Ewing sarcoma

Summarize

1.General Introduction
●Overview: Ewing sarcoma is a rare small round cell malignant tumor that occurs most often in children and adolescents.
●Presentation: Localized bone pain or lump, often mistaken for "growing pains", which can progress to a palpable soft tissue mass.
Treatment: Chemotherapy, surgery, and radiation therapy are the mainstay of treatment.
Prognosis: Ewing sarcoma is highly malignant, prone to recurrence, and has a poor prognosis.
2. Disease definition
Ewing sarcoma, also known as Ewing's sarcoma and Ewing's sarcoma, is a type of bone tumor that occurs in children and adolescents, mainly in the pelvis, femur, tibia, humerus, and ribs, but also in the soft tissues adjacent to the bones (e.g., the chest wall, gluteal muscles, pleural cavity, and neck muscles). It is the second most common primary malignant bone tumor affecting children and adolescents and is highly aggressive.

Epidemiological

Epidemiology
The incidence of Ewing sarcoma in children and adolescents aged 10-19 years in the United States is 9-10 cases per million. The mean age of diagnosis of Ewing sarcoma is approximately 15 years, and the majority of patients are adolescents, with slightly more male patients (59%) than female patients (41%).

Etiolog & Risk factors

1. General
The cause of Ewing sarcoma is not fully understood, but researchers have identified genetic variants that lead to Ewing sarcoma. These gene variants are non-inherited. For some currently unknown reason, these variants occur in a child's body cells after birth, leading to the development of the tumor.
2. Underlying Causes
It is currently believed that Ewing sarcoma cells are derived from bone marrow primitive mesenchymal stem cells and that almost all Ewing sarcoma cells produce a mutation in the EWSR1 gene. Specifically, the EWS region on human chromosome 22 (the EWSR1 gene) is genetically displaced from the FET region on chromosome 11 (containing the FLI1, ERG, ETV1, ETV4, and FEV genes), resulting in the production of a mutant fusion protein, FET-ETS, which leads to the disruption of regulation of a large number of genes in the genome, causing the originally normal cells to become cancerous. This fusion protein leads to a large number of gene expression disorders in the genome, causing the normal cells to become cancerous.
3. Predisposing factors
According to the studies on children with Ewing sarcoma, no external triggering factors other than genetic mutation have been found.

Classification & Stage

Disease Types
1) Disease typing
Ewing sarcoma is a collective term for a group of small round cell tumors that includes Ewing sarcoma of bone, extraosseous Ewing sarcoma, primitive neuroectodermal tumors (PNET), and small cell malignant tumors of the chest wall (also known as Askin tumors).
2) Disease classification
Ewing sarcoma is a malignant bone tumor that can be graded according to the American Joint Committee on Cancer (AJCC) histologic grading system for all malignant bone tumors. Histologic grading classifies all bone cancers into four grades - GX, G1, G2, and G3 - based primarily on the appearance of the cells in the biopsy sample. Low-grade tumor cells look more like normal cells and are less likely to grow and spread rapidly, while highly malignant tumor cells look more abnormal. All Ewing sarcomas are highly malignant tumors that fall into the G3 grade.
3) Disease Staging
Ewing sarcoma can be broadly divided into two stages: focal Ewing sarcoma and metastatic Ewing sarcoma. Focal Ewing sarcoma means that the tumor has only one primary site (initial point of onset) and no tumor is found elsewhere in the body. Metastatic Ewing sarcoma indicates that the tumor is found in a part of the body other than the primary site.
The specific staging of Ewing sarcoma is mainly based on the American Joint Committee on Cancer (AJCC) TNM staging system for all malignant bone tumors, which stages the tumor in four ways:
● Tumor size (T): describes the size of the primary tumor and whether it is present in different regions of the bone.
○T0: There is no evidence of a primary tumor.
○T1: The width of the tumor does not exceed 8 cm.
○T2: The width of the tumor is greater than 8 cm.
○T3: The tumor was in multiple areas of the same bone.
●Lymph node involvement (N): describes the extent of lymph node spread to nearby areas.
○N0: No spread to nearby lymph nodes.
○N1: The cancer has spread to nearby lymph nodes.
● Presence of distant metastasis (M): Whether the cancer has metastasized (spread) to other organs in the body; the most common sites of metastasis are the lungs or other bones.
○M0: No spread to distant organs.
○M1a: The cancer has spread only to the lungs.
○M1b: The cancer has spread to other distant parts of the body.
Histologic Grading (G): All Ewing sarcomas fall into the G3 grade.
Once the T, N, M, and G categories have been determined, the information can be combined to indicate an overall stage staging. These stages are described by Roman numerals I through IV (1-4), with larger numbers indicating more advanced stages, and include the following groups:
● ⅠA stage
T1, N0, M0, GX, or G1: The tumor is no more than 8 cm in diameter (T1), the histologic grading is not evaluable or is of a low grade (GX or G1), and it has not yet spread to nearby lymph nodes (N0) or metastasized to distant parts of the body (M0).
● Stage IB
T2 or T3, N0, M0, GX or G1: Tumor diameter is greater than 8 cm (T2) or is located in multiple sites in the same bone (T3), histologic grading cannot be assessed or is low grade (GX or G1), has not spread to nearby lymph nodes (N0) or metastasized to distant parts of the body (M0).
● Stage IIA
T1, N0, M0, G2, or G3: The tumor is no more than 8 cm in diameter (T1) and is highly malignant in histologic grade (G2 or G3), and has not spread to nearby lymph nodes (N0) or metastasized to distant parts of the body (M0).
● Stage IIB
T2, N0, M0, G2 or G3: The tumor is greater than 8 centimeters in diameter (T2) and is highly malignant (G2 or G3) in histologic grading and has not yet spread to nearby lymph nodes (N0) or metastasized to distant parts of the body (M0).
●Stage III
T3, N0, M0, G2 to G3: Highly malignant tumor (G2 or G3) in more than one location (T3) in the same bone that has not spread to nearby lymph nodes (N0) or metastasized to distant parts of the body (M0).
● Stage IVA
Any T, N0, M1a, any G: Tumor that has spread only to the lungs (M1a) and has not yet spread to the lymph nodes (N0) or to other parts of the body.
● Stage IVB (Stage IVB if either of the following applies)
Any T, N1, any M, any G: If the tumor has spread to nearby lymph nodes (N1), then it is stage IVB regardless of tumor size, histologic grade, and distant metastases.
Any T, any N, M1b, any G: If the tumor has spread to distant parts of the body other than the lungs (M1b), then it is stage IVB regardless of tumor size, lymph node involvement, and histologic grading.

Clinical manifestations

1. General description
The most common clinical manifestations of Ewing sarcoma are localized pain or mass and compression symptoms caused by the mass. In addition, the symptoms may vary according to the location of the lesion, its size, invasion of surrounding organs and distant metastasis.
2. Typical symptoms
1) Localized symptoms
Ewing sarcoma most commonly occurs in the pelvis (hip bone), chest wall (e.g., ribs or shoulder blades), and legs, but may also occur in other parts of the body. 80% of children and adolescents with Ewing sarcoma experience pain and swelling in the area of the tumor, which may be intermittent, sometimes occurring at night, and worsening over time. Bone pain may occur because the tumor has spread beneath the outer layer of bone (periosteum) or because the bone has been eroded by the tumor and a fracture has occurred.
As the disease progresses, most Ewing sarcomas of bone and almost all non-bone (soft tissue) Ewing sarcomas cause lumps or swelling that are more easily found in tumors of the arms or legs. For tumors in the chest wall or pelvis, they are harder to notice because they are difficult to touch.
2) Metastatic symptoms
About 20-25% of patients with Ewing sarcoma have metastases by the time they are diagnosed. Metastases are most often found in the lungs, bones, bone marrow, and inside the skull. If the tumor metastasizes near the spine, it can cause back pain and weakness, numbness or paralysis in the arms or legs, and even symptoms of spinal cord compression (e.g., urinary or bowel retention or incontinence). Tumors that metastasize to the lungs can cause shortness of breath. Children who develop bone marrow invasion may present clinically with fever, anemia, bleeding, infection, and other symptoms arising from abnormal blood cells. If the tumor metastasizes to the skull, it may cause symptoms of cranial hypertension due to the occupying effect, which mainly manifests as headache, nausea, and projectile vomiting. In addition, due to the tumor compression symptoms intracranial nerves, it may lead to neurological symptoms, mainly manifested as motor disorders, sensory disorders, seizures and so on. In general, different symptoms will appear depending on the location, size, invasion of surrounding organs and distant metastasis.
3. Accompanying symptoms
10%~20% of patients have systemic symptoms, such as fever, fatigue, low appetite, weight loss or anemia.

Clinical Department

1. General
In children or adolescents, bone pain is often mistaken for "growing pains" and confused with injuries caused by daily life or sports (e.g., tendonitis, muscle pain, muscle injury, or osteomyelitis). Therefore, parents who have children with unexplained bone pain that has persisted for more than a month should have their children examined in a hospital.
2.Department of consultation
Bone Oncology, Orthopedics, Surgical Oncology.

Examination & Diagnosis

1. Diagnostic Process and Basis of Diagnosis
Doctors will first take a medical history and examine the painful area or mass. Imaging tests will then be performed to evaluate the lesion, to help determine if the suspicious area may be cancerous, and to determine the extent and spread of the tumor.
If the results of the imaging tests point to a high likelihood that the child has Ewing sarcoma, the doctor will perform a pathology test to further confirm that it is Ewing sarcoma. Because Ewing sarcoma is typically characterized by the genetics of chromosomal variants, a molecular diagnosis of specific chromosomal variants is important in the diagnosis of Ewing sarcoma.
In addition, the doctor will also perform organ function and routine tests to get a complete picture of the child's general health to assess the child's physical load to look for any problems or side effects that may arise from the treatment.
Finally, depending on the location of the tumor, the doctor will perform targeted tests. For example, for children with head tumors, the doctor will perform a lumbar puncture and sample the cerebrospinal fluid; for children with blood cell changes and suspected bone marrow metastases, the doctor will often perform a bone marrow puncture and sample the bone marrow for biopsy.
2 Related examinations
1) Medical history
The doctor will ask about the patient's medical history, including past health, family history of oncological diseases, and exposure to harmful physical and chemical factors in life and work.
2) Physical examination
The doctor will find out the patient's height, weight, body surface area, tumor size, texture and tenderness through physical examination. If there are symptoms of tumor compression and central nervous system symptoms, neurological examination is needed. For metastatic lesions, lung examination, skin, mucous membrane, bone, liver, spleen, lymph node size and other examinations are needed.
3) Imaging
●X-ray flat film: Ewing sarcoma tumor of bone usually presents as a destructive lesion with poorly defined borders, and 10%-15% of cases have pathologic fracture at the time of diagnosis.
●CT: Compared with X-ray plain film, CT can better show the extent of cortical destruction and soft tissue lesions, which is suitable for extraosseous Ewing sarcoma. It can also be used to find out whether there is any tumor hemorrhage and inflammatory changes, and a CT scan of the chest can also be used to evaluate the lungs for pulmonary metastases.
● Magnetic Resonance Imaging (MRI): Compared to plain X-rays and CT, MRI can better distinguish the size of the tumor, the extent of localized intrabony and extrabony lesions, as well as the relationship of fascial surfaces, blood vessels, nerves, and organs to the tumor, and determine the extent of the tumor for subsequent surgery or radiation therapy. Magnetic resonance imaging of the head may be used to see if intracranial metastases are present.
●B ultrasound: ultrasound can be used to understand the size and nature of the tumor, the extent of the tumor, the blood supply, and the relationship with the surrounding tissues in the primary and metastatic sites, and it is the most non-invasive and convenient imaging examination.
●PET-CT: Children with conditions can have a whole body examination by PET-CT to evaluate the initial stage of the tumor.
●Bone scan: If the child has obvious symptoms of generalized limb pain, a radionuclide bone scan can be performed to evaluate the presence of multiple lesions in the bones of the whole body, if possible. If PET-CT has been performed, a bone scan is not necessary.
4) Histopathology
Histopathologic testing can provide a more definitive diagnosis of Ewing sarcoma. In order to obtain a histopathology sample, the doctor will need to obtain a pathological tissue sample through puncture, excisional biopsy, or surgery. Histopathology tests include examining tissue cell morphology, immunocytochemical features, cytogenetic features, and molecular biological features. Since Ewing sarcoma has typical genetic features of chromosomal variants, specific chromosomes are important diagnostic features of Ewing sarcoma and are usually examined by immunofluorescence staining (FISH). The more sensitive polymerase chain reaction (PCR) may also be performed in some qualified medical institutions.
5) Organ function and routine tests
● Biochemical and dynamic erythrocyte sedimentation rate tests: liver and kidney function, lactate dehydrogenase (LDH), electrolytes, and dynamic erythrocyte sedimentation rate need to be checked. Patients with Ewing sarcoma with high tumor load may have elevated blood uric acid and lactate dehydrogenase levels.
● Electrocardiogram and cardiac ultrasound, which are used to check the patient's cardiac function.
● Routine blood tests; if the tumor invades the bone marrow, patients often have elevated white blood cells and decreased hemoglobin and platelets.
● Coagulation tests, which are used to check a child's blood clotting function and the presence of bleeding and blood clots before treatment.
Depending on the diagnosis and treatment needs, patients may also be screened for pre-transfusion infectious diseases (Hepatitis B, Hepatitis C viral antibodies, syphilis, and HIV tests), blood biochemistry, routine urinalysis, routine stool tests, and other test items.
6) Cerebrospinal fluid examination (lumbar puncture examination)
Patients whose tumors invade the orbit, nasal cavity, sinuses, nasopharynx, infratemporal fossa, or intracranial area are required to undergo a cerebrospinal fluid examination by taking a sample through lumbar puncture in order to find out whether the tumor invades the central nervous system (brain and spinal cord) if the condition permits.
7) Bone marrow examination (bone marrow aspiration)
If the patient presents with blood cell changes, and/or imaging studies suggestive of bone marrow invasion, a bone marrow aspiration is required in order to perform routine bone marrow and chromosomal karyotype analysis tests to aid in diagnosis.
3. Differential diagnosis
Subacute osteomyelitis, eosinophilic granuloma and giant cell tumor of bone, osteosarcoma, primary lymphoma of bone, undifferentiated high-grade pleomorphic sarcoma of bone, acute leukemia, and metastatic tumors of other non-bone tumors are easily misdiagnosed as all of the above are more similar to Ewing's sarcoma because of imaging findings. They can be differentiated by pathologic biopsy.

Clinical Management

1. General description
Because Ewing sarcoma is a systemic disease, most patients have subclinical metastases at the time of diagnosis, even in the absence of obvious metastases. The recurrence rate is as high as 80%-90% if localized treatment is administered alone. Therefore, patients with first-treatment Ewing sarcoma generally receive a combination of multiagent chemotherapy and local control measures (surgery and/or radiation).
Currently, the treatment of Ewing sarcoma in children and adolescents mainly refers to the treatment protocols of the U.S. Children's Oncology Research Collaborative Group (COG).
2.Chemotherapy
1) Chemotherapy regimen
Chemotherapy for Ewing sarcoma generally includes preoperative neoadjuvant chemotherapy and postoperative adjuvant chemotherapy. The commonly used chemotherapy regimens are VDC regimen (vincristine + doxorubicin + cyclophosphamide) and IE regimen (isocyclophosphamide + etoposide), which are usually alternated every 2 to 3 weeks. For preoperative neoadjuvant chemotherapy, if the patient's myelosuppression is restored and there are no obvious contraindications to chemotherapy, the chemotherapy interval can be appropriately reduced.
If the patient has no disease progression, 4-6 courses of neoadjuvant chemotherapy are usually given preoperatively, followed by the same regimen of adjuvant chemotherapy after surgery. The total course of treatment is usually about 48 weeks.
Prior to chemotherapy, the patient's condition should fulfill all of the following conditions: absolute neutrophil count (ANC) ≥1×109/L, platelet (PLT) ≥100×109/L, alanine aminotransferase (ALT) <10 times of the high limit of normal, and normal urine routine.
2) Adverse reactions
Common side effects of chemotherapy include hair loss, mouth sores, loss of appetite, nausea and vomiting, diarrhea, increased chance of infection (low white blood cells), easy bruising or bleeding (low platelets), and fatigue (low red blood cells). Most of these side effects go away after treatment is over, and can also be reduced by medications, transfusions of component blood, and other methods.
Also, different chemotherapy drugs may cause certain side effects. Cyclophosphamide, isocyclophosphamide, and doxorubicin are nephrotoxic and may cause hemorrhagic cystitis, which can lead to blood in the urine, and can be prevented with mesylate. Doxorubicin can be damaging to the heart, and an echocardiogram is needed to monitor this risk during treatment; it may also be pulmonary toxic, and can be treated symptomatically with glucocorticoids. Etoposide may increase the risk of distant leukemia, although it is uncommon. Vincristine, etoposide, and isocyclophosphamide are neurotoxic and may cause symptoms such as limb pain, constipation, abdominal colic, numbness of the limbs, sensory abnormalities, decreased vibratory sensation, gait disorders, lethargy, and mental abnormalities. Usually, these symptoms disappear or get better after stopping treatment, but in some patients, these side effects may persist for a longer period of time.
3.Radiotherapy
1) Radiation therapy program
Ewing sarcoma is very sensitive to radiation, so radiation therapy can be combined with surgery and chemotherapy to enhance the effectiveness of treatment. The timing of radiotherapy can be preoperative and/or postoperative.
For primitively treated tumors without distant metastases and with the potential for complete resection, preoperative radiation therapy can be used to shrink the tumor and increase the likelihood of complete resection. Preoperative radiotherapy is usually given at the beginning of the 13th week of treatment and at the end of the 6th course of chemotherapy.
Postoperative local radiation therapy is required if there is postoperative gross or microscopic residue, intraoperative tumor contamination, lymph node or pleural metastases. The timing of postoperative radiation therapy is usually initiated at week 15 of treatment, concurrently with course 7 of chemotherapy.
The dose of radiation therapy for first-treatment Ewing sarcoma without distant metastases is usually 45 Gy. If the tumor originates in extraosseous soft tissue without skeletal involvement, the dose of radiation therapy is 50.4 Gy. It is delivered in fractions, depending on the patient's condition.
For primary tumors with distant metastases at the time of diagnosis, radiotherapy is usually started at the same time as the fifth course of chemotherapy. If there are no conditions, radiotherapy can also be started after the 5th course of chemotherapy, and subsequent chemotherapy can be delayed appropriately. The radiotherapy dose is generally as follows: 55.8 Gy for residual lesions in bone and soft tissue in 31 sessions; 50.4 Gy for residual microscopic lesions in 28 sessions; 45 Gy for vertebral bone involvement in 25 sessions; and 55.8 Gy for lymph node metastasis without resection and 50.4 Gy after resection in 28 sessions.
2) Adverse effects
The side effects of radiotherapy depend mainly on the dose of radiation and its site, and their effects can be categorized as short-term and long-term.
Short-term problems are mainly effects on the skin of the irradiated area, which may range from mild sunburn-like changes and hair loss to more severe skin reactions. Radiation may also lower blood counts and neutrophil levels. If radiation reaches the abdomen or pelvis, it may cause nausea, diarrhea and urinary problems.
4. Surgical treatment
1) Surgery for Ewing sarcoma
Surgical resection is an important part of Ewing sarcoma treatment, and its main goal is to remove all tumor tissue. Since a small amount of residual cancer cells can cause the tumor to recur, in order to reduce the risk of recurrence, the surgeon removes the tumor and some of the normal tissue around it in order to achieve negative margins (i.e., no more cancer cells at the edges of the site of surgical resection). Surgical removal of the lesion reduces the problem of local recurrence and secondary tumors compared to local radiation therapy alone.
For most tumors in the arm or leg, surgery can remove some or all of the affected bone while the arm or leg remains largely intact, which is called limb-sparing surgery. The bone that needs to be removed can be replaced with a bone graft (bone from another part of the body or someone else's bone) or a built-in prosthesis (usually a rod-shaped device made of metal and other materials). However, if the tumor is located in a part of the bone that is difficult to repair, or if the tumor extends into important nerves or blood vessels, it may be difficult to remove the tumor completely with limb-sparing surgery. Amputation should be considered if it is required to enable achievement of negative margins.
In addition, there is a surgical option, rotationplasty, for leg tumors in younger patients, especially near the knee. Rotational plasty can be thought of as a special type of amputation, in that it removes the tumor and its growing bone segment, as well as the knee joint, and then rotates the patient's lower leg (including the foot) and attaches it to the remaining femur (i.e., the thigh bone), with a calf prosthesis replacing the shortened part of the leg. In this way, the original ankle joint will replace the function of the knee joint, which can enhance the function of the leg after surgery and improve the mobility of the patient. However, the appearance may be difficult to accept because the area where the original knee was has become an inverted foot.
For tumors in the chest wall, the surgeon usually must remove the diseased area and remove nearby ribs, which can then be replaced with artificial material. If the tumor has spread to the lungs, the chest may be opened and the lung tumor removed during open-heart surgery. Often, these patients will also need to undergo radiation therapy to the chest.
For pelvic tumors, radiation therapy is often the treatment of choice. However, if the tumor responds well to initial chemotherapy, surgery may be an option. For pelvic areas removed during surgery, it is sometimes possible to reconstruct the pelvis after surgery, but in some cases it may be necessary to remove the pelvis and that side of the leg in order to completely remove the tumor.
For spinal tumors, surgery is difficult to remove completely, so radiation therapy is sometimes a better option. If surgery is performed, postoperative radiotherapy is usually needed to kill any remaining tumor cells.
2) Post-operative complications
Ewing sarcoma surgery is usually less prone to serious short-term complications; possible short-term side effects include reaction to anesthesia, excessive bleeding, development of blood clots, and infection. After surgery, patients often experience pain and may need to use strong pain medication for a period of time.
Long-term side effects of surgery depend on the tumor site as well as the surgical option.
Patients undergoing limb-sparing surgery have a relatively long healing time compared to other surgical options because the chemicals used before and after surgery increase the risk of infection and interfere with wound healing. Since limb-sparing surgery involves bone grafts or built-in prostheses, if an infection occurs, it may be difficult to treat and may even require further surgery. Also, the grafted bone or built-in prosthesis may break or become loose, requiring more surgery to repair. And for growing children, the body grows and develops, so more surgeries may be needed in the coming years to replace the built-in prosthesis in order to make it fit the growing body.
Amputation patients recover more quickly than limb-sparing surgeries, but they are also susceptible to infections, especially for leg amputees. This is especially true for leg amputation patients, because over time, the pressure on the skin at the amputation site can cause the skin to break down, increasing the likelihood of infection.
These postoperative complications require long-term follow-up and prompt medical attention.
5. Cutting-edge treatments
1) Autologous hematopoietic stem cell transplantation
Autologous hematopoietic stem cell transplantation for Ewing sarcoma is a treatment still being studied in clinical trials for Ewing sarcoma that is difficult to treat with other therapies, such as tumors that have metastasized to other parts of the body or that have recurred after standard therapy.
In this approach, the patient's own blood stem cells are collected, and high doses of chemotherapy are used to kill the tumor cells in the patient's body, followed by hematopoietic stem cell transfusions to rebuild the blood-forming system that was damaged during chemotherapy.
According to the results of foreign clinical trials Euro-E.W.I.N.G.99 and EWING-2008, children with high-risk localized tumors had a 3-year event-free survival (EFS) rate of 67% after high-dose leucovorin combined with melphalan chemotherapy and autologous hematopoietic stem cell transplantation, which is a 14% increase in the 3-year EFS rate compared to that of the standard chemotherapy regimen of 8 cycles.
2) Targeted Therapy
Targeted therapy is a therapy that uses drugs to specifically attack cancer cells. Targeted therapies usually cause less damage to normal cells than chemotherapy and radiation. Targeted therapies for the treatment of Ewing's sarcoma are currently being studied and include:
● Monoclonal antibody therapies: a monoclonal antibody (Ganitumab) against the type 1 insulin-like growth factor receptor (IGF-1R) is in phase II clinical trials for the treatment of metastatic Ewing sarcoma.
● Kinase inhibitor therapy: Cabozantinib is a tyrosine kinase inhibitor that blocks proteins needed for cancer cells to divide. This therapy is in phase II clinical trials for the treatment of recurrent Ewing sarcoma.

Prognosis

1. General description
According to international statistics, the survival rate of limited Ewing sarcoma is 70-80%; if distant metastases have already appeared at the time of diagnosis, the long-term survival rate is less than 30%; however, if the metastases are confined to the lungs, the survival rate is about 50%.
2. Sequelae
The risk of sequelae in Ewing sarcoma depends on many factors, such as the size and location of the tumor, the treatment and dosage received, and the age at diagnosis. Some chemotherapy drugs or radiation therapy to the chest may cause heart or lung problems. Radiation therapy can cause bone growth to slow down in children, and the effects are especially pronounced in younger children. For example, radiation to the bones on one side of the leg may cause that leg to be shorter than the other in the future. Pelvic tumors and their treatment may affect a patient's sexual development and fertility.
If a patient undergoes limb-sparing surgery, the presence of grafted bone or a built-in prosthesis may interfere with the patient's ability to participate in many physical activities. Amputations and rotational plastics can also have some impact on limb mobility, although usually less so than limb preserving surgery.
In addition, radiotherapy may lead to the risk of secondary tumors. For patients with Ewing sarcoma, the risk of secondary tumors is predominantly for osteosarcoma. Therefore, it is very important to follow up after treatment so that problems, if any, can be detected and treated as early as possible.
3.Rehabilitation
Patients with Ewing sarcoma often need to regain their mobility after surgery, so they can consider visiting the rehabilitation department for rehabilitation treatment and follow the doctor's instructions to formulate a rehabilitation plan according to their actual conditions.
On average, it takes about one year for a child to learn to walk after limb preserving surgery. Rehabilitation after limb-sparing surgery is extremely important. If the patient does not actively participate in the rehabilitation program, the saved arm or leg may lose its function.
Amputation patients need to practice and adapt to the use of a prosthesis. With proper rehabilitation, patients can usually walk on their own with a prosthesis 3-6 months after amputation. Patients who undergo rotational plasty often require less rehabilitation time.
4. Recurrence and metastasis
More than a quarter of children with limited Ewing sarcoma will have a recurrence at the end of treatment. If metastases are present at the time of diagnosis, the chance of recurrence is even higher. More than 70% of recurrences occur within 2 years of the initial diagnosis and are considered early recurrences. The majority of late recurrences occur within 2 to 3 years of the initial diagnosis, and there are cases that recur even 5 or more years later.
At least 2/3 of first recurrences occur distant from the original lesion, usually in the lungs and/or bones. This pattern of recurrence is particularly common in patients who have metastases at first diagnosis. Local recurrence occurs in approximately 1/5 of patients, and this pattern of recurrence is more common in patients with only limited tumors at first diagnosis. If chemotherapy is not standardized at the time of initial treatment and the course of treatment is inadequate, this may increase the risk of recurrence after discontinuation of the drug.
Recurrence is usually accompanied by pain and swelling, so regular follow-up, especially with imaging to track for metastasis, is extremely important. After recurrence, the patient will need to undergo chemotherapy and/or radiotherapy again. In cases of late recurrence, continuation of the previous treatment regimen may be considered. Recurrent Ewing sarcoma is more difficult to treat, and depending on the site of metastasis, 50-80% of patients with recurrence will fail treatment.

Follow-up & Review

1. General
After the completion of treatment for Ewing sarcoma, attention should be paid to timely review and follow-up, on the one hand, to monitor the side effects caused by the treatment, and on the other hand, to closely monitor whether the disease recurs.
2. Review
Within 2 years after the completion of treatment, comprehensive physical examination, routine blood test, chest imaging, magnetic resonance imaging (MRI) of the head and local imaging of the primary foci should be performed every 3 months, and bone scan should be performed if necessary. Patients with bone marrow invasion and central nervous system invasion need regular review of bone marrow routine and cerebrospinal fluid examination.
In the 3rd-5th year after the end of treatment, these examinations are performed every 6 months.
After 5 years from the end of treatment, these tests are performed once a year.

Routine

1.Daily life management
1) Diet
Care should be taken to provide patients with a nutritious and well-balanced diet. After undergoing surgery, chemotherapy or radiotherapy, patients may need extra protein to heal tissues and help prevent infections. Therefore, it is necessary to safeguard the intake of high-quality proteins (e.g. meat, eggs, milk, poultry, fish and shrimp, soybeans and soybean products, etc.), as well as to eat plenty of grains and cereals and vegetables and fruits, and to consume a moderate amount of dairy products and nuts in order to ensure the intake of other nutrients.
In addition, it is necessary to ensure the patient's water intake because of the possibility of vomiting or diarrhea during treatment, which may cause dehydration.
Some of the medications used to treat cancer may reduce levels of calcium and vitamin D, which are particularly important for bone growth, so children with Ewing sarcoma need to be more aware of this and can consult their doctor about the need for vitamins, calcium tablets or other dietary supplements.
A clinical dietitian in the hospital's nutrition department can be consulted to provide the patient with an appropriate nutritional program. If weight loss is severe, nutritional support through tube feeding or parenteral nutrition may be considered.
2) Exercise
Studies have shown that physical exercise has a positive impact on cancer survivors. Physical activity can improve lung function and cardiovascular tolerance. Regular exercise can also gradually restore muscle weakness caused by being bedridden. Physical activity is an important part of post-treatment rehabilitation and can also help most patients return to a normal lifestyle and socialization.
3) Lifestyle
If the child has neutropenia due to treatment, care should be taken to prevent infection. Pay attention to personal and living environment hygiene, do not approach patients with infectious diseases, and do not go to crowded places.
If thrombocytopenia is caused by treatment, care needs to be taken to avoid bleeding by staying away from sharp, prickly toys and objects, as well as avoiding impact-intensive sports (e.g., bungee jumping, soccer, basketball, etc.).
4) Emotional psychology
Most Ewing sarcomas occur during childhood or adolescence, a time of great psychological sensitivity. Ewing sarcoma and its treatment can affect the patient's appearance and how they view themselves and their body, so it is normal to experience some anxiety or other emotional reactions often after treatment.
After treatment is over, patients' lives may still be affected by the disease and treatment in various ways, including learning, school life, work or recreational activities. These subsequent effects are usually greatest during the first year of treatment, but may last longer for some patients.
Therefore, even after treatment has ended, patients still need the support of family, friends, other cancer survivors, and professional counseling/therapy staff to help them overcome excessive worry or frustration, re-establish relationships, and return successfully to school, work, and all aspects of life.
2. Daily monitoring of disease
Post-operative complications, side effects caused by radiotherapy (e.g. hair loss, fatigue, vomiting, etc.), recurrence of tumor metastasis, and growth and development problems need to be monitored. Consult your doctor when you experience pain, lumps, and side effects caused by treatment.
3. Special Precautions
As a result of radiotherapy, patients with Ewing sarcoma have a risk of distant second tumors, the onset of which may occur many years after the completion of treatment for Ewing sarcoma, and this risk is related to the regimen and dosage of treatment for Ewing sarcoma. Therefore, care should be taken to keep records of all the patient's visits and treatments, even after treatment is completed, so that the patient's medical and health care information can be recorded for future review and consultation.
6. Prevention
There is no method or scientific basis to prevent the occurrence of Ewing sarcoma. Early medical treatment is an important part of improving the cure rate of Ewing sarcoma.

Cutting-edge Therapeutic & Clinical Research

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References

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3. https://www.cancer.org/cancer/ewing-tumor/
4. National Health and Wellness Commission of the People's Republic of China Standardized Diagnosis and Treatment of Ewing Sarcoma in Children and Adolescents (2019 Edition)
5. Guo W, Wang Z, Guo Z, et al. Clinical evidence-based diagnosis and treatment guidelines for Ewing sarcoma tumor family (ESFT). Chinese Journal of Bone and Joint Surgery, 2018, 11(4): 260-275.
6. van Mater, D. & Wagner, L. Management of recurrent Ewing sarcoma: challenges and approaches. onco. targets. ther. volume 12, 2279- 2288 (2019).
7. https://clinicaltrials.gov/ct2/show/NCT04129151
8. https://clinicaltrials.gov/ct2/show/NCT02243605
9. https://www.cancer.org/ treatment/children-and-cancer/when-your-child-has-cancer/nutrition.html

Audit specialists

Prof. Zhengdong Cai, Director, Department of Orthopedics, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
Link to Baidu Encyclopedia of Experts: https://baike.baidu.com/item/%E8%94%A1%E9%83%91%E4%B8%9C