Limb Salvage Surgery in Pediatric Patients with Osteosarcoma

Abstract

Osteosarcoma, although rare, is acknowledged as the most common primary bone tumor in children and adolescents. Osteosarcoma is a highly malignant osteogenic tumor that can develop in any bone, but commonly develops at the metaphysis of long bones. The positive diagnosis of osteosarcoma is based on the pathology exam, since there are no other specific diagnostic tools, and the patients with osteosarcoma are typically treated by a multidisciplinary team of specialists. The mainstream for the surgical treatment of limb osteosarcoma is the limb salvage surgery, whenever this approach does not compromise the oncological outcomes. A large spectrum of reconstructive surgical procedures is used in various centers, and to date there is no large consensus on recommending one over another. It is often that the practitioner has to decide whether the final impact on the quality of life of the child undergoing endoprosthetic replacement or osteoarticular allograft is better with the subsequent inequality of the length of the limb or the radical approach by amputation is better. Special consideration has to be given on the aspects of psychosocial wellbeing of the patients following the initial surgical intervention.

Introduction

Osteosarcoma, although rare (with an incidence of 0,3/100 000/year), is acknowledged as the most common primary bone tumor in children and adolescents [1].

The incidence is highest during childhood and adolescence (0,8-1,1/100 000/year at age 15-19 years), slightly more frequent in boys (1,4:1), and then later there is a bimodal slight increase in incidence over the age of 70 years [2].

Osteosarcoma may emerge in any bone, but in most instances is located at the smaller age in the long bones, usually in the metaphysis of the proximal regions of the tibia and humerus, and the distal region of the femur, in contrast with the axial locations that are more common at the old age.

The positive diagnosis of osteosarcoma is based on pathology exam, since there are no other specific diagnostic tools.

Patients with osteosarcoma are typically treated by a multidisciplinary team of specialists, including but not limited to: Orthopedic Surgeons, Pediatricians, Oncologists, Pathologists, and Rehabilitation Specialists.

The protocol combines chemotherapy (neoadjuvant and adjuvant) and surgery for the local control of the malignancy.

The surgical intervention used to be almost invariable the amputation (and still remains a valid indication in particular instances), followed by functional recovery using exoprosthesis.

During the last decades, limb salvage surgery (LSS) became the preferred method, associated with biological with/or endoprosthetic reconstruction.

The strategy including the latter approach results in approx. 70% survival rates at 5 years [3].

Management by LSS results in up to 80%-90% of the patients with favorable oncological outcomes [7].

Materials and Methods

Two databases (PubMed and Scopus) were searched, from inception to April 2024, using Boolean operators and the following key phrase: “limb salvage surgery”, and the key words “osteosarcoma” and ”children”.

To exclude duplicates EndNote was used, and further we compared the names and the institution of the authors, the sample size, and the characteristics of the patients.

The reference lists of all potentially included articles were hand-searched.

The search (Figure 1) presented a number of 3160 articles (i.e. 1149 from PubMed and 2011 from Scopus).

Figure 1.

Article retrieval.

The duplicates were removed (n=474).

After article screening 2582 articles were excluded (i.e. non-human, not pediatric age group, article language, wrong topic), whilst 104 were extracted.

After supplementary analysis, 31 articles were selected for the review.

Tumor resection

The tumor is recommended to be diagnosed by type as stated by the current (2020) World Health Organization (WHO) ”Classification for tumours of soft tissue and bone” [4].

There are also available a number of systems used for staging, such as the Enneking Surgical Staging System (by Musculoskeletal Tumor Society) [5], AJCC (American Joint Committee on Cancer), etc.

The goal of osteosarcoma surgery must always be complete tumor removal since both R1 and R2 augment the local recurrence risk, with negative impact on the rate of survival.

The excision should be R0 [6], i.e. the tumor (including the biopsy scar) has to be removed surrounded by healthy tissue.

LSS is a viable alternative to amputation

LSS has significantly improved the treatment landscape for children with osteosarcoma, offering a viable alternative to amputation in terms of effectiveness and outcomes.

Effectiveness is supported by:

a) Survival rates: Studies have shown that limb salvage surgery, combined with chemotherapy, offers survival rates comparable to amputation. Evans et al. studying a large database even found that younger patients, particularly those with lower-stage tumors and no metastases, tend to have better survival outcomes [7];

b) Functional outcomes: The primary goal of limb salvage surgery is to preserve limb function. Research indicates that many children regain significant mobility and can participate in daily activities and sports, mainly because of the recent complexity involved in biological reconstructions and the use of personalized prostheses [8];

c) Psychosocial benefits: Preserving the limb can have substantial psychosocial benefits, helping children maintain a sense of normalcy and self-esteem, a normal growth and development and a better quality of life.

Outcomes require individual, case by case consideration mainly on three issues [7, 8]:

a) Long-term health: children who receive LSS are at risk for chronic health conditions later in life (i.e. cardiovascular disease, and secondary malignancies duet o the aggressive treatments they receive);

b) Complications such as infection, prosthesis loosening, and nonunion (where the bone does not properly heal): these issues often necessitate additional surgeries;

c) Growth considerations: In children, the need to accommodate future growth adds complexity to the surgery, expandable prostheses which can be adjusted as the child grows had shown to be effective, although they requires periodic adjustments and sometimes additional surgeries.

As such, currently the mainstream for the surgical treatment of limb osteosarcoma is the limb salvage surgery, whenever this approach does not compromise the oncological outcomes.

In most published studies, this situation is met in about 80% to 90% of the patients [8].

Furthermore, most specialists support the net superiority on rehabilitative outcomes of the limb salvage/reconstruction over the amputation [8, 9, 10].

Nevertheless, the orthopedic surgeon must carefully consider the situation of large bony defect when the priority becomes the safe clearance of the tumor.

If the healing after the surgical intervention is much prolonged, among other inconveniences, of paramount importance for the patient is the postponement of adjuvant therapy witch impacts directly on disease free survival and functional outcomes [11, 12, 13].

Children vs. adults undergoing LSS

There is important difference between pediatric and adult patients who undergo the LSS, regarding:

a) Survival rates. Generally, children with osteosarcoma have better survival rates compared to adults (partly due to the differences in tumor biology and the ability of younger patients to tolerate aggressive treatments). Adults often have lower survival rates, which can be attributed to more aggressive tumor behavior and the presence of comorbidities [12];

b) Growth considerations. Surgeons must account for the ongoing growth of bones in children, which often involves using expandable prostheses that can be adjusted as the child grows. In adults’ growth is not a concern, so standard prostheses or allografts are typically used [10, 11];

c) Complication rates. Rates of complications are higher in children, related to prosthesis (such as loosening or breakage), due to the need for the prosthesis to accommodate growth; children may also require multiple surgeries to adjust or replace the prosthesis as they grow. In adults while complications like infection and prosthesis failure are still concerns, the management strategies are more straightforward without the need to consider growth;

d) Functional outcomes can be more variable in children due to the need for multiple surgeries and the impact of growth on the reconstructed limb;

e) Psychosocial impact can be significant in children, since they must cope with the physical and emotional challenges of cancer treatment during formative years (this is why the support from family, peers, and mental health professionals is crucial). Adults also face psychosocial challenges, but these are often related to their roles and responsibilities, such as work and family life [11, 13];

f) Long-term health impacts. Younger patients are at a higher risk of developing chronic health conditions later in life, such as cardiovascular disease and secondary malignancies, due to the long-term effects of cancer treatment. Adults may also face long-term health impacts, but these are often compounded by age-related health issues [11].

Reconstruction

Deciding between amputation and limb salvage therapy for a child with osteosarcoma involves a thorough/comprehensive evaluation by a multidisciplinary team to tailor the treatment plan to the individual needs of the patient, aiming for the best possible outcome. Of significant value for the practitioner are [10, 11, 12, 13]:

a) Tumor characteristics: location and size (tumors involving critical structures like major blood vessels or nerves may necessitate amputation), extent of spread (if the cancer has spread beyond the primary site, it might influence the decision);

b) Patient factors: age and growth (younger children with significant growth potential might benefit more from limb salvage to avoid complications with prosthetics);

c) Functional outcomes: expected limb function (the potential for the limb to function effectively post-surgery is a major consideration), quality of life (the impact on the child’s daily activities and psychological well-being is to be evaluated);

d) Technological and surgical expertise: availability of advanced techniques (access to specialized surgical teams and advanced prosthetics can influence the decision), post-surgical rehabilitation (the availability and quality of rehabilitation services are essential for recovery and adaptation);

e) Family preferences: informed decision-making (families are involved in the decision-making process, considering their preferences and values), support systems (the family’s ability to support the child through recovery and adaptation is also considered);

f) Long-term prognosis: survival rates (the likelihood of long-term survival with each option is carefully weighed), risk of recurrence (the potential for cancer recurrence with each approach is assessed).

Type of procedures

DA broad spectrum of reconstructive surgical procedures is used in various centers, and to date there is no large consensus on recommending one over another [10, 14, 15].

Largely, they can be grouped into biological (i.e. vascularized autografts, non-vascularised bone autografts, allografts, segmental bone transport, and others), endoprosthetic (among others metal, expandable, 3D printed endoprostheses) and composite reconstructions (auto-, allo-, and auto-allograft prostheses)[8,16, 17, 18, 19].

The decision has to be personalized by a multidisciplinary team conforming to the tumor characteristics (type, localization), age of the patient, and the oncological regimen prescribed [12,20, 21, 22].

Techniques of Limb Salvage Surgery

1. Endoprosthetic reconstruction involves replacing the resected bone with a metal prosthesis, commonly used for large bone defects. Advantages: immediate stability and function, adjustable for growth. Disadvantages: risk of mechanical failure, infection [22].

2. Biological reconstruction utilizes autografts (patient’s own bone) or allografts (donor bone). Advantages: potential for biological integration, lower risk of mechanical failure. Disadvantages: longer healing time, risk of graft rejection [19].

3. Expandable prostheses are specialized prostheses that can be lengthened non-invasively as the child grows. Advantages: accommodates growth, maintains limb length and function. Disadvantages: complex, expensive, risk of mechanical issues [17, 18].

4. Composite techniques combine multiple reconstruction methods to optimize outcomes. Advantages: tailored to patient needs, benefits of multiple techniques. Disadvantages: increased complexity, potential for complications [22].

Specific aspects in skeletally immature patients with osteosarcoma

In children the resection of the growth plates may impair the final length of the limb, with different impact by localization (i.e. minor cosmetic issues for humerus or in the case of lower limbs more severe functional issues (i.e. hip and knee osteoarthritis and lower back pain) [23, 24].

Although one can involve different methods (i.e. the Anderson-Green Predictions of Growth in the Lower Extremities, the White-Menelaus Calculation for the Timing of Epiphysial Arrest), we found that the Paley’s multiplier method using one multiplier table and the chronological age of the patient is handier to use [25, 26].

In specific cases, it is difficult to spare the physis to an extent that the length discrepancy does not hamper the growth, or furthermore, the aseptic loosening of prosthetis might have the same effect [27].

Most centers record the Musculoskeletal Tumor Society Rating Scale developed in 1993 and subsequently revised, which allow quantification of six domains: 1) pain, 2) function, 3) emotion, 4) support, 5) walking, and 6) gait [28].

It is often that the practitioner has to decide whether the final impact on the quality of life of the child undergoing endoprosthetic replacement or osteoarticular allograft is better with the subsequent inequality of the length of the limb or the radical approach by amputation is better; this decision has to be made by the surgeon in most osteosarcomas located in the distal femur and the peri-knee region of tibia [23, 24, 25, 26, 27].

Challenges and complications of limb salvage surgery

Limb salvage surgery present a variable number of short-term complications, either major one (infections, graft nonunion, fractures that require another surgery intervention), either minor complication (like osteoporosis and others solved non-surgically) [30, 31].

Current data have shown that the minor complication account for about one third of the cases, whereas the major one’s account for another 30% [32].

The International Society of Limb Salvage during its over three decade-long scientific activity proposed several definitions (notably by the group of Henderson et al.) to classify the non-success of the limb salvage after reconstruction, thus allowing the quantification and correspondence of outcomes of the interventional surgery among different patients [33].

Infections after LSS

Infections after limb salvage surgery in children with osteosarcoma can be influenced by several risk factors, including [22, 33]:

Surgical factors:

-Length and complexity of the surgery: longer and more complex procedures increase the risk of infection;

-Use of prosthetic implants, which can be a source of infection, especially if not handled with strict aseptic techniques;

Patient factors:

-Immunosuppression: children undergoing chemotherapy or with weakened immune systems are more susceptible to infections;

-Nutritional status: poor nutrition can impair wound healing and immune response;

Postoperative care:

-Wound care: inadequate wound care and hygiene can lead to infections;

-Hospital environment: exposure to hospital-acquired infections, especially in intensive care units, can be a risk;

Pre-existing conditions:

-Diabetes can impair healing and increase infection risk;

-Previous infections: a history of infections can predispose to new infections.

Managing these risk factors involves meticulous surgical technique, careful postoperative care, and monitoring for signs of infection to ensure prompt treatment [35].

Infections are a significant complication following limb salvage surgery in children with osteosarcoma, and the follow represents a concise enumeration of the issues [30]:

a) Incidence and risk factors. The incidence of infection after limb salvage surgery is notably higher compared to conventional orthopedic surgeries. Also, the children are immunosupressed and often with a poor nutritional status following chemotherapy. The most frequently isolated pathogens include coagulase-negative staphylococci.

b) Types of infections: either superficial infection (which affect the skin and soft tissues around the surgical site, and are usually managed with antibiotics and local wound care), either deep infection (which involve deeper tissues, including the bone and prosthesis, are more challenging to treat and often require surgical intervention).

c) Management strategies [36]:

-Prevention: prophylactic antibiotics (administering antibiotics before and after surgery to reduce the risk of infection), aseptic techniques (strict adherence to aseptic techniques during surgery to minimize contamination);

-Treatment: antibiotic therapy (tailored based on the specific pathogen identified), surgical debridement (removal of infected tissue and, in some cases, the prosthesis which may be followed by the placement of antibiotic-impregnated cement spacers) and reconstruction (after infection control, reconstructive surgery may be necessary to restore limb function) [37, 38, 39, 40];

-Long-term monitoring by regular follow-ups, continuous monitoring for signs of infection and other complications.

Physical rehabilitation

Physical rehabilitation is a crucial component of recovery for children who undergo limb salvage surgery for osteosarcoma [41, 42].

The goals of rehabilitation are to restore function, improve mobility, and enhance the overall quality of life.

We underline some key aspects of the rehabilitation process [43]:

1. Early postoperative phase:

-Pain management: effective pain control is essential to facilitate early movement and participation in rehabilitation;

-Wound care: proper care of the surgical site to prevent infections and promote healing;

-Initial mobility: Gentle range-of-motion exercises to prevent stiffness and maintain joint flexibility;

2. Strength and conditioning:

-Muscle strengthening consisting of targeted exercises to strengthen the muscles around the affected limb, which is crucial for regaining function;

3. Functional training:

-Gait training for lower limb surgeries, learning to walk again, often with the help of assistive devices like crutches or walkers initially;

-Prosthetic training, if a prosthesis is used, specialized training to adapt to and effectively use the prosthetic limb;

-Daily activities, especially by occupational therapy to help the child regain independence in daily activities such as dressing, bathing, and school-related tasks;

4. Psychosocial support [35]:

-Emotional support, by counseling and support groups to help the child and family cope with the emotional challenges of cancer treatment and recovery;

-Motivation and encouragement, since keeping the child motivated and engaged in their rehabilitation program is vital for long-term success;

5. Long-term follow-up [44]:

-Monitoring growth by regular follow-up to evaluate the growth and development of the child, especially if expandable prostheses are used;

-Periodic adjustments and modifications to the rehabilitation plan and prosthetic devices as the child grows and their needs change.

Adapting to prosthetic limbs

Children adapting to prosthetic limbs after limb salvage surgery face several challenges, both physical and emotional. Here are some of the key difficulties they might encounter [17, 22, 45]:

1. Physical challenges:

-Pain and discomfort: initial discomfort and pain are common as the child gets used to the prosthetic limb;

-Skin issues: skin irritation, sores, and blisters can occur due to friction and pressure from the prosthesis;

-Weight and balance: adjusting to the weight and balance of the prosthetic limb can be difficult, especially for younger children;

-Mobility and coordination: learning to walk, run, and perform daily activities with a prosthetic limb requires significant practice and coordination.

2. Emotional and psychological challenges [35]:

-Body image: children may struggle with body image issues and self-esteem, especially if the prosthesis is visible;

-Social acceptance: concerns about fitting in with peers and being accepted can be significant, particularly in school settings;

-Fear and anxiety: fear of falling, anxiety about using the prosthesis correctly, and concerns about future surgeries or adjustments can be overwhelming.

3. Practical challenges [47]:

-Maintenance and care: Learning how to properly care for and maintain the prosthetic limb is essential but can be challenging;

-Growth adjustments: as children grow, their prosthetic limbs need frequent adjustments or replacements, which can be disruptive and stressful;

-Activity limitations: while prosthetics can greatly enhance mobility, there may still be limitations in certain activities, which can be frustrating for active children.

4. Rehabilitation and training:

-Intensive therapy: ongoing physical and occupational therapy is often required, which can be time-consuming and tiring;

-Learning curve: there is a steep learning curve associated with using a prosthetic limb effectively, requiring patience and perseverance.

Support strategies for children undergoing LSS

Adapting to a prosthetic limb is a journey that involves overcoming various challenges, but with the right support and resources, children can achieve remarkable levels of independence and functionality [47].

-Comprehensive rehabilitation programs: tailored programs that address both physical and emotional needs [35, 46];

-Peer support groups: connecting with other children who have similar experiences can provide emotional support and encouragement;

-Family involvement: Active involvement of family members in the rehabilitation process can provide essential support and motivation.

Conclusion

Limb salvage surgery represents a significant advancement in the treatment of osteosarcoma in children.

It offers a balance between effective cancer treatment and the preservation of limb function, greatly enhancing the quality of life for young patients.

However, the procedure comes with its own set of challenges, particularly related to growth and long-term health.

Reaching a unitary surgical management of pediatric patients with osteosarcoma (as well as generally, musculoskeletal tumors) remains a burdensome task for clinicians.

There are only a limited number of both efficient and safe procedures which are widely accepted.

Limb salvage surgery has proved its cornerstone position in the management of osteosarcoma in pediatric patients and while currently a proliferation of the limb salvage indication is taking place (with very good survival rates), we see a similar rising trend of the late onset complications in children maintaining their own limb, which might mandate subsequent interventions in certain patients.

Since in the lower limbs the surgical treatment aims at preserving in time the functionality criteria based on allowing the same length of both limbs, individualized decisions must be taken based on numerous variables mentioned above.

The long-term concern about the wellbeing of the child affected and the measures recommended are based upon the initial decision, and prioritizing the oncological treatment success.

Conflict of interests

The authors have no conflict of interest to declare.