Abstract

The impact of bone tumours on clinical practice remains as large today as it was at the turn of the century and as it is likely to remain so for several decades more. Bone and soft tissue cancers create challenges for patients that are not seen in most other malignancies, such as changes in gait, function, stability, strength, and appearance. Moreover, the economic burden can be great: the more advanced the disease at diagnosis, the worse the prognosis and, accordingly, the more expensive the treatments. This chapter of the White Book on Tumours aims to present an impartial review and a comprehensive overview of the current healthcare situation for patients with bone tumours in Europe.

2. Introduction

The economic burden of bone cancers can be great. The more advanced the disease at diagnosis, the worse the prognosis and, accordingly, the more expensive the treatments It is likely that early detection, and prevention if possible, could drastically reduce costs. A number of expensive treatments are currently deployed to address these tumours.

3. Epidemiology

3.1 Incidence

The impact of bone tumours on clinical practice remains as large today as it was at the turn of the century and as is likely to remain for several decades to come. Bone and connective tissue neoplasms, which include bone and joint sarcoma, myeloma and soft tissue sarcomas, are uncommon when compared with other cancers, and indeed with other musculoskeletal conditions. They accounted for about 2.2% of global annual cancer cases between 2006 and 2010 (approximately 43,000 cases). According to the Surveillance, Epidemiology, and End Results (SEER) Program of the National Institute of Health, the average annual incidence of bone cancers in U.S. between 2006 and 2010 was nine in one million, a rate that has remained constant for the last decade (https://seer.cancer.gov/statfacts/). The number of new cases of bone and joint cancers in a population is 0.9 per 100,000 people per year (Statista Research Department 2019).

In 2019, 550 males and 500 females were estimated to be newly diagnosed with primary bone cancer in Italy. Pertaining to a new diagnosis of metastatic bone disease among males, prostate cancer had the highest incidence (37,000). In both sexes combined, the highest incidence is seen in breast, colorectal and lung tumours, with 53,000, 49,000 and 42,500 new cases respectively (Statista Research Department 2019).

Sarcomas are a heterogeneous group of over 80 different tumours arising from mesenchymal or connective tissue. They make up less than 1.5% of all new cancer diagnoses. There were an estimated 1762450 new cancer diagnoses in 2019 in the United States, of which only 12750 cases were soft tissue sarcomas (STS), and 2970 cases were bone sarcomas. Sarcomas can be broadly categorized into soft tissue sarcomas, comprising approximately 1% of tumours in the UK and 2% of cancer deaths, and bone sarcomas, which, according to the figures from the Office of National Statistics, comprised 0.18% of all cancers and 0.21% of all cancer deaths in 2006 (Smith et al. 2011).

Annual population-based mortality rates due to cancers of bones and joints are low, averaging four deaths per one million people since the early 1990s in the U.S. as reported by the National Cancer Institute (https://seer.cancer.gov/statfacts/).

While the mortality rate from bone and joint cancer has dropped by approximately 50% since the late 1970s, no significant further improvement has been observed over the past 20 years (Figure 1). Although there are many histologic subtypes of bone and soft tissue sarcomas, the general principles of treatment remain the same, with surgical excision accompanied, at times, by adjuvant or neoadjuvant chemotherapy and sometimes by radiotherapy.

Figure 1

Total number of deaths due to a malignant tumour of bone and articular cartilage in Spain from 2005 to 2019.

Almost all cancers have preferential sites to which they spread or metastasize, resulting in secondary cancers. Secondary deposits of cancer in bone are much more common than primary bone cancers, and result in great morbidity and pain overall. The skeleton is the most common organ affected by metastatic cancer, and the site of disease that produces the greatest morbidity. The most commonly encountered cancers that readily and frequently spread to bone are cancers of the breast, lung, kidney, prostate, gastrointestinal tract and thyroid gland. The prognosis of metastatic bone disease is dependent on the primary site, with breast and prostate cancers associated with a survival measured in years rather than the months typical of lung cancer. Timely diagnosis, followed by a combination of local and systemic treatments (surgery, radiation therapy, embolization, chemotherapy, bisphosphonates) represents the therapeutic strategy used to obtain an improvement in the quality of life, functional outcome and disease control. Survival rates for secondary bone cancer depend on patient factors such as age, overall health, treatment and response to treatment. However, metastatic disease has by definition already spread, therefore signifies advanced cancer, so survival rates are much lower than seen in primary cancer without such spread. The fundamental treatment for bone metastases arising from advanced cancer is disease control by systemic chemotherapy and radiation of the bone lesions. Prevention and treatment of bone metastases is highly dependent on an effective treatment being available for management of the primary cancer (Coleman 2006). As of today, there is increasing evidence that surgical resection of a solitary metastasis or oligometastases (2 to 4 distant metastases in the same anatomic region) is associated with a better prognosis in certain favourable tumour histiotypes (breast, prostate, kidney, bowel, thyroid cancer, or myeloma)(Cappellari et al. 2020).

3.3 Risk factors

The statement of Smith et al. (2011), that “early diagnosis of cancer has been topical for many years and has recently become a political imperative” is still true. Earlier diagnosis can improve outcomes both in terms of local control and overall survival (Smith et al. 2011).

Surgical excision of sarcomas is usually attempted with a limb salvaging technique, which is possible when local invasion is minimal and the tumour is of low volume. Patients who have small tumours or who are free of metastases at diagnosis have an increased survival rate and the chance of survival is increased with more rapid diagnosis (Mavrogenis et al. 2015). The prognosis for any individual is determined by a combination of many factors including the effectiveness of treatment and response to chemotherapy, when used. Other prognostic factors include grade, site and size of the tumour, along with the age of the patient. Of all of these factors, size is the only one that can be influenced significantly by earlier diagnosis. Earlier diagnosis should lead to smaller tumours at diagnosis, which in turn should result in a better prognosis and easier treatment (Mavrogenis et al. 2015). Smith et al (2011) reported an analysis of a total of 4,934 patients with newly diagnosed bone (2568 - 52.0%) and soft tissue sarcomas (2366 - 48.0%) from 1985 to 2009 in UK. In their analysis, they found that there is no difference in the symptom duration at presentation reported by men and women for either bone (p=0.154) or soft tissue sarcomas (p=0.416). Patients with superficial soft tissue sarcomas (n=615, 26%) had considerably smaller tumours at diagnosis (6cm) than those with deeper ones (11.2cm) (p<0.0001) but had a longer median duration of symptoms (45 weeks vs 26 weeks respectively, p<0.0001) (Figure 2).

Figure 2

Mean duration of symptoms reported at presentation by patients (upper part of the graph) and mean tumour size at diagnosis (lower part of the graph) from a large series of bone and soft tissue sarcoma at the Royal Orthopaedic Hospital, Northfield (UK) (more...)

4. Impact

4.3 Direct costs (Healthcare costs, diagnosis, treatment, surgical/non-surgical costs)

There is an intense debate surrounding the cost of cancer treatment and the value of new therapies. However, there is limited data on the true cost of cancer in the European Union (EU) and how costs relate to the burden of disease. Direct health cost of cancer (DHCC) in the whole EU increased from €79 to €86 billion during the period 2005-2014 (in 2014 prices) (Jönsson et al. 2016). The cost of cancer drugs as a share of direct health costs increased from 12 to 22% during the same period. Other direct costs remained stable or decreased since 2005, probably linked to the shift from inpatient to outpatient care for many interventions (Jönsson et al. 2016).

The management of musculoskeletal tumours aims to improve patients’ survival and quality of life. Direct costs of treatment for patients with musculoskeletal tumours include those incurred prior to diagnosis and surgical treatment (including chemotherapy regimens and adjuvant treatments), during any inpatient stay and over the course of the postoperative management. It is not easy to define the typical treatment pathway, because the correct management should be customized according to patient characteristics and tumour histotype. Combined wide excision and adjuvant therapy remains the standard treatment for local control without increased recurrence or mortality. The traditional treatment in patients with sarcomas of the upper or lower limb was amputation. Recently limb-sparing surgery has become the standard of treatment for soft tissue sarcoma (STS), as advances in adjuvant therapy enable adequate margins to be achieved without the need for amputation.

Summarizing, therefore, patients with primary bone tumours should be directed to a specialized centre if there is a suspicion that the diagnosis is tumour (based on a consultation with a primary-care physician or general orthopaedic surgeon/other specialist). Treatment usually includes preoperative chemotherapy and continues with the surgical management in a specialized hospital. After surgery, the patients undergo rehabilitation, further adjuvant treatments and, always, follow-up ambulatory care by the oncology team.

Therefore, healthcare providers who are directly involved in the treatment of a musculoskeletal tumour, from diagnosis to follow-up, also incur healthcare expenses. Beyond this, physicians prescribing medications, therapeutic products or medical technical aids also add to further healthcare expenditure as do prescriptions for other care providers (for example, physiotherapists, pain management etc.) in addition to material costs for equipment and consumables.

There are different direct costs based on the type of bone lesion (primary tumour vs metastatic bone disease), and the use of chemotherapeutic drugs is of course one of the most relevant direct costs incurred in oncology patients. The following graph (Figure 3) shows the trend of consumption of cancer drugs in Italy from 2013 to 2018. According to data, the level of consumption of medicines to treat cancer peaked in 2018, reaching a value of 9.8 defined daily dose per 1,000 inhabitants per day.

Figure 3

Level of consumption of cancer drugs in Italy from 2013 to 2017

Whilst drug costs are relatively easy to identify, it is nevertheless really difficult to estimate the costs of reconstructive surgery, as there are different prosthetic designs for specific sites, different materials, variations in the length of reconstruction and emerging biologic options. These account for the differences observed between expenditure, with and without endoprosthetic replacements, in different hospitals. The costs for the replacement itself are to be considered as an estimate based on the lowest determined value, and this value is higher than the average expenditure for conventional arthroplasty, as it includes treatment costs related to tumour.

5. Sarcomas

Considering primary bone tumours, it has been observed that the most frequent initial treatments used vary widely in their rate of deployment, based on the histotype of sarcoma (Mavrogenis et al. 2015, Damron et al. 2007). Damron et al. (2007) reported that surgery alone was the most common initial treatment for chondrosarcomas (69%), whereas for Ewing sarcoma treatments were divided between surgery and chemotherapy (24% of cases), radiation and chemotherapy (23%), and chemotherapy alone in 18%. With osteosarcoma, where the initial treatment was known, the largest group received surgery and chemotherapy (46%). Surgery was reported as part of the initial treatment in 71% of osteosarcoma patients, 83% of chondrosarcoma patients and 47% of Ewing sarcoma patients. Multiple therapies may be needed later in the course of the patients’ disease, especially in the more advanced cases. In the later stages of the disease, for those who have not been cured by surgery alone, significant costs will accumulate as these patients may develop pulmonary disease and ultimately die. Hormone therapy, immunotherapy and bone marrow transplant/endocrine treatments each accounted for 1% or less of initial treatments. However, in severely affected individuals in whom standard treatments fail, these alternative treatments may be tried more frequently (Mavrogenis et al. 2015). All of these treatments are costly to administer. Per-patient cost will vary widely depending on the treatments utilized, and the number and intensity of treatments. Overall, treatment for a bone and joint cancer can easily exceed $100,000 for a single patient based on the “The Burden of Musculoskeletal Disease in the United States” evaluation (United States Bone and Joint Initiative 2014). This is particularly true if that patient receives surgery, chemotherapy, and radiation therapy. If one includes the cost of bone-replacing endoprostheses or the costs of artificial limbs used in those cases that required amputations, the cost will be much higher.

6. Metastatic Bone Disease.

SREs may occur as frequently as every 3–6 months in someone with skeletal metastatic disease (Coleman 2006). As mobility and functional independence diminish with subsequent SREs, overall health-related quality of life also declines. Furthermore, patients with metastatic bone disease and an SRE have a poorer prognosis and increased risk of death compared with patients who are SRE naïve. With FDA approval of the use of bisphosphonate medications to reduce the risk of pathologic fractures in 1995, the incidence of fractures in treated patients with metastatic bone disease in the USA has significantly decreased. The fracture rates reported in cases of metastatic disease and myeloma have been demonstrated in multiple studies to diminish with a roughly a 50% reduction in fracture rates in many studies. Body et al. (2016) reported a multinational, before-and-after, retrospective study that enrolled patients from hospitals in Austria, the Czech Republic, Finland, Greece, Poland, Portugal, Sweden, and Switzerland. They strongly demonstrate that in real-world practice SREs are associated with substantial increases in health resource utilization across all countries investigated.

A retrospective analysis from the Netherlands (Ter Heine et al. 2017) estimated that the mean per-patient cost to treat SREs in individuals with prostate cancer and bone metastases was €6973 (range, €1187–€40948). Despite the differences in the healthcare systems in the Netherlands and the UK, similar values have been reported for patients in the UK (Body et al. 2016) with breast cancer and bone metastases, with an estimated mean lifetime SRE-associated cost of £11314–£19121 (€14029–€23710; 1 GBP = 1.24 EUR). Notably, total medical care costs are substantially higher for patients who have bone metastases and one or more SREs than for those with bone metastases and no SREs (estimated US$48173 [€37093; 1 US$ = 0.77 EUR] more per patient per 60 months in the USA). Some recent studies reported the treatment patterns and health care costs in patients with prostate cancer and bone metastases. When the tumour progresses from localized or regional disease to metastatic disease, the 5-year relative survival rate drops from nearly 100% down to 29.3%. In mCRPC patients, 80%-90% present with bone metastases, which significantly lowers the 5-year survival rate to 3% versus 56% in patients without bone metastases. The presence of bone metastases has been strongly linked to increased resource utilization and costs (Yong et al 2014). In comparison with patients without bone metastases, those with prostate cancer bone metastases have increased use of skilled nursing facilities (22.3% vs. 8.1%), hospice care (20.0% vs. 4.8%) and hospitalization (60.9% vs. 43.1%) [Yong 2014]. Moreover, these patients have longer hospital stays (mean of 3 days longer). In fact, overall hospitalization costs of patients with bone metastases versus those without differed by more than US$2000 per visit between 2006 and 2010. A 2014 retrospective analysis of the linked SEER cancer registry and Medicare claims found that hospitalization rates among patients with prostate cancer without distant metastases was 43.1%, whereas the hospitalization rate among those patients with distant metastases was 60.9% at 1 year after diagnosis (Yong et al 2014). A study based on 342 patients with prostate cancer found that the average annual cost after the diagnosis of an SRE was about US$12500 (2006), ranging from $8484 to $26384 depending on the number of SREs that patients had experienced. Barlev et al. (2010) reported costs of inpatient treatment for each admission associated with different types of SREs. Among them, the cost of inpatient services for treating spinal cord compression (US$59788, 2009) was the highest, followed by pathologic fracture (US$22390, 2009) and surgery to the bone (US$42094, 2009). Hagiwara et al. (2013) measured costs of an SRE episode and found that the mean cost per episode was US$20984 (2010). Another study showed that the estimated lifetime SRE-related cost per patient suffering from metastatic lung cancer was US$11979, and that radiotherapy accounted for the greatest proportion of cost (61%) by SRE type.

In patients with metastatic spine tumours, overall complication rates range between 19% and 28%, whereas the incidence of surgical site infection and wound breakdown after surgery is 4%–20% (Demura et al. 2009). Crucially, the most common reason for reoperation after the resection of spinal metastases is surgical site infection, which commonly leads to wound breakdown. Spinal tumour resections are complicated by the fact that many patients have had previous radiotherapy or repeated surgeries, which diminish the capacity for wound healing following tumour resection. Reoperations in this cohort of patients with metastatic spine tumour are potentially devastating due to the potential risks of hardware exposure, delay in the administration of systemic treatments, increased costs, and prolonged hospitalizations.

7. Conclusions and List of Activities Needed

Overall, cancers that metastasise to bone cause significant pain and morbidity. Approximately 50% of patients with metastatic cancer of the lung, breast, prostate, and kidney develop bony metastases prior to death. Untreated, these metastases can lead to pathological fractures and cause great pain and disability. Thus, the elucidation of the biochemical steps involved in bone destruction and the development of drugs to target such steps are examples of tremendous scientific advancement and achievement, furthering the field of cancer research and treatment. Considering healthcare considerations, there is a need for even better collaboration between oncologists and other physicians and orthopaedic (oncology) surgeons in experienced centres in order to develop strategies to reduce the incidence of SREs, which are one of the main cost drivers in the management of musculoskeletal oncology patients.

The remuneration that a hospital receives for inpatient treatment constitutes the direct health insurance fund costs for the cases treated. Many European hospitals receive fees on a case-per-case basis (case fees) for individual inpatient stays (the case fees are also labelled Diagnosis Related Groups (DRGs)). The case fees reflect the average costs of treatment during a patient’s stay in hospital. A major issue that deserves consideration is the inadequacy of DRGs in meeting the real-world costs of the management of oncologic patients: for example, the DRGs received for managing a case that requires a proximal femur resection or pelvic resection is the same as for a case that requires primary total hip arthroplasty or revision total hip arthroplasty, and does not consider the staggering difference in implant costs. A further problem is the futility of attempted specific statistical analysis of DRGs. As can be seen from the terms used to describe the DRGs, the fees usually cover several different types of interventions. Consequently, extracting data related to the average costs of a specific treatment separately is not possible. This is because the DRG system remunerates similar cases and treatments based on the average costs of a range of different interventions.

What is strategically/politically needed for European Union: EFORT should promote initiatives which are of strategic importance in improving the outcomes of cancer patients, and in reinforcing the specialization of Orthopaedic Oncology:

1)

Strategic aspects

Worldwide, cancer registries have been shown to be critical for the accurate determination of cancer burden, conduct of research, and in the planning and implementation of cancer control measures. Information from cancer registries is vital for monitoring the incidence, prevalence and mortality of cancer, the effectiveness of national cancer prevention and cancer control initiatives, resource allocation and public policy related to cancer control. In Europe there are a range of different treatment strategies related to National protocols. Even if these are evidence-based, particularly when considering rare tumours, there is a need for data sharing. We need to promote registries, both national and European.

2)

Procedural aspects

Cancer research is constantly advancing. Evidence-based medicine helps to transfer the results of that research into new standards and methods for clinical practice. At present, most of the National Societies are involved in their own elaboration of a set of recommendations (“guidelines”) for the best standards of cancer care. Unfortunately, in most of the cases, these guidelines are in the native language and are being developed specifically for the Country of origin. We recognize that musculoskeletal oncology requires a multidisciplinary team for optimal patient evaluation and management. A formal governing Board or Committee with representatives from National professional organizations, together with National and European Oncologic Societies, should be commissioned with the aim of defining agreed European guidelines dedicated to the improvement of the quality of care and monitoring of outcomes for patients with bone tumours.

3)

Educational aspects

EFORT is very active in the field of education, with numerous projects and activities.

Courses co-organized by EFORT in collaboration with National Societies or European Societies related to oncologic diseases should be considered to be a great opportunity to share the knowledge of experienced Centres across the European community.

Moreover, multicentre research confers many distinct advantages over single-centre studies, including larger sample sizes and more generalizable findings, sharing resources amongst collaborative sites, and promoting networking. Well-executed multicentre studies are more likely to improve provider performance and/or have a positive impact on patient outcomes. We think that Europe should therefore promote and support European courses and multicentre studies, validated for quality by EFORT.

4)

Specific aspects related to soft tissue tumours

The orthopaedic community should take care of most of the soft tissue tumours that arise in the extremities. Soft tissue sarcomas should be treated in tumour referral centres. Ideally, a patient should be referred to a tumour centre when a sarcoma is suspected and before undergoing a biopsy or excision. It is essential that a meticulous diagnostic and staging workup is performed and that a multidisciplinary tumour team draws up a management plan and considers the range of reconstructive surgery options. There is a need for wide-ranging activity in the education of all physicians and healthcare staff about the risk of underestimating general symptoms (swelling, pain etc.) that could lead to an early suspicion and diagnosis, with the consequent advantages of early treatment. Moreover, there is a need to educate physicians to avoid the inadequate treatment of STS. Europe should promote the awareness of these aspects through a range of media.

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