Diagnosis & treatment

Diagnosis of Ewing’s sarcoma

The importance of early diagnosis of Ewing’s sarcoma, or indeed any cancer, cannot be overstated. If a patient experiences any of the symptoms they should consult their GP at the earliest opportunity.

“Presentation” is the term used by medical professionals to describe the first time a patient attends a doctor regarding their symptoms. This can be a GP, a clinic or an emergency department. In most cases of Ewing’s sarcoma the patient will visit their GP.

The doctor will document a “clinical history” which is general information about the symptoms. They will then examine the affected area, to discover whether it hurts to touch and whether the pain is in the bone or muscle. At this stage, the doctor will be investigating for soft tissue and muscle injuries.

If the doctor is concerned that there is a possible tumour, there are national guidelines that they should follow. National Institute for Clinical Excellence (NICE) guidelines for suspected bone cancer recommend that a patient must receive an urgent referral to hospital for an X-ray.

On arrival at the hospital, the patient will undergo an X-ray to produce an image of the bone in the affected area. If the X-ray shows signs of abnormal bone growth, the hospital will conduct more detailed scans of the bone using CT (computerised tomography) or MRI (magnetic resonance imaging).

CT scans are often undertaken after the diagnosis of cancer is confirmed to determine whether it is localised (contained in the bone) or is metastatic (has spread). These scans involve the injection of contrast, before a camera rotates extremely fast around the body taking a number of images to build up a 3D picture of the body.

MRI scans use magnetism and radio waves to build a detailed 3D image of the affected bone. The hospital might also carry out a blood test to check the overall health of the patient, although at present there is no specific blood test for Ewing’s sarcoma.

If the detailed scans confirm an abnormal growth or tumour, the hospital will refer a patient to a specialist Bone Tumour Centre.

Bone Tumour Centres are specialist NHS hospitals that perform the diagnosis and surgical treatment of bone cancer, rather than a general hospital that does a bit of everything. Bone Tumour Centres comprise medical professionals that have received extra specialist training in orthopaedics as well as expertise in the medical and radiation treatment of bone cancers.

In England, there are five Bone Tumour Centres, in Birmingham, Newcastle, Oswestry, Oxford and Stanmore (London). Patients in Wales usually travel to Oswestry or Birmingham. In Scotland, there are three Bone Tumour Centres and these are in Edinburgh, Glasgow and Aberdeen. In Northern Ireland, patients are usually seen in Belfast.

At the Bone Tumour Centre, a multidisciplinary team (MDT) will be assigned to an individual patient. This team is a group of medical and healthcare professionals who are experts in their various fields and they work together to ensure that a patient is accurately diagnosed and if appropriate, treated accordingly. An MDT may consist of:

  • An oncologist who is a doctor with expertise in managing patients with cancer. Oncologists specialise in treatments such as chemotherapy.
  • A diagnostic radiologist who has undergone highly specialised training in interpreting X-rays and scans.
  • A therapeutic radiologist who has undergone highly specialised training to perform radiotherapy treatment. 
  • A histopathologist who is a doctor with expertise in the microscopic examination of tissues and cells.
  • An orthopaedic surgeon who is an expert at removing tumours and reconstructing bone.
  • A sarcoma nurse specialist who has undergone highly specialised training in caring for patients with sarcoma (any cancer of connective tissue such as bone, fat and muscle)

At the Bone Tumour Centre, the MDT will assess the original scans taken at the initial hospital and will organise for the patient to receive a biopsy. A biopsy is the use of a needle (needle biopsy) or surgery (open biopsy) to take a sample of cells and/or tissue from the suspected tumour, which is often performed under general anaesthetic. The histopathologist will assess the biopsy material under a microscope and will look for abnormal cells that may confirm Ewing sarcoma. Increasingly, histopathologists are integrating the use of genetic sequencing on biopsy samples to support and guide their accurate diagnosis. 

Together with the scans and biopsy results, which can take around a week after the biopsy is performed, the MDT will determine whether a patient has Ewing sarcoma or not. Sometimes a repeat biopsy is required to establish the diagnosis. If not Ewing sarcoma, other possible conditions include:

  • Another type of bone cancer, for example, osteosarcoma.
  • Eosinophilic granuloma, which is a non-cancerous (“benign”) bone tumour that is found mainly in children under the age of 10. 
  • Osteomyelitis, which is an infection inside the bone.

If Ewing sarcoma is confirmed, most patients will be referred to their nearest sarcoma treatment centre. This will be a hospital with experience of treating sarcoma cancers, which are different to more common cancers such as breast, prostate, colon, etc. This may or may not be the same hospital that performed the original scans after referral from the GP but will be closer to a patient’s home than the Bone Tumour Centre. 

The treating sarcoma centre will want to ‘stage’ a patient. This means they will perform more scans, often a CT of the chest, a whole-body magnetic resonance imaging (WB-MRI) and, or Positron emission tomography (PET) scan to determine if the sarcoma has spread or not and to what extent. This provides information about prognosis, helps determine management of the tumour and provides a baseline from which response to treatment can be measured against. A PET scan uses a small amount of radioactive glucose injected into a vein which is taken up in the body by cells, such as cancer cells using glucose at the highest rates. These areas of high metabolic activity or rapid cell growth show up brightly, known as ‘hot spots’ on a PET scan that can detect metastases (deposits of tumour spread).

The patient will usually start treatment within a week, under the direction of the MDT, who while based at the Bone Tumour Centre work very closely with the sarcoma treatment centre. The National Ewing sarcoma Multidisciplinary Team Meeting (NEMDT) was formed in 2011 and is a national forum set up to improve treatment planning and clinical decisions made for Ewing sarcoma patients. This forum brings together clinicians and specialists from around the UK to discuss the best treatments, clinical management and decisions for current patients.

Treatment of Ewing’s sarcoma

Patients with Ewing sarcoma may have slightly different treatment plans depending on the location and stage of the disease. These aggressive bone tumours are challenging to treat and require multiple modes of treatment, including chemotherapy as the mainstay, surgery +/- radiation. Typically, treatment for Ewing sarcoma starts with killing cancer cells throughout the whole body with chemotherapy (“neoadjuvant chemotherapy”) as well as shrinking the tumour. Then there is removal of the primary tumour with surgery and/or treatment with radiotherapy. Chemotherapy is given again after surgery (“adjuvant chemotherapy”) to try and make sure there are no cancer cells left anywhere in the body. It takes around 6 months to complete Ewing sarcoma treatment from start to finish (described below). 

In addition to the multidisciplinary team, during  treatment the patient will also be cared for by a large team of health professionals including nurse specialists, physiotherapists and occupational therapists to help with rehabilitation after surgery, dieticians to ensure proper nutrition and maintain weight for healing and faster recovery from treatments and social workers/psychologists to help with emotional, social and educational needs.

Types of Treatment

Chemotherapy given before surgery is called “neoadjuvant chemotherapy”. Patients are given a combination of chemotherapy drugs. In Ewing sarcoma, drugs are usually delivered as an injection or infusion directly into the blood. This is achieved by inserting a central line under the skin into a vein, often a peripheral central catheter line (PICC) to gain safe access to the large central veins near the heart. A PICC line avoids frequent needle sticks and thus prevents vein scarring and pain and reduces the risk of irritation and damage from strong chemotherapy agents to the smaller veins.  The PICC insertion is actually quite a simple procedure performed under local anaesthetic, usually by a nurse specialist. 

There are alternatives to PICC lines such as a small implantable PORT (portacath), which is a reservoir with a thin silicone tube that sits just under the skin and attaches to a vein; this can also be used to take blood samples and deliver medicines and fluids into the body. The aim of treatment at this stage is to shrink the tumour and kill any cancer cells that may have already spread.

The Euro Ewing 2012 trial conclusively found that an intensive combination of chemotherapy drugs used as the standard in North America for many years (VDC/ IE) increased event free survival by 9% over three years as well as overall survival by 8%; compared to the previous European combination of similar chemotherapy drugs (VIDE/ VAI). 

The protocol called VDC/IE, is now globally accepted as the standard of care for first line treatment of Ewing sarcoma. This protocol uses five different chemotherapy drugs used at different times throughout treatment. These drugs are vincristine (V), doxorubicin (D), cyclophosphamide (C) that alternates every fortnight with ifosfamide (I) and etoposide (E). One cycle is the frequency or administration of chemotherapy every two to three weeks. The purpose of using five different drugs and compressing the chemotherapy cycles to every two weeks is to maximise their effect. If the cancer stops responding to one of the drugs, the aim is that the other drugs will still be effective in killing cancer cells. 

There are usually nine cycles of neoadjuvant VDC/IE and 14 chemotherapy cycles in total. Neoadjuvant chemotherapy takes around four months in total to finish and is the longest phase of treatment for Ewing sarcoma. The first cycle comprises vincristine, doxorubicin, cyclophosphamide (VDC) given over 1-2 days and this cycle alternates every fortnight with ifosfamide, etoposide (IE) given over 5 days. 

Most of the time the patient is at home for their treatment and visits the cancer treatment centre during the day for their chemotherapy. Treatment response (i.e., how well the tumour is responding to chemotherapy) is assessed by regularly reviewing the patient’s symptoms and by performing scans at certain intervals. The patient will be seen frequently by their medical team to assess chemotherapy side effects throughout. The goal for the oncologist is to maximise the effects of chemotherapy but not to make the patient too sick, so  the patient can expect dosing alterations, delays to treatment when normal blood counts are too low or delays when the patient is suffering residual side effects from the previous chemotherapy cycle. The oncologist works with the patient to find a treatment plan that meets the needs of the patient.

Each patient responds differently to chemotherapy. Some patients may have a very mild reaction, other patients may react strongly. Typical general symptoms can include:

  • Nausea (feeling sick) and vomiting 
  • Gastrointestinal changes , diarrhoea or constipation
  • Tiredness/extreme fatigue (lack of energy)
  • Loss of appetite and taste changes
  • Hair loss
  • Dry mouth and ulcers
  • Skin and nail changes
  • Tingling and numbness in fingers and toes
  • Infection and, or bruising and bleeding which is  one of the most important side effects of chemotherapy. The immune system is weakened through chemotherapy and makes the patient vulnerable to infections during their treatment. Minor infections can become life-threatening in a matter of hours if left untreated.

Every patient is different and not everyone has all these side effects, most of which are temporary. Supportive medications routinely required during treatment include: anti-nausea medications, transfusions (red cells to correct anaemia, platelets to help with bleeding), GCSF or granulocyte colony-stimulating factor that stimulates the cell factory of the body (the bone marrow) to produce new white blood cells or infection fighting cells into the bloodstream.

There are more specific potential side effects associated with particular chemotherapy agents, such as weakness of the heart, irritation of the bladder, irritation to the brain, allergic reactions and reduced fertility that are less common and your oncologist will tell you more about. Certain organs systems such as the heart and kidneys will be closely monitored throughout and after treatment. Some patients are eligible for a cardioprotective agent called dexrazoxane, administered along with the chemotherapy agent doxorubicin that helps to protect the heart muscle.

Cancers and the treatments used can affect a person’s appearance, how their body feels and functions. Physical changes may include surgical scars, loss of a part of the body, loss of normal sensation, weight changes and hair loss. These physical changes can all affect a person’s body image, their confidence, energy levels and their mental and sexual health. There are charities, support groups and professionals who can support patients and help them adapt to these changes. The patient should ask their doctor or nurse specialist for advice.

There is some research to show that light exercise such as walking and swimming can help alleviate chemotherapy side effects and in some cases can boost chemotherapy effectiveness. Involvement with rehabilitation services can help the patient achieve life skills and offer psychological support with a positive impact on wellbeing.

Radiotherapy is designed to target the tumour (or where the tumour was residing before it was removed) and not affect the whole body in the way that chemotherapy does. Radiotherapy can be given for different reasons including if the tumour is large, if not all or none of the tumour can be safely removed by surgery and if more than 10% of tumour is still alive when examined under a microscope after surgery. 

Radiotherapy involves using high energy particles or waves, such as X-rays and gamma waves, to kill cancer cells that make up the tumour or to kill cancer cells left behind after the tumour has been removed. The high energy beams damage the DNA inside cancer cells to prevent the cells from dividing and this causes them to die. The treatment is usually given as a single dose each day (a few minutes) for 5-6 weeks after surgery has been performed.

Side effects can be similar to chemotherapy but may also include sore skin where the energy beams are focused. The effects of radiotherapy depend on what normal tissues or organs are close to the tumour and may be unavoidably included in the radiation field. Radiotherapy can be given during chemotherapy cycles, before and after surgery.

A new and revolutionary type of radiotherapy called proton beam therapy is now offered to some patients in the UK, but is used less frequently than photons (beams of X-rays) which is still considered the most appropriate and effective treatment for most cancers. This type of radiotherapy uses proton beams (energised particles) instead of x-ray beams (photons). 

Although the radiotherapy dose to the tumour is essentially the same, protons cause less damage to the tissues they pass through. This means that radiologists can administer a high dose of radiotherapy with less damage on nearby normal healthy tissue. This may reduce late effects of radiation as well as radiation induced second cancers, which is especially important for children, adolescents and young adults. This also means that patients with bone tumours near to critical tissues such as the spinal cord will benefit from radiotherapy treatment where this was not an option before. 

There are two proton beam therapy centres in the UK. These are at the Christie Hospital in Manchester and UCLH in London. Each UK patient put forward for proton beam therapy will have their case assessed by the national Proton Clinical Reference Panel. Certain criteria  must be met for eligibility for protons and the benefits of proton therapy for each case is carefully assessed before approval. If approved the NHS will cover the cost of proton beam therapy at approved treatment centres whether in the UK or abroad. 

Now that we have proton centres in the UK, this is less likely to be necessary, but patients can be sent to the USA, Germany and Switzerland. If sent abroad for proton beam therapy, the NHS will also fund economy travel plus approved accommodation for the patient and one or two parents/carers. 

When the tumour is removed, it is examined under a microscope by a histopathologist to make sure that the tumour has been completely removed. Complete removal of the tumour is referred to as having ‘clear margins’. The histopathologist will also assess how much of the tumour has been killed by chemotherapy, called the ‘percent necrosis’. A pathologic response is considered >90%. The results of this examination may affect treatment after surgery.

The multidisciplinary team  at the Bone Tumour Centre makes the decision whether surgery is possible and, if feasible, this is usually planned for after neoadjuvant chemotherapy. Less commonly, some patients have surgery before chemotherapy and some patients have surgery at the end of all their chemotherapy. There are two aims of surgery:

  1. to remove the tumour from the body.
  2. to reconstruct the affected bone.

Surgeons have developed different surgical techniques in reconstructing the bone after removal of the Ewing sarcoma tumour in order to preserve the function of the limb. Limb sparing or limb salvage surgery is where the entire tumour is removed along with some bone and muscle, but the use of the arm or leg is saved because a special implant is put in to replace the missing bone or joint. The most commonly used reconstructive technique is replacement of the affected bone with a metal implant (“prosthesis”).

Other techniques for reconstruction include:

  1. bone transfer (usually the fibula bone from the lower leg or part of the pelvic bone)
  2. allografts (where donated bone from a bone bank is used to rebuild the limb)
  3. irradiation/re-implantation, which involves removing the bone containing the tumour and treating with a very high dose of radiotherapy; the bone can then be put back into the patient).

While every effort is made to preserve a limb and maximise function for a patient, this must be balanced against the benefits of completely removing all the tumour and preventing tumour recurrence. Despite advances in surgical techniques, around 15% of patients require an amputation (removal of the limb) to safely remove the tumour. A prosthetic (“artificial”) limb can be designed for the patient in these cases. 

Surgical reconstruction can be complicated in children and adolescents who are still growing. Special ‘growing endoprostheses’ can be used that can be lengthened by a magnetic coil as the patient grows and reduce the number of surgeries required in the future.

All types of surgery to remove tumours can be complicated and require careful individual planning for each patient, including patients undergoing a planned surgical resection (i.e., removal of all or part of tissue, structure or organ). All patients undergoing planned surgical resection of Ewing sarcoma are discussed before surgery at the National Ewing sarcoma Multidisciplinary Team. 

“Adjuvant chemotherapy” is chemotherapy that is given after surgery. The aim is to clear up any remaining cancer cells that have survived the previous treatments. There is usually a two week gap between surgery and adjuvant chemotherapy to give the patient time to recover after surgery. There are usually five cycles of adjuvant chemotherapy to complete, to make up a total of 14 cycles of chemotherapy. In total, adjuvant chemotherapy takes around ten weeks to complete. 

Radiotherapy may also be given along with chemotherapy during this time if required. At this stage, most patients have completed their Ewing sarcoma treatment. End of treatment scans are performed to ensure that there is no trace of cancer anywhere in the body. If the multidisciplinary team  determines that there is no cancer detected, the patient is said to be in “remission”. 

In some cases, it becomes apparent that treatment did not work. Ewing sarcoma may  return after treatment has finished (“recurrent”) and if this happens, it is usually within the first two years, or where the treatments did not kill the Ewing sarcoma cells (“refractory”). The best course of action in these scenarios is to speak to the oncologist to enquire about joining a clinical trial. In most cases, the oncologist will already have this information to offer the patient after learning that treatment was not successful. 

Clinical trials come in all shapes and sizes, but generally are medical experiments to test new medicines, chemotherapies or treatment protocols that are not yet routinely available. Currently in the UK there is one such international clinical trial for recurrent/refractory Ewing sarcoma called the “rEEcur” trial (https://www.ucl.ac.uk/cancer/research/centres-and-networks/euro-ewing-consortium/clinical-trials/reecur). The rEEcur trial is comparing different treatments and trying to identify the best treatment for Ewing sarcoma that has returned or never went away after treatment. There are currently two available treatments on the trial the patient could be randomly assigned to, although the protocol changes with time and provides an opportunity to add new treatments:

  • Carboplatin and etoposide (CE)
  • Ifosfamide (IFOS)

Chemotherapy is administered in cycles of treatment, usually 3 weeks apart. Those receiving ifosfamide have 4 cycles of treatment. Those in the group having carboplatin and etoposide will have 6 cycles. If the treatment proves successful the doctor may decide to give more cycles of treatment.

There are other lines of standard chemotherapy that have shown benefit, including combinations of topotecan and cyclophosphamide, irinotecan and temozolomide and gemcitabine and docetaxel. It can become difficult for the body to cope with multiple lines of chemotherapy if there have been several recurrences and different treatments. Oral agents such as etoposide or cyclophosphamide can be an alternative option. 

There may be trials in the early phase of development (phase 1 and 2 trials), that recruit patients from a range of different cancer types, including Ewing sarcoma. There are units in the UK that are specifically set up to offer new anti-cancer drugs in clinical trials for children, teenagers and young adults and adults and in some circumstances can offer access to investigational drugs for sarcoma.

When cancer returns in younger people living in the UK, it is often recommended that another biopsy of the recurrent cancer is taken and the tumour sample can be genetically sequenced through the Stratified Medicines Paediatric Programme (SMPaeds). This can potentially identify a gene fault or target in the tumour that could be treated with a new investigational drug. This is not always the case and treatments are limited, but it can open up new options for treatment. An oncologist may be able to refer patients to such units for a consultation, so it is important that patients speak to their oncologists about trials.

Doctors will try to predict how a cancer will affect the patient, how likely it is that the treatment will work and whether the patient is curable. This is called ‘prognosis.’ Several factors are taken into account when considering the prognosis for Ewing sarcoma, including the patient’s age and general fitness, the size of the tumour, where the tumour is, whether the disease has spread and importantly, whether the patient responds to chemotherapy and whether the disease can be surgically removed.

Ewing sarcoma patients will require follow-up for many years after finishing treatment. Outpatient hospital visits will be needed every 2-3 months for the first two years following treatment, then consultations become less frequent up to 5 years following the end of treatment. From 5 years the patient is seen on an annual basis. Investigations, including bloods, urinalysis, chest X-rays and echocardiograms (ultrasound picture of the heart) are often checked routinely. Referrals to other services are possible if additional input is required.

The aim of the visits is to monitor for recurrence, assess the patient’s general health and importantly, to monitor for any long term effects from the specific chemotherapy agents. Most patients experience side effects during treatments that go away or improve after treatment is completed. However, some effects become permanent or develop over months to years. These are known as the late effects of treatment and the patient is followed by their oncology team or long term effects team. Late effects of treatment vary and depend on the cancer, location of the cancer and what type of treatment the patient received. 

The Late Effects Clinic is a service which aims to support people suffering with long-term effects from radiotherapy and chemotherapy. The clinic offers practical advice and signposting or access for a range of physical and psychological effects. It also offers a wide range of support and guidance about  late effects, such as bowel and bladder problems, heart issues, infertility, osteoporosis, sexual dysfunction, pain management and psychological concerns. The emotional and social effects for a patient can be as severe as the physical effects and it is not uncommon for patients to require psychological support, either by the hospital or through their GP and other appropriate support within the community.