis replacement (84). Polymethyl methacrylate's thermal attributes might reduce tumor cell viability, but more research is needed (44).
The case of a 66-year-old woman, with complex health issues, who has suffered a pathological fracture in the humerus due to metastasis. (A) Highlights the osteolytic metastasis in the humerus. (B) Scintigraphic image showing systemic spread. (C) Postoperative image showing an intramedullary rod used for osteosynthesis, allowing immediate arm movement.
Citation: EFORT Open Reviews 9, 6; 10.1530/EOR-23-0178
The case of a 78-year-old patient who has a confirmed diagnosis of renal carcinoma and is also experiencing widespread metastatic disease, as confirmed by whole-body bone scintigraphy (A). The patient received treatment at our oncology clinic, where a team of specialists closely observed the progression of the disease. Due to the patient’s high likelihood of experiencing fractures caused by disease, especially in the right femur where metastatic involvement was found (C), and in multiple vertebral bodies, it was decided to perform palliative surgical procedures with the goal of enhancing the patient's quality of life and reducing discomfort. In order to mitigate the imminent danger of a femur fracture, a procedure called comfort osteosynthesis was conducted using gamma nails (D). This technique was selected due to its minimally invasive characteristics and its ability to effectively stabilize metastatic lesions. Furthermore, the stabilization of the vertebral column was accomplished by means of segmentation (as shown in E), which additionally aids in pain reduction and provides structural support. The patient's metastatic burden, as revealed in CT imaging (B), was too extensive to allow for curative resection and reconstruction. The extensive tumor infiltration in the femoral region emphasizes the need for a cautious surgical strategy. Due to the patient's advanced age and the existence of multiple comorbidities, which made her especially susceptible, it was determined that a forceful surgical procedure was not feasible. The therapeutic approach was customized to prioritize the management of symptoms and the preservation of functional independence for as long as feasible, recognizing the inherent complexities in treating metastatic renal carcinoma with substantial skeletal involvement.
Citation: EFORT Open Reviews 9, 6; 10.1530/EOR-23-0178
For parts not amenable to internal fixation, prostheses are an option. The choice of prosthetic replacement should be robust, targeting vulnerable bone areas to minimize future bone degradation (85).
Prognosis
The prognosis of RCC varies considerably depending on the stage, histological subtype, and the presence of metastases. Although localized RCC can be effectively managed, resulting in positive outcomes, the occurrence of metastases, particularly in the bone, often indicates a negative prognosis. Advancements in systemic therapies have significantly improved the management of RCC. However, the intricate nature of metastatic disease necessitates the implementation of a comprehensive and multifaceted strategy. Bone metastasis in metastatic RCC is an unfavorable sign, often pointing to a poor prognosis. Although systemic chemotherapy can sometimes alleviate the condition, larger bone lesions need to be controlled, as solely relying on systemic therapy might not be effective. Combining enhanced radiation and surgery seems promising (7, 11, 86).
Early-stage RCC, if promptly detected and treated, generally leads to a favorable prognosis with a high rate of survival. Medical advancements have brought about targeted therapies and immunotherapies, leading to a notable enhancement in the outlook for patients with advanced renal cell carcinoma (RCC) (3, 5). Nevertheless, the existence of metastases, specifically bone metastases, is linked to a more difficult prognosis, emphasizing the significance of comprehensive treatment approaches (7, 11).
The presence of bone metastasis in RCC is a crucial factor that adds complexity to treatment and has a negative impact on patient outcomes. To effectively manage larger bone lesions, a combination of radiation and surgical interventions is often necessary, despite the potential relief offered by treatments such as systemic chemotherapy (86). The histological subtype of RCC has an impact on the spread of cancer to different organs, such as the lungs, lymph nodes, and bones. Subtypes like clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chrRCC) have different tendencies to metastasize, which ultimately affects the OS of patients (5, 8, 86, 87).
The RECIST criteria, commonly employed for assessing treatment response, may not sufficiently capture the effectiveness of therapies in bone metastases. The MD Anderson bone response criteria, originally designed for breast cancer, provide a more customized evaluation for RCC bone metastases, particularly in assessing the feasibility of combining radium 223 dichloride with targeted therapies (22, 88).
Advancements in treatment have resulted in a decrease in the activity of osteoclasts and an increase in the occurrence of sclerotic tissue changes, which are reliable indicators of successful treatment. Nevertheless, the treatment of bone metastases without radiation or the administration of targeted therapies and immune checkpoint inhibitors has certain restrictions. The distinct molecular characteristics of RCC spreading to the pancreas and the varying rates of survival observed among patients with metastatic clear cell RCC (chrRCC) based on the location of metastasis emphasize the intricate nature of RCC prognosis and underscore the necessity for tailored treatment strategies (11, 34, 50, 89, 90, 91). There is an alarming prognosis for brain metastases, with ccRCC displaying an 8% brain involvement compared to lower rates in pRCC and chrRCC. The actual prevalence of brain metastases may be underestimated due to challenges in detecting asymptomatic cases. Intriguingly, non-clear cell histological RCC variations have lower recurrence and mortality rates (92, 93).
The outlook for RCC, especially when it spreads to the bones, continues to be a major concern. Continued investigation into the molecular mechanisms of RCC and the creation of new therapeutic approaches are essential for enhancing outcomes at every stage of the disease. The incorporation of systemic therapy alongside radiation and surgical interventions is crucial in the management of metastatic RCC, with the objective of improving both the quality of life and survival rates of affected patients (94, 95, 96). RCC staging, such as the TNM system, is instrumental for treatment planning (Table 1). Prognostic studies for RCC bone metastasis have identified various factors tied to unfavorable outcomes, critical for clinicians to adjust their treatment strategies (Table 2) (92, 97, 98, 99).
TNM classification system for renal cell carcinoma.
| Staging | Tumor | Node | Metastasis | 5-year survival rate (94) |
|---|---|---|---|---|
| I | T1: tumor confined to kidney | N0 | M0 | 81% |
| a) ≤4 cm | ||||
| b) >4cm and ≤7cm | ||||
| II | T2: tumor confined to kidney | N0 | M0 | 74% |
| a) >7 and ≤10 cm | ||||
| b) >10 cm | ||||
| III | T1 or T2 : tumor confined to kidney | N1 | M0 | 53% |
| Or | ||||
| T3: tumor extension | N0 or N1 | M0 | ||
| a) Into the renal vein or segmental branches or invades perirenal and/or renal sinus fat but does not invade beyond Gerota fascia | ||||
| b) Into the vena cava below the diaphragm | ||||
| c) Into the vena cava above the diaphragm or invades the wall of the vena cava | ||||
| IV | T4: tumor invades ipsilateral adrenal gland or beyond Gerota fascia | Any N | M0 | 8% |
| Or | ||||
| Any T | Any N | M1 |
An overview of prognostic factors that have been identified in the literature.
| Study | Prognostic factor | Patients, n | RR | 95% CI | P |
|---|---|---|---|---|---|
| (3) | Age ≥60 years | 384 | 2.0 | 1.2–3.2 | 0.008 |
| (97) | High Fuhrman grade | 1435 | 2.14 | 1.70–2.68 | <0.001 |
| (98) | Clear cell histology | 400 | 1.5 | 1.1–2.0 | 0.01 |
| (71) | High serum LDH | 1084 | 1.6 | 1.4–1.9 | <0.001 |
| (99) | High serum ALP | 645 | 2.0 | 1.6–2.6 | <0.001 |
| (100) | Metastatic disease at diagnosis | 1605 | 6.73 | 5.18–8.73 | <0.0001 |
| (73) | High serum CRP | 76 | 6.64 | 2.19–20.17 | 0.001 |
| (101) | High platelet count | 109 | 3.28 | 1.40–7.69.0 | 0.006 |
ALP, alkaline phosphatase; CRP, C-reactive protein; LDH, lactate dehydrogenase; RR, relative risk.
Discussion
Treating bone metastases in RCC is a difficult task for doctors, as it is often associated with a negative outlook and a significant decrease in quality of life due to skeletal-related events (SREs). Although systemic therapies have made progress, the distinct orthopedic complications linked to bone metastases from RCC require a more focused treatment approach. This highlights the crucial role of surgical intervention and palliative care in managing this group of patients (10, 32, 100, 101, 102).
The introduction of enhanced surgical techniques and palliative interventions has significantly improved the treatment of bone metastases in RCC. Radical surgery, which involves removing the tumor as a whole and using modular prostheses, has the potential to improve survival rates, especially in patients without fractures caused by the tumor and when complete removal of the tumor is possible. These surgical techniques have the dual purpose of relieving symptoms and restoring function while also preventing additional complications, such as pathological fractures and spinal cord compression, which are common in patients with metastatic RCC (10, 32).
Intra-arterial embolization is a novel method used to decrease the excessive blood supply associated with metastases of RCC, resulting in a reduction of complications and blood loss after surgery. When considering this technique, as well as other local treatments like metastasectomy and radiation therapy, it is important to carefully evaluate the accessibility of the metastasis and the overall health of the patient (63, 64). The decision-making process for these interventions emphasizes the need for a multidisciplinary approach, incorporating the knowledge and skills of medical oncologists, radiation oncologists, and orthopedic surgeons in order to maximize patient outcomes.
In the era of targeted therapies, the role of nephrectomy has changed. Previously, cytoreductive nephrectomy was found to be beneficial in improving survival and causing regression in certain metastatic lesions. Nevertheless, the fact that treatments for metastatic RCC are only able to provide temporary relief underscores the significance of promptly managing symptoms and addressing treatment-related concerns. These actions are crucial for improving the quality of life for patients (50, 65).
Although systemic therapies are effective in treating metastases in organs other than bones, their effectiveness in treating bone lesions is limited. This constraint highlights the necessity for surgical and palliative interventions that are specifically tailored to target the orthopedic symptoms caused by RCC metastases. Methods such as internal fixation, prosthesis replacement, and the use of polymethyl methacrylate (PMMA) have shown promise in promptly alleviating pain and enhancing functional outcomes in individuals with bone metastases (69, 70).
The treatment of bone metastases from RCC in orthopedics is currently at a crucial point, as advancements in surgical methods and materials are providing new possibilities for managing this condition. The utilization of gamma nails and other minimally invasive stabilization techniques has become more widespread, offering effective relief and stabilization for patients at a high risk of fractures caused by metastatic lesions (84). The significance of early intervention and customized surgical approaches in preventing complications and improving patient mobility and comfort is highlighted by these advancements.
Spinal metastases originating from RCC present a specific difficulty because of the potential for spinal cord compression and the resulting significant negative effect on the patient’s quality of life. Segmental stabilization and vertebral augmentation techniques have demonstrated potential in addressing these complications, providing pain relief and halting the progression of spinal instability (81, 82). In order to determine whether or not to proceed with these treatments, it is important to thoroughly evaluate the location of the lesion, the degree to which the spinal cord is affected, and the overall health of the patient. This emphasizes the importance of a comprehensive assessment conducted by a team of experts from various disciplines.
The intricate nature of handling RCC bone metastases requires a cooperative strategy that combines the knowledge and skills of orthopedic surgeons, medical oncologists, radiation oncologists, and palliative care specialists. This comprehensive care model ensures that all aspects of the patient’s condition are taken into account, including the direct treatment of bone lesions, the prevention of the progression of systemic disease, and the improvement of quality of life through palliative interventions (102). The treatment of RCC, especially when bone metastases are present, necessitates a thorough and interdisciplinary strategy that weighs the advantages of systemic therapies against the specific requirements of orthopedic intervention. It is crucial to combine surgical and palliative care approaches, customized to the specific patient's condition and prognosis, in order to reduce the orthopedic complications of RCC and enhance overall patient outcomes. In order to advance the field of orthopedic oncology, it is imperative to conduct continuous research and foster collaboration among different specialties. This will play a vital role in the development of groundbreaking treatments that can significantly improve the quality of life and increase the survival rates of patients with RCC bone metastases (19, 58, 103, 104).
Conclusion
RCC poses a major difficulty in the field of orthopedic oncology, primarily because it has a strong tendency to spread to the bones, leading to a significant negative impact on patient health and survival. Effectively managing bone metastases caused by RCC necessitates a comprehensive comprehension of both the biological characteristics of RCC and the mechanical consequences of skeletal engagement. As orthopedic surgeons, we go beyond just relieving symptoms and actively work to improve the structural integrity of affected bones. This not only enhances the quality of life for patients but also has the potential to increase their lifespan.
The surgical procedure for bone metastases of renal cell carcinoma (RCC) has undergone significant development, as advancements in techniques and materials have provided fresh opportunities for treatment. Modular prosthetic reconstruction, minimally invasive stabilization, and targeted embolization are essential elements of our surgical toolkit. They enable us to create customized treatment strategies that cater to the specific requirements of every individual patient. When used alongside systemic therapies, these interventions provide a comprehensive method for managing the intricate relationship between cancer progression and skeletal health.
Moreover, the emergence of targeted therapies and immunotherapies has ushered in a new era in the comprehensive treatment of RCC, offering optimism for enhanced results. Nevertheless, the enduring presence of treatment resistance highlights the imperative for continuous research and advancement in both systemic therapies and surgical methods.
The treatment of bone metastases caused by renal cell carcinoma (RCC) requires a flexible and collaborative approach, combining cutting-edge surgical techniques with progress in systemic therapy. Our dedication to improving surgical methods, combined with a comprehensive comprehension of the molecular foundations of RCC, will remain crucial in improving patient results. Providing patients with information and comprehensive treatment is crucial as we navigate the intricacies of RCC treatment together, aiming for both increased survival rates and enhanced quality of life for our patients.
ICMJE Conflict of Interest Statement
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported here.
Funding Statement
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
IAE reviewed the literature, contributed to data synthesis. BS wrote and edited the manuscript. MP and AI performed the literature search. SN performed literature search. CC contributed to the conception, planning and preparation of the final manuscript. All authors contributed to final edits and revisions prior to submission.
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