Functional outcomes of bony sarcoma (BS) in Adolescent and Young Adult Oncology (AYAO) patients—a scoping review

Introduction

Sarcomas are rare cancers, accounting for 1% of all adult malignancies, and 7% of childhood malignancies (1,2). It is however more common in adolescents and young adults (AYAs), affecting about 10–20%. Sarcomas are a heterogeneous group of malignancies linked by their mesenchymal origins and can occur at any anatomical site. They can be divided into soft tissue sarcomas (STS) (including fat, muscle, nerve and nerve sheath, blood vessel, connective tissue) and bony sarcomas (BS). The 5-year survival rate ranges from 55–60% for STS and 50–55% for BS (3,4).

Adolescent and Young Adult Oncology (AYAO) patients have often been neglected and have been referred to as the “lost tribe” (5). They are a unique population of patients as they have a cancer diagnosis in the prime of their lives when there are multiple concurrent life changes. The primary site of BS also often makes morbidity significant where treatment is concerned. While we focus on survival rates, understanding how it affects the patients’ quality of life and function is also important. However, this has hardly been addressed in this population as survival rates have usually been of priority.

As BS inevitably result in some form of functional loss, we will be focusing on the more common primary BS. We will be reviewing the current evidence regarding functional outcomes, its determinants post-treatment and the tools utilized to assess functional outcomes.

Primary BS

BS can be categorized into chondrogenic, osteogenic, fibrogenic, vascular and osteoclastic giant cell origins as per World Health Organization (WHO) classification (6). Primary BS account for <0.2% of malignant neoplasms across all ages. The more common BS include osteosarcomas, Ewing’s sarcoma (ES) and conventional chondrosarcoma (CS). Primary bone sarcomas have an overall incidence rate of 0.8 to 0.9 cases per 100,000 persons per year (7). They usually present due to symptoms such as persistent non-mechanical pain that is often worse at night. Swelling and functional impairment can occur if the tumor has progressed through the cortex causing periosteum distension, causing intense pain, swelling and restricted mobility.

What is AYAO?

There are varying definitions of AYAO Oncology. In general, AYAO patients are defined as those 15 to 39 years old with cancer by the National Cancer Institute (8). They are diagnosed with cancer while in varying stages of physical and psychosocial developments. AYAOs have been identified as a special population with vastly differing needs compared to their pediatric and older adult counterparts. These needs encompass physical, psychological, emotional and spiritual. Furthermore, 80–85% of AYAOs are expected to have long-term survival >5 years (9). Yet, surviving cancer during young adulthood is associated with substantial economic burden, and many survivors experienced initial delays in education and employment due to their cancer diagnosis and treatment (10).

Furthermore, even among the AYAO population, patients are in differing life stages, characterized by pubertal changes, work and life experiences, romantic relationships and financial responsibilities. Few institutions have dedicated AYAO care, and they are hence often managed either with pediatrics or with older adults. As they belong to neither group, their needs are often overshadowed. It has been increasingly shown that AYAOs ought to be emergently managed in an individualized holistic manner to facilitate best outcomes (11). It is known that AYAO patients generally have poorer outcomes compared to other ages. It has been consistently shown that AYAOs have a worse survival than younger patients in cancers such as osteosarcoma, Ewings, rhabdomyosarcoma (RMS), and acute lymphoblastic leukemia (ALL) (12). Long-term AYAO survivors are also at risk for other medical conditions such as metabolic syndrome, accelerated atherosclerotic disease and subfertility. These issues can arise either from the cancer itself or from treatment-related long-term side-effects (13,14). The worse outcomes seen in AYAOs have been attributed to multiple factors. These include delayed diagnoses, a likely more aggressive tumor biology, lower clinical trial participation, poorer compliance, no standard treatment guidelines, differing chemotherapy metabolism and financial concerns, among other factors. Delayed diagnosis is potentially more significant in BS as this may affect viability of limb salvage (LS) surgery, and with it, functional outcomes.

In the care of AYAOs with BS, functional outcomes are even more important as it will affect not only their health-related quality of life (HRQoL), but also their activity levels and independence. Furthermore, their functional outcomes have a direct connection to their self-confidence and future job endeavors.

Patient-reported outcome measures (PROMs) and HRQoL

HRQoL is a PROM. It is a multidimensional encompassment of physical, social, psychological, cognitive, and spiritual aspects of wellbeing. There is increasing focus on PROMs by both patients and healthcare teams (15-18). PROMs can be utilized in various clinical contexts to assess patient’s healthcare needs, preferences, and difficulties (19).

Functional outcomes

When cancer outcomes are discussed, this is usually in terms of overall survival (OS), progression free intervals and recurrence rates. However, the mainstay of treatment in BS involves surgery which can have significant impacts on mobility, function and body image. This, coupled with the fact that AYAOs are usually most active during this phase of life, preserving and maximizing functional outcomes becomes especially vital (2).

Assessing functional outcomes

Functional outcomes among adult sarcoma patients have typically been measured in several distinct ways:

• Objective physical function;
• Clinician-assessed disability;
• Patient-reported functional disability;
• Patient-reported generic cancer-specific HRQoL.

Objective physical function

It refers to an independent assessment of what one can accomplish physically. It is assessed by objective tests such as the 6-minute walk test (6MWT), time to get up and go (TUG), timed up and down stairs (TUDS), evaluation of range of motion (ROM), limb volume and Assessment of Motor and Process Skills (AMPS).

Clinician-assessed disability

It is often measured by Musculoskeletal Tumor Society Score (MSTS).

Historically, musculoskeletal oncology has utilized physician-dependent measurements of function to compare treatment outcomes. With the MSTS, the clinician will rate the patients on seven parameters including pain, ROM, strength, joint stability, deformity, emotional acceptance of procedure and general functional ability.

Patient-reported functional disability

It is often measured by Toronto Extremity Salvage Score (TESS) or the PROMIS Physical Function.

In recent years, the value of measuring patient perceptions of their own function after treatment has been widely recognize (20). Measures such as the TESS was developed by a multidisciplinary sarcoma team from the University of Toronto after identifying specific functional difficulties faced by sarcoma patients in daily living, work, leisure, mobility, sexual activity. It is utilized in extremity sarcomas (upper or lower) to identify PROM of their function.

Patient-reported generic cancer-specific HRQoL

Subjective PROM often utilizes a myriad of tools, the most common of which are highlighted in Table 1.

These tools have been validated in multiple studies, and disease types to obtain a quantitative assessment of various domains of function, including physical, social, emotional (21,22). However, it needs to be reiterated that none of these scores are designed specifically to understand the exact functional implication it has on the AYAO population.

Objectives and aims

We chose to focus on AYAO BS due to the high physical burden of disease on the patients compared to other cancer types. Curative intent treatment often involves surgical resection of the lesion, achieved through either limb amputation or LS surgery.

When HRQoL was analysed by the disease-related factors, the survivors of osteosarcoma scored significantly lower on the physical functioning score and demonstrated deficits in mobility and hearing compared to the reference group (leukemia survivors) (23). The significant effect of osteosarcoma on the physical component summary (PCS) score was also seen in the multiple regression analysis. Our findings were in keeping with the results reported from the UK, where the survivors of bone tumors scored significantly below UK-norm in PCS scale (23).

With increasing survivorship, the analysis of residual function of AYAO is vital to identify gaps in our management of these patients. This paper hopes to act as a scoping review to identify and map out existing evidence on functional outcomes in AYAO bone sarcoma, to inform on our goals for future research.

In our scoping review, we noted systematic reviews such as a paper published in 2015 (2) that focused on assessing differences between limb salvaging and amputation. However, it included patients ages 0 to 24, not the entire age range of AYAO, focused on studies with local control and excluded metastatic disease, comparing LS and amputation. We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-23-30/rc).

Methods

Literature search

An extensive literature search was conducted on PubMed and ScienceDirect using key search terms as described in Table 2. We obtained 858 results in total, including publications between January 1, 2003, and March 13, 2023. The timeline of studies was selected a priori, to focus on recent studies that reflect up to date evidence.

Screening and selection of studies

Two authors conducted independent screening of the search results, based on the titles and abstracts. Full texts of relevant studies were obtained, and along with reviewing bibliographies of the studies, screened for relevant content. Table 2 describes the literature search terms used, and number of results initially obtained.

The two authors then collated the selected studies and upon discussion, 18 research studies met the inclusion criteria and were included in the final scoping review. The PRISMA flowchart detailing the study selection is in Figure 1.

Figure 1 PRISMA flow diagram.

Inclusion criteria included literature published in English and focused on AYAOs, diagnosed with bone sarcoma, that assessed functional outcomes. We also included studies that investigated survivorship in pediatric bone sarcoma, as these patients will transit into AYAs as childhood cancer survivors, with similar survivorship issues.

We excluded papers published in other languages, and studies that did not focus on functional outcomes, or single case reports or case series, as well as focus on adult/elderly population.

Before discussing the functional outcomes of bone sarcoma after treatment and survivorship, it is important to highlight the common bone sarcomas and treatment principles.

Epidemiology of bone sarcomas

Secondary bone cancers (or what is commonly known as bone metastases from another primary cancer) are more common than primary bone malignancies. The most common primary BS include osteosarcoma, Ewing sarcoma and chondrosarcoma. These commonly occur in the first three decades of life (24).

Malignant primary bone tumors account for approximately 3% of all AYAO population, with the incidence of osteosarcoma and ES being most common.

In the Asian population, several databases have concurred with the Western population that frequency of bone sarcoma was higher in pediatrics and AYAOs. In Japan’s Bone and Soft Tissue Tumor (BSTT) registry, it recognized that the frequency of bone sarcoma was highest among AYAOs (25). The Taiwan Cancer Registry, identified a bimodal distribution of primary BS. Osteosarcoma peaked at 10–19 years of age, while ES peaked earlier at 5–9 years of age (26).

Osteosarcoma

Epidemiology

Osteosarcoma is the most common primary bone cancer, with incidence in all age groups at 0.3 per 100,000 persons per year (27).

The incidence of osteosarcoma is higher in adolescents (0.8 to 1.1 per 100,000/year at age 15–19 years) and has a bimodal distribution with the second peak in the seventh and eighth decades of life (7,27). This is seen in several Asian populations, where AYAOs account for a significant bulk of osteosarcoma incidence such as Korea (28).

Pathophysiology and associations

Risk factors include previous radiotherapy (RT), Paget’s disease of the bone, and other genetic abnormalities such as Li-Fraumeni syndrome, Bloom syndrome, Werner syndrome and hereditary retinoblastoma (6,29-31).

Treatment

The current standard of care for localized osteosarcoma involves multimodality treatment with chemotherapy and surgery. Treatment is intensive for this potentially curable disease, with the likely presence of micro-metastases at diagnosis. Systemic treatment usually comprises of chemotherapy given in a sandwich fashion (24).

The standard-of-care involves 2–3 cycles of doxorubicin and cisplatin (AP) pre-operatively followed by surgery, followed with adjuvant chemotherapy. In patients less than 40 years old, AP is given together with high-dose methotrexate (24). Meta-analysis in patients with localized osteosarcoma showed that a 3-drug regimen is more effective than two drug-regimens (24,27).

It has been shown that chemotherapy improves survival of osteosarcomas by 2- to 3-fold (27). In addition, neoadjuvant chemotherapy gives us the pathological response rate, a prognostic marker. Based on the degree of tumor necrosis post-neoadjuvant treatment, patients are divided into good or poor responders. This correlates with disease-free survival (DFS) and OS. However, at this juncture, there is no evidence that intensifying treatment for poor responders yields better survival rates (32).

In cases where complete surgical resection is not amenable or positive margins are present, additional radiation therapy is considered to improve local control. However, osteosarcoma is relatively resistant to RT (33-35). In addition, RT post-operatively can result in wound dehiscence and prosthetic destruction.

Primary metastatic osteosarcoma can still be treated with curative intent, following same principles in local osteosarcoma, and resection of metastatic lesions that are technically feasible is recommended, and has shown to increase long-term survival to be comparable with localized disease (36). However, it is also of note that patients who present with metastatic disease have disseminated disease, and this usually portends a more aggressive disease.

There are few prospective, randomized trials beyond first-line therapy, and evidence is even more limited in relapsed osteosarcoma. Available data often comes from small, single-arm clinical trials (30). In addition, while chemotherapy at diagnosis has been proven to improve EFS and OS, there have been few improvements since then (27).

As with the management of STS, it is recommended that the management of BS be taken care of by a dedicated sarcoma team. ESMO guidelines emphasize the need for surgeons with experience in the field of pediatric bone tumors. This is even more pertinent in dealing with AYAOs as puberty and bone growth will result in age-specific reconstruction challenges (30).

Survival rates

In 2015, cause-specific 10-year survival for local disease after osteosarcoma diagnosis was 65.8%, and metastatic disease at presentation lowers this to 24% (37). This survival rate is much improved with the addition of chemotherapy. Patients who have recurrence or progression to metastases after initial treatment are associated with poor prognosis (32,38).

Secondary cancers may arise in bone sarcoma survivors, either related to, or independent of irradiation. Secondary leukemia, acute myeloid leukemia (AML) may be observed as early as 2–5 years after treatment (27).

Ewing sarcoma

Epidemiology

Ewing sarcoma is the second most common bone tumor in children and adolescents. With a median age of 15 years, there is a slight predominance in males. The incidence at 0.3 per 100,000 per persons per year, is seven times higher in whites compared to blacks, and with intermediate incidence in Asians and Hispanics (30). ES typically originates in bone and soft tissue, with bone involvement most common in the lower extremities and axial skeleton (30). About 20% originates in soft tissue, usually in the extremities or trunk. Metastasis is present in up to 25% of patients at diagnosis, occurring typically in lungs and bone (24). Some of the prognostic factors identified in the Western population include staging, tumor size and site, age, gender and histological response to induction chemotherapy (39).

Pathophysiology

Ewing sarcoma has not generally been shown to be linked to any genetic syndromes. Ewing sarcoma is a small round-cell tumor derived from primordial bone-marrow mesenchymal stem cells. Its pathophysiology revolves around a characteristic spontaneous mutation by a fusion transcript involving the Erythroblast Transformation Specific (ETS) gene on chromosome 11 and EWS gene on chromosome 22—EWRS1-FLI1 or EWSR1-ERG genes (40). In 85% of patients, reciprocal translocation t(11;22) (q24;q12) resulting in EWRS1-FLI1 fusion can be detected, whereas EWSR1-ERG fusion t(21;22)(q22;q12), is found in ~10% of cases. Molecular confirmation is required to distinguish ES from other round cell sarcomas (RCS) (40). ES typically originates in bone and soft tissue, with bone involvement most common in the lower extremities and axial skeleton (30). About 20% originates in soft tissue, usually in the extremities or trunk. Metastasis is present in up to 25% of patients at diagnosis, occurring typically in lungs and bone (24).

Treatment

For Ewing sarcoma, first-line treatment is multi-modality, with surgery being essential for a chance at cure. If surgery is not possible, then radical RT will be preferred (41,42).

Treatment usually consists of radical surgery sandwiched by systemic chemotherapy. The exact chemotherapy regimen used is very much physician- and institution-dependent, but almost all drug protocols are based on the active agents including doxorubicin, cyclophosphamide, ifosfamide, vincristine, dactinomycin and etoposide.

In pediatrics, the current standard of care in America includes a VDC-IE induction chemotherapy backbone (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide every 2–3 weeks). Ifosfamide and etoposide, or vincristine and cyclophosphamide is given as consolidation, which has proven activity in large collaborative trials (39,41-44). In Europe, historically the standard chemotherapy regimen utilized was the VIDE regime (vincristine, ifosfamide, doxorubicin, etoposide). The Euro-Ewing 12 study compared VIDE against VDC-IE and it was noted that VDC/IE chemotherapy is superior to VIDE for both DFS and OS with no excess toxicity (45). Young adults tend to tolerate aggressive chemotherapy like children (24,46), and treatment of patients <40 years old follows similar principles in both AYAO and pediatric patients.

In patients with metastatic disease, a similar approach to local disease is taken, and local treatment in the form of either surgery or radical RT has been associated with outcome improvement and should be attempted (46).

Radical RT is also a standard option for local control. In patients with extremity and pelvic tumors, local control is significantly improved in patients who received surgery over definitive radiation therapy, although meta-analyses have found no difference in OS between the 2 (47).

In situations where surgery is too morbid, such as in the pelvis where exenteration is required, or when it is not possible to obtain complete surgical resection, then radical RT is considered (24,27,32,48). Local control of primary tumor and metastatic sites is important for disease control (49).

Adjuvant RT is also considered in large volume tumors, inadequate surgical margins, or poor histological response in Europe.

Chemotherapy regimens in relapsed patients are not standardized, but normally using alkylating agents (e.g., cyclophosphamide, high dose ifosfamide) in combination with topoisomerase inhibitors (etoposide, topotecan) (30).

Survival rates

In ES, the most important prognostic factor is the presence of metastatic disease at time of diagnosis. Large tumor volume, pelvic tumors, and older age >15 also confer worse prognosis (50). Like Osteosarcoma, histological response to chemotherapy is postulated to be prognostic of treatment outcomes, but data is not as mature.

Patients with metastases have a 5-year OS of less than 30%, except for those with isolated pulmonary metastasis (approximately 50%). Median survival time was 78 months, and 5-year OS rate 52%, and survival was reciprocally correlated with age. Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Five-year survival rates have increased from 60% in the 1970s to 83% (43).

AYAO patients have been found to be more likely present with metastatic disease in ES (51).

Chondrosarcoma

Epidemiology

CS is the most frequent BS in older adults. Unlike Osteosarcoma and ES, chondrosarcoma incidence increases with age, with an incidence of 0.2/100,000 per year (52). Eighty percent of patients are diagnosed after 40 years, with a median of 30–60 years old. It most commonly affects long bones, pelvis and ribs (53,54). Most CSs are locally aggressive, or are low-grade, non-metastasizing tumors rather than high grade tumors. Most chondrosarcomas are solitary, but they can occur as multiple lesions in syndromic patients with multiple osteochondromas and enchondromatosis (27).

Pathophysiology and associations

Most CSs are primary tumors that originate in the bone’s medulla (known as central chondrosarcoma). However, a proportion arises secondarily within an enchondroma (secondary central chondrosarcoma) or at the bone surface from a pre-existing osteochondroma (secondary peripheral chondrosarcoma) (6). Occasionally, convention chondrosarcoma can de-differentiate into aggressive high-grade sarcoma. This is known as de-differentiated chondrosarcoma (DCS) and accounts for ~10% of chondrosarcomas. There are also other rarer subtypes including mesenchymal osteosarcoma (MCS) and clear cell chondrosarcoma (6). Some of the associated syndromes include that of Ollier’s disease and Maffucci’s syndrome, which is associated with enchondromas that can transform into chondrosarcoma. The diagnosis of chondrosarcoma is based on morphology. Molecular analysis is not routinely required, but 50% of central chondrosarcomas carry ID1 or IDH2 mutations.

Treatment

CSs are chemotherapy-resistant, likely contributed by the cartilaginous matrix and its inherent more indolent disease biology. In chondrosarcoma, local surgical management is the mainstay of treatment, and adjuvant systemic therapy is not routine (24,55).

Both low- and high-grade peripheral chondrosarcomas should be surgically excised, preferably with good margins. If wide margins cannot be reliably achieved with LS, amputation should be considered for high-grade chondrosarcomas. This is so as there is a high risk of local recurrence or metastasis especially in high-grade subtypes such as DCS (56).

Radiation therapy is indicated if positive margins are present, for unresectable disease and can be considered for palliative symptomatic management (56).

In patients with widely metastatic disease, chemotherapy is of limited benefit, with higher responses seen in patients receiving combination anthracycline-based therapy (55).

MCS and DCS are more sensitive to chemotherapy. Should a patient present with a CS in an area where resection can be morbid or dangerous, neoadjuvant chemotherapy combining anthracycline and alkylating agents can be considered. Should these patients present with more aggressive disease as determined by a larger tumor at diagnosis, a deep-seated tumor et cetera, adjuvant chemotherapy can also be discussed (55,57).

Similarly, if patients develop metastatic disease or have unresectable local recurrence, their prognosis is poor. Depending on the extent of disease and performance status of patient, chemotherapy may be trialed, but clinical trials would be the main consideration (55,58).

Survival rates

The median OS is affected by lesion grade, subtype of chondrosarcoma and presence of metastatic disease. Grade I lesions rarely metastasize and recur, and have a 10-year survival of >80%. In contrast, grade III lesions have a 10-year survival of <30% (56).

For rarer subtypes, different median survival was found in juxtacortical (97 months), clear cell (79 months), myxoid (60 months), mesenchymal (33.5 months) and lowest in dedifferentiated (11 months) on a review of the SEER database (59). Age, grade of tumor, number of metastatic sites, surgery of metastases was significantly associated with OS (60).

Surgical management of BS

Amputations used to be the mainstay of surgical management of BS. This is potentially morbid and has lasting irreversible consequences for our patients. This is magnified several-fold when we take into consideration the expected lifespan of an AYAO cured from cancer as opposed to an older adult.

Since the 1980s, with the introduction of chemotherapy and radiation therapy, the world has largely moved away from amputation where possible, and LS surgeries are generally preferred. This allows for a higher possibility of successful reconstruction of upper and lower-extremity long bones after tumor resection. It is now well-established that survival rates following limb salvage surgery (LSS) is similar to amputation for the majority of bone sarcomas (60-63).

Interestingly, the specific functional advantages of LSS compared to amputation remain unclear. Several studies have attempted to compare overall HRQoL between LSS and amputation, but showed no differences, while others have provided evidence that LSS may prove superior (64-67). A meta-analysis by Stokke et al. comparing LSS and amputation did not show differences in clinician-assessed and patient-reported disability or HRQoL (2). There are also studies that did report worse functional and HRQoL domains after amputation (68). Patients after amputation appear to be less content with cosmetic results of surgery as well (69). Bekkering also did show that patients after endoprosthetic replacement encounter more surgery-related complications than those after amputation, due to replacement’s risk of loosening, infection and structural problems (70).

Interestingly, LSS has been traditionally less adopted for children as compared with adults. This is in part due to the thinking that children have not reached their maximal skeletal maturity and are more adaptable to amputations compared to adults. In addition, surgical reconstruction after LSS in children is more complicated due to the physics that is typically sacrificed during operation. This may lead to clinically significant limb-length discrepancy (67).

There is also a need to consider longevity of implant and the need for implant change, which will be more frequent if done at a younger age and with activities that cause more wear and tear (68). As such, some believe it to be more ideal to have a single amputation procedure with a lower likelihood of complications that may require future surgical interventions. Groundland et al. concluded the recommended treatment for skeletally immature patients remains a matter of debate as evidence comes from case series and reports of functional outcomes remain limited (60).

A systematic review of 60 studies focusing on LSS by Groundland et al. identified that rates of failure in pediatric population correlated well with previously published results for adults, with lower subsequent amputation incidence (60). There is an estimated 5- and 8-year implant longevity of 68% and 58% respectively before requiring revision surgery (71). A longitudinal study in young patients (<25 years old) had 78% of patients having endoprosthesis complications. Younger patients possibly loaded their endoprosthesis more intensively during daily work and leisure activities (72).

Results

Eighteen papers were included in the review, out of 858 identified papers from PubMed and ScienceDirect. Of the 18 papers, 12 were cross sectional studies, 5 prospective studies, and 1 retrospective study.

Table 3 shows a summary of the results, including study design, sample size and measurement tools utilized to assess functional outcomes.

Twelve papers assessed physical function, 10 papers assessed psychological function, and 10 papers assessed psychosexual functioning.

A systematic review studying function and HRQoL among pediatrics and AYAO patients identified that sarcoma survivors tended to have inferior HRQoL across all categories on longitudinal follow-up, even up to 5 years. These measures included HRQoL, physical function, clinician- and patient-reported disability.

Two studies utilized both paediatric and adult scales in the study to assess HRQoL. Budde utilized data from EURAMOS-1 trial cohort, which recorded both QLQ-C30 and PedsQL in different age populations, had patients between 5 to 40 years old, and found potential utility of linking paediatric and adult patient reported outcome measures—as both had substantial overlap in contents in the questionnaires—but no previous studies have been found (82).

A cross-sectional study assessing HRQoL using EORTC-QLQ-C30 among sarcoma survivors showed that AYAO survivors reported statistically significant worse physical, role, emotional, cognitive functioning in comparison with the normative population (15). A pooled analysis on the effect of age on HRQoL in cancer populations noted generalized impairment in cancer patients, but with a varying impact depending on age. AYAOs were noted to have more financial, social, and functional role impairments in comparison with the general population.

Physical function

Physical function for sarcoma survivors is significantly lower than that of the general population (2,64,86,87). There is a directly positive correlation between postoperative function and quality of life, leading to the need to improve functional outcomes (68).

Of the physical function assessments, only two studies utilized functional mobility tools such as TUDS, TUG, rate of perceived exertion (RPE) (75,77). Both studies did not show correlation between functional mobility assessment and subjectively reported tools like MSTS and patient reported disabilities via TESS, SF-36.

Factors affecting physical functioning included tumor location, as it will directly impact reconstructive options and physical function (70,88). Patients treated with amputation required more aids (67), but several papers did not show better HRQoL when comparing LS with amputation (65,75), but noted patients with amputation had worse functional mobility than LS (75,85).

Other factors affecting physical function included age, gender, no pain, ability to manage affected limb (76).

Differences between HRQoL measured at long term follow-up, from post operatively months to 2 years since surgery was small and insignificant. Improvement in HRQoL was most pronounced in 1 year post operation (66).

Psychosocial functioning

AYAO had lower emotional and cognitive functioning compared to their counterparts (89). Several longitudinal studies followed patients from diagnosis to treatment and noted that patients with sarcoma had lower emotional functioning. This had noted significant improvement post treatment (65,86). After transiting into survivorship, body image issues also correlated with perceptions of physical functioning (66,79). Patients with amputation had better emotional functioning scores than those in LS (78).

Most prevalent problems among patients include delayed studies, limited job searching, and changes in social relationships due to limited activities—from treatment and post treatment disabilities (65,74,80).

Married survivors had significantly better HRQoL scores in vitality and mental health compared to unmarried survivors but was unclear if this correlation with mental health was due to their marital status.

However, post-treatment, adolescents had high expectations towards their future (84). A cross-sectional study by Ottaviani also showed survivors >20 years post treatment adapted well to their limitations, educational level and net income similar than average of US population (81).

Discussion

AYAOs are generally expected to be active and independent, especially during this phase of life. When stricken with a BS, this can severely impact their mobility and hence independence.

Compared to other childhood cancer survivors, bone sarcoma survivors had more physical problems such as disabilities, limb pain, secondary cancers due to high usage of RT (65,82).

The SURVSARC study was a cross-sectional survey that evaluated HRQoL in sarcoma survivors based on age stratification. It noted that extremity localization of tumor had increased odds ratio 2.35 for low physical function in AYAO patients, but not in older adults and elderly (15). This function of lower limbs is important as it allows independence and freedom. Patients with more functional lower limbs report better HRQoL in various subscales (psychological, physical, social). It was also a statistically significant predictor of body image and confidence in romantic relationships (66).

Robert et al. also discussed that adolescence is a major developmental milestone, with changes in physical appearances and need for adjustment, and may be vastly different from those in preschool or school-age children (66). Their study found that age >18 years old at diagnosis was significantly associated with TESS score <25^th percentile. Older age at diagnosis was frequently associated with poorer outcomes in physical functioning, but the definition of older age varied among studies (from 10 to 13) (2,90,91).

Patients who undergo treatment at a younger age are better able to accommodate and adapt physically and psychologically to treatment-related changes, and thus report elevated self-perceptions of function. Important symptom control is also crucial. Physical function and physical domains in HRQoL scores were significantly lower among those reporting pain (2,87).

Social functioning

Social functioning refers to how well an individual can meet the expectations of oneself with the immediate social environment and society at large. Social functioning has been shown to be a domain of HRQoL that is severely affected in survivorship. Notably, decreased social support, decreased self-esteem, sexual inactivity, unemployment, and financial difficulties were all associated with impaired social function. Weschenfelder et al. demonstrated in a cohort study that the success of occupational reintegration has a significant correlation to mental health, with patients reporting higher Hospital Anxiety Depression Scale (HADS) scores (68). Several studies found similar marital status between survivors and healthy peers (73,81,85). whereas studies such as Nagarajan et al., reported lower educational levels, higher unemployment rates and lower marital percentage in survivors compared to their siblings (64).

Interestingly, Bekkering’s study found comparable social and emotional functioning between AYAO bone sarcoma survivors and control population of healthy peers, and similar functioning on comparing LS and amputation surgery (65). They postulate that a phenomenon known as “response shift”, previously described among children/adult populations as patients feel a sense of happiness to have survived the disease and completed treatment. However, more should be done to ascertain if this perceived emotional function is long-lasting throughout years of treatment completion, and how they affect other domains of function—especially psychological health. We recognize that however, this may lead to underreporting of symptoms or overcompensation in HRQoL reporting, causing a “false-negative” situation that underplays the benefits of limb-preserving surgery.

Psychological functions

Psychological functioning can be defined as how a person’s mood and cognitive abilities are affected by various activities such as cognition, emotional and even the circumstance surrounding the individual. AYAO patients compared to older adults had lower emotional functioning scores (89).

Studies that utilized measures of psychological distress such as HADS revealed that a significant proportion of the studied cohorts had psychological distress. There was a clear correlation with higher anxiety and depressive trait scores with poorer quality of life in all domains (physical, emotional, cognitive, social functioning). Weiner et al. found that unemployed sarcoma survivors were more likely to display psychological distress compared to those who were employed (92).

Psychological distress may cause patients to develop negative thoughts and pessimism towards their disease and even outcomes. This may result in decreased motivation to undergo rehabilitation to regain mobility, setting off a vicious cycle where their decision-making process towards treatment subsequently might be affected. However, it should be noted that few studies used instruments specifically to evaluate depression or anxiety. Neither were they validated for use specifically in this population of interest. Rather, it was encapsulated as one of the components in the HRQoL tools such as EORTC-QLQ (86).

Limitations

We recognize several rooms for improvement and gaps in current functional outcome studies.

Different definitions and age cut-off

For several studies, centres utilized different cut-off ages for inclusion criteria for their studies (15,69,75,78,79,81,83-85). This is likely because the adolescent young adult age group bridges include both patient populations managed at paediatric/adult hospitals. Patients younger than 18-year-old were commonly managed at a paediatric oncology centre, whereas patients older than 18 years old were managed at an adult oncology centre.

Instruments utilized to assess HRQoL

Furthermore, HRQoL data is often collected by self-reporting surveys. The tools validated and utilized to measure HRQoL also differ among paediatric and adult populations. Tools such as PedsQL/PEDQOL are validated in <18 years old age group, whereas others like SF-36 are used in the adult population.

However, to assess the longitudinal trajectory of patients from diagnosis into survivorship, patients cross the age thresholds of these tools, and it becomes difficult to compare results. Hence, more robust, and accurate measurements for adolescent and young adult patients are required to provide context to their situation, functional demands in various settings of life—from career, relationships, to mental development.

There appears to be a large heterogenous pool of functional outcome tools and measurements utilized. Alongside the various notable and common ones described (FACT-G, EORTC, PEDSQL), several other papers utilized tools such as SF-36, Bt-DUX and this precludes our ability to compare these papers and form an objective conclusion on functional outcomes. These tools are often validated in population groups clearly defined by either adult (>18 years old) or pediatrics setting and are not validated in AYAOs specifically, much less validated for use in AYAOs with BS (21,93). Many papers also include both pediatrics and adolescent age groups in their study design, using both paediatric and adult tools to measure HRQoL (48,65,69,74).

Quinn et al. concluded that currently assessed HRQoL domains are not comprehensive for the AYAO population, as AYAOs were undergoing vital changes in their lives such as parenthood, changing relationships and induction into work life from studies (94).

This corresponds to our understanding that even among AYAO patients, there is a significant heterogeneity of developmental stages, with different age subgroups prone to different challenges and risks for poor HRQoL (95).

Lack of longitudinal follow-up

Furthermore, most of the studies report HRQoL assessments at a single timepoint via cohort studies, at varying durations post-surgery. The few papers that describe longitudinal progression of HRQoL after tumor surgery suggest that the most improvement occurs within the first year of diagnosis (96). This correlated with the SURVSARC study, which noted that survivors more than 5 years since diagnosis did not have significantly better HRQoL scores in comparison with those less than 5 years from diagnosis (15). However, sample sizes for these prospective studies are small, and due to the overall 5-year survival of these patients being around 55%, a larger sample size is needed.

Conclusions

Although several studies have addressed that increasing age is associated with poorer HRQoL, this age-cut off is not well-defined with no clear postulations. There is a clear lack of studies in assessing survival and functional outcomes for pediatrics and AYAO patients due to multiple unvalidated HRQoL measurements being utilized. Research efforts are also further hampered by the inherently smaller population size. Studies are often conducted on pediatric and adolescent patient groups and do not involve the young adult population.

Several studies have suggested that survival outcomes are improved when treated at high volume hospitals or specialist sarcoma centers, and all patients should be referred to a bone sarcoma reference center or an institution belonging to a sarcoma network (97,98).

As part of the multidisciplinary discussion, understanding functional outcomes in these patients better can allow us to recruit relevant specialties to provide higher degree of holistic care to them, from diagnosis to treatment and into survivorship.

Several systematic reviews have attempted to compare or combine populations, but this is an area of lack. It is imperative that more AYAO-specific research is done, with more focus on HRQoL and functional outcomes with the available treatments. This will then allow us to improve outcomes of AYAOs in a holistic and meaningful manner.

Acknowledgments

This research was previously presented in ASCO Breakthrough Conference, with an abstract published in JCO Global Oncology, dated August 2023.

Funding: None.

Footnote

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-30/coif). The authors have no conflicts of interest to declare.

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