<Delete this line and print on hospital headed paper> International Randomised Controlled Trial for the Treatment of Newly Diagnosed Ewing's Sarcoma Family of Tumours PARENT INFORMATION SHEET R1 We would like to invite your child to take part in a clinical trial called which concerns the treatment of his/her disease. This trial is not being run by a drug company. Before you decide whether you want your child to take part, it is important that you understand why the research is being done and what it involves. Please take time to read the following information sheet carefully and discuss it with others if you wish. Ask us if there is anything that is not clear or if you would like more information. This document is provided to help you understand what treatment will be given to your child, and will provide answers to the following questions: Section 1 What is the standard treatment for Ewing s sarcoma? This section explains what the standard treatment for Ewing s sarcoma involves. Section 2 What are clinical trials and what is the trial? This section explains why the research is being done, and what it involves. Section 3 What else do I need to know about taking part in the trial? This section answers any additional questions you may have about taking part in this trial. Version 5.0 19-Feb-2016 Page 1 of 11
Section 1: What is the standard treatment for Ewing s sarcoma? The aim of treatment is to shrink the main tumour and to destroy any cells that may have spread. For all patients with Ewing s sarcoma, treatment involves giving a combination of anti-cancer drugs called chemotherapy, as well as surgery and/or radiotherapy. Before treatment starts Before your child starts treatment, his/her doctor will perform the following routine tests: Physical check-up including measuring height and weight Blood tests Biopsy Bone marrow aspirate and biopsy. This is a test to see if the disease has spread to the bone marrow. The doctor will explain how this will be done. Scans (CT, MRI, PET-CT, bone scan, x-ray). The doctor will decide which type of scans your child needs depending on where the tumour is located. Assessment of your child s heart (called an echocardiogram or echo for short) As part of the trial we will send a sample of your child s tumour biopsy for review by a national expert trial pathologist to confirm the diagnosis. In order to receive chemotherapy, your child will need a central line. This is a tube which is inserted through the side of the chest and into one of the major veins of the body. This procedure is usually done by the surgical doctors in the operating theatre but may be done by other health practitioners in radiology departments. Your child s doctor will discuss this with you. The central line enables the doctors to give all the drugs directly into the bloodstream (intravenously) and to take blood samples without using any extra needles. Treatment There are three phases of treatment for Ewing s sarcoma which are outlined below: START 1) Induction chemotherapy 2) Local control - surgery and/or radiotherapy 3) Consolidation chemotherapy END Phase 1: Induction chemotherapy The first phase of treatment is called induction chemotherapy. The induction chemotherapy given as standard treatment in the UK is: 6 cycles of VIDE chemotherapy VIDE VIDE VIDE VIDE VIDE VIDE VIDE cycles are given at three week intervals. VIDE chemotherapy consists of 4 drugs: Ifosfamide Doxorubicin Etoposide Version 5.0 19-Feb-2016 Page 2 of 11
Phase 2: Local control surgery and/or radiotherapy After the induction chemotherapy, your child will have surgery and/or radiotherapy, depending on where the tumour is and how it has responded to the induction chemotherapy. Some tumours are easier to operate on and remove than others. Tumours that can be removed will be examined under the microscope to see how much of the tumour has been killed by the induction chemotherapy. If the tumour is in an area of the body where it is impossible to operate, it will be treated with radiotherapy. Phase 3: Consolidation chemotherapy The final phase of treatment is called consolidation chemotherapy. The consolidation chemotherapy given as standard treatment in the UK depends on the size of the tumour, the response to the induction chemotherapy, and whether the tumour has spread to other areas of the body. If the tumour is small and/or has responded well to induction chemotherapy, patients receive: 1 cycle of VAI chemotherapy, followed by 7 cycles of VAC chemotherapy VAI chemotherapy consists of 3 drugs: Actinomycin D Ifosfamide VAI VAC VAC VAC VAC VAC VAC VAC VAI and VAC cycles are given at three week intervals. VAC chemotherapy consists of 3 drugs: Actinomycin D Cyclophosphamide If the tumour is larger and/or has responded less well to induction chemotherapy or has spread to other areas of the body, the patients receive: 8 cycles of VAI chemotherapy plus radiotherapy if the disease has spread. VAI VAI VAI VAI VAI VAI VAI VAI VAI cycles are given at three week intervals. VAI chemotherapy consists of 3 drugs: Actinomycin D Ifosfamide Version 5.0 19-Feb-2016 Page 3 of 11
How will the doctor know if things are going well? During treatment, your child will have routine tests to monitor progress. After each cycle of chemotherapy, your child will have blood tests and a physical examination. Scans (CT or MRI) and echocardiograms will be performed as required. What are the side effects of standard chemotherapy? Chemotherapy destroys the tumour cells, but can also damage normal healthy cells in the body. Side effects occur when healthy cells become damaged. Common side effects of chemotherapy drugs include: Hair loss, but it will grow back after the chemotherapy has finished Nausea (feeling sick) and vomiting Reduced bone marrow function The bone marrow makes red blood cells, white blood cells and platelets. o Red blood cells carry oxygen. If these are low, your child may be tired or pale and need a blood transfusion. o White blood cells fight infection. If these are low, your child will be at risk of developing an infection. If he/she develops a fever, admission to hospital will be necessary for intravenous antibiotics (through a drip). In very rare cases, infections can be fatal. o Platelets help stop bleeding and bruising. If these are low, a platelet transfusion can be given. The effect on the bone marrow is temporary. Before each cycle of chemotherapy, blood tests will be done to check that your child s bone marrow function has recovered enough to continue. Other side effects include a sore mouth, diarrhoea and abdominal pain. This is temporary but may reduce your child s appetite. Your child s doctor or a dietician will be able to advise you if necessary. Medication is available to help manage some of the side effects. Vincristine can cause damage to the nerves. Damage to the nerves in the gut can cause constipation. Vincristine can sometimes cause jaw pain, and aches and pains in the legs which may make walking difficult. Ifosfamide can affect the central nervous system leading to drowsiness, confusion, disorientation, restlessness and hallucinations. Ifosfamide can also cause kidney problems. Doxorubicin can damage the muscle of the heart when given in high doses. The dose that your child will receive is below the dose that we expect to cause problems in a significant number of young people, however the risk of heart damage is not zero. The doctor will monitor your child s heart by performing echocardiograms throughout treatment. Etoposide and Vincristine can damage the genetic material (DNA) in cancer cells and sometimes in normal cells. This can increase the risk of your child getting a second cancer in years to come but this risk is very small. Etoposide can also cause allergic-type reactions characterised by fever, flushing, increased heart rate and low blood pressure. Actinomycin D can cause liver problems and rashes or reddening of the skin. Version 5.0 19-Feb-2016 Page 4 of 11
Cyclophosphamide can irritate the lining of the bladder which can cause it to bleed. We therefore give lots of fluids with cyclophosphamide to prevent this. There are other side effects of chemotherapy and your child s doctor will be available to discuss these with you. Chemotherapy can also have long term effects such as a reduction in fertility, mainly in boys. If your child is male, has reached puberty and his general condition allows it, the doctor will discuss fertility (sperm) preservation with you before any chemotherapy is given. Another long term effect of chemotherapy is the increased risk of a second cancer after the completion of treatment. Radiation risk Your child may have up to five CT scans depending on the location of the tumour. The CT scans are standard practice and will be performed even if your child does not participate in this study. Radiation may cause cell damage which can, after many years or decades, become cancerous. Harm to the unborn child It is important that pregnancy does not occur during treatment because chemotherapy can damage an unborn baby. If your child has reached the age of puberty, we shall need to discuss matters concerning contraception or pregnancy with him/her. This may or may not be in your presence as your child can request that this discussion takes place confidentially. If your child is sexually active, he/she must agree to use an effective form of contraception during the time that he/she is receiving trial treatment. Girls must continue to use contraception for 12 months after the end of treatment, and boys for 6 months after the end of treatment. If your child is female and of child-bearing age, she will have a pregnancy test before treatment starts. If your daughter becomes pregnant whilst on the study, the pregnancy will need to be monitored. Information about the outcome of the pregnancy will be collected from the mother s and baby s medical notes. If your son s partner becomes pregnant during the study, the outcome of the pregnancy will also be monitored. Version 5.0 19-Feb-2016 Page 5 of 11
Section 2: What are clinical trials and what is the trial? What are clinical trials? Clinical trials are research studies which compare different types of treatment to help find more effective and safer ways of treating patients with a specific disease. Each trial is aimed at improving survival rates and/or reducing side effects. It is largely because of clinical trials that such progress has been made in the treatment of children s cancer over the last few decades. What is the trial? The aim of the trial is to compare different chemotherapy regimens to determine which is more effective and/or has fewer side effects. The best way of testing this is through a randomised trial. In a randomised trial, patients are randomly assigned to different treatments (known as treatment arms). The treatment assignment is done by computer. This method means that neither the patient/parents, nor the doctor will be able to influence which treatment arm is allocated and helps to ensure that the results are not biased in any way. Equal numbers of patients are treated in each arm and at the end of the trial the results are compared. The trial contains two randomisations. This information sheet provides details about randomisation 1. If you agree for your child to take part in randomisation 1, you will be asked to sign a consent form before treatment starts. At the end of your child s induction chemotherapy, his/her response to the treatment will be assessed and the subsequent treatment given will depend on the extent of the remaining disease. At this point, you may be given an information sheet about randomisation 2 and once you have had an opportunity to read it and discuss its contents with your doctor, you may be asked if you want your child to take part in the second part of the trial. If your child takes part in randomisation 2, the consolidation chemotherapy he/she receives may be different to any of the treatments described in this information sheet (it may include an additional drug or consist of a more intense treatment depending on the response to induction chemotherapy). Deciding to take part in randomisation 1 does not mean that you have to take part in randomisation 2. When patients are entered into the trial, they are randomly assigned to one of two different treatment arms: either Arm A the standard UK treatment described in section 1 above or Arm B an established chemotherapy regimen used in other countries. We do not know which treatment arm is best. A randomised study will allow us to compare the two treatments. Why has my child been invited to take part? Your child has been invited to participate in this trial because he/she has recently been diagnosed with Ewing s sarcoma. About 600 children and young adults in the UK and elsewhere will take part in this study. Does my child have to take part? No. You may decide whether or not you want your child to take part in this trial. If your child does take part, we will ask you to sign a consent form. You are free to withdraw your child from the study at any time, without giving a reason and your child will continue treatment at the same hospital with the same medical team. If your child is of an age to be able to give his/her opinion, your child may express a wish not to take part in the trial. If this is the case, his/her views must be taken into consideration. If you decide for your child not to participate, the doctor will discuss with you the treatment options available. Version 5.0 19-Feb-2016 Page 6 of 11
What will happen to my child if he/she takes part? If you agree for your child to participate, the doctor will review your child s diagnostic tests and medical notes to confirm that he/she is eligible to take part in the trial. Your child will then be entered into the trial and randomly assigned to either treatment arm A or treatment arm B: Arm A Standard treatment Induction chemotherapy: VIDE Consolidation chemotherapy: VAI/VAC (see section 1) OR Arm B Patients randomised to Arm B receive: Induction chemotherapy: VDC/IE Patients receive alternating cycles of VDC and IE. Nine cycles are given at two week intervals. VDC IE VDC IE VDC IE VDC IE VDC Consolidation chemotherapy: IE/VC Patients receive alternating cycles of IE and VC. Five cycles are given at two week intervals. IE VC IE VC IE VDC chemotherapy consists of 3 drugs: Doxorubicin Cyclophosphamide IE chemotherapy consists of 2 drugs: Ifosfamide Etoposide VC chemotherapy consists of 2 drugs: Cyclophosphamide Patients also receive radiotherapy if the disease has spread. Expenses and payments Neither you nor your child will receive any money or travel expenses reimbursement for taking part in this trial. Version 5.0 19-Feb-2016 Page 7 of 11
What will my child and I have to do? If you agree to your child to taking part in the trial, you and your child will be asked to: Attend all scheduled clinic appointments Tell the study doctor about any medications your child takes, even if it is medicine you buy without a prescription or is a natural or herbal remedy Tell the doctor about any side effect, injury, symptom or complaint your child experiences, including any unplanned hospital admissions If your child is sexually active, ensure that they use an adequate method of birth control while receiving treatment. Girls must continue to do so for 12 months after the end of treatment, and boys for 6 months after the end of treatment. Will any additional samples be taken from my child? With your consent, we would like to collect some additional tumour, bone marrow and blood samples at times when we are collecting samples for diagnosis and monitoring of treatment. These samples will be used in ethically approved research studies designed to further improve treatment for future patients with Ewing s sarcoma. Samples may be sent to and analysed at laboratories in Europe. You will be offered the chance to consent to this. What are the side effects of the non-standard chemotherapy (Arm B)? The side effects experienced by patients randomised to receive the chemotherapy regimen that is not standard in the UK (Arm B) are expected to be very similar to those experienced by patients receiving the standard UK chemotherapy (Arm A) see section 1. The side effects are common to both treatment arms because the same drugs are used (with the exception of actinomycin D which is used in Arm A only). The extent to which patients experience some of the side effects may differ between treatment arms because different doses are used. For example, Arm A involves a higher dose of ifosfamide, but Arm B involves a higher dose of doxorubicin. What are the alternative treatments? In the UK, the standard treatment is VIDE induction chemotherapy and VAI/VAC consolidation chemotherapy (Arm A treatment), as described in section 1 above. The VDC/IE induction chemotherapy and IE/VC consolidation chemotherapy (Arm B treatment) is not available as standard treatment in the UK. What are the possible disadvantages and risks of taking part? As this is a randomised trial, there is a risk that your child may not be assigned to the treatment group that you or your child would prefer. As mentioned above, this cannot be selected by choice. If your child is randomised to Arm B, he/she will receive treatment that is not usually given in the UK. We do not know for certain whether this will be more or less effective than standard UK chemotherapy. What are the possible benefits of taking part? We cannot promise that your child will benefit from taking part in this study. It is possible that the treatment that is not standard in the UK (Arm B) will be more effective and/or have fewer side effects, but we will not know this until the results of the trial are available. The information gained Version 5.0 19-Feb-2016 Page 8 of 11
from this study will help improve treatment for other children and young adults with Ewing s sarcoma in the future. How long will my child be involved in the trial? After treatment has finished, the study team will continue to collect data about your child s health for at least 5 years. Your child will only need to attend routine clinic appointments for this information to be collected. Section 3: What else do I need to know about taking part in the trial? What if relevant new information becomes available? Sometimes during the course of a trial we get new information about the treatment being studied. If this happens, the doctor will tell you and discuss whether your child should continue in the trial. If you decide you do not want your child to carry on, the doctor will make arrangements for his/her care to continue. If you decide for your child to continue in the trial, the doctor may ask you to sign an updated consent form. If new information becomes available, the doctor might consider it to be in your child s best interests to change your child s treatment. The doctor will explain the reasons and arrange for your child s care to continue. What will happen if I don t want my child to carry on with the study? You are free to withdraw your child from trial treatment at any time without giving a reason and this will not affect his/her standard of care. If this happens, you will be asked to allow the continued collection of follow-up data (your child will not need to attend more clinic appointments than normal for his/her condition), though you are also free to withdraw consent for further data collection if you wish. What if there is a problem? If you have a concern about any aspect of this trial, you should contact the local medical team who will do their best to answer your questions. You can use the contact number at the end of this sheet. If you remain unhappy and wish to complain formally, you can do this through the National Health Service (NHS) Complaints Procedure. Details can be obtained from your hospital. In the event that something does go wrong and your child is harmed during the trial, there are no special compensation arrangements. The Cancer Research UK Clinical Trials Unit (the Trial Office) does not hold insurance against claims for compensation for injury caused by participation in this trial and they cannot offer any indemnity. If your child is harmed and this is due to someone s negligence, then you may have grounds for legal action for compensation against the sponsor of the trial (University of Birmingham) or the NHS Trust but you may have to pay your legal costs. NHS Trust hospitals have a duty of care to patients treated, whether or not the patient is taking part in a clinical trial and the normal NHS complaints mechanisms will still be available to you (if appropriate). Version 5.0 19-Feb-2016 Page 9 of 11
Will my child s taking part in this trial be kept confidential? All information collected about your child for this trial will be subject to the Data Protection Act 1998 and will be kept strictly confidential. All information will be securely stored at the Cancer Research UK Clinical Trials Unit at the University of Birmingham (the Trial Office) on paper and electronically and will only be accessible by authorised personnel. With your permission, your child s GP will be notified that your child intends to participate in the trial. A copy of your child s consent form will be sent in the post to the Trial Office and to your child s GP. We may also share information with and show your child s consent form to other hospitals involved in the care of your child. In the Trial Office, your child will be identified by a unique trial number. In routine communication between the hospital and the Trial Office, your child will only be identified by their trial number, initials and date of birth. We will also need to record your child s full name, hospital number and NHS number which is required to keep track of his/her long-term progress. Data may be provided to the Trial Office on paper or electronically. By allowing your child to take part in the trial, you will be agreeing to allow research staff from the Trial Office to look at the trial records, including your child s medical records. It may be necessary to allow authorised personnel from government regulatory agencies (e.g. the Medicines and Healthcare products Regulatory Agency (MHRA)), sponsors and/or NHS bodies to have access to information about your child. This is to ensure that the trial is being conducted to the highest possible standards. In addition, anonymised data from the trial may be provided to other 3 rd parties (e.g. other academic institutions) for research or safety monitoring. In addition, the initials, date of birth and pathology number of patients who donate tumour tissue, blood samples and bone marrow samples for the trial will also be passed on to personnel at external research laboratories/institutions or tissue banks to help them identify the samples. Anonymised details about these donated samples will be stored on a European database. We would also like to obtain information about your child s progress through his/her GP and the national health registries (such as at the Cancer Registries or the NHS Information Centre for Health and Social Care Medical Research Information Service (MRIS)). In order to do this, we will need to provide his/her full name and NHS (CHI) number. All individuals who have access to your child s information have a duty of confidentiality to your child. Under no circumstances will your child be identified in any way in any report, presentation or publication arising from this trial. If you choose to withdraw your child from the trial treatment, we would still like to collect relevant information about his/her health, as this will be invaluable to our research. If you have any objection to this please let your child s doctor know. You can withdraw your consent to our processing of your child s data at any time. Under the provisions of the Data Protection Act 1998 you have the right to know what information the Trial Office have recorded about your child. If you wish to view this information please contact Legal Services at the address below. Please note that a small fee may be payable to retrieve this information. Legal Services University of Birmingham Edgbaston BIRMINGHAM B15 2TT Version 5.0 19-Feb-2016 Page 10 of 11
What will happen to any samples taken from my child? Routine samples will be disposed of once the required standard tests have been completed. Samples taken from your child for trial purposes will be stored at an approved laboratory. After the samples have been used for research associated with this trial, there may be spare material left over. With your consent, this may be stored and used for other ethically approved Ewing s sarcoma studies. Will any genetic tests be done? Genetic tests may be done on samples taken from your child in order to confirm diagnosis, and with your consent, for research purposes. No testing for inherited diseases or paternity will be carried out. What will happen to the results of the trial? When the trial is complete the results will be published in a medical journal but no individual patients will be identified. If you would like to obtain a copy of the published results, please ask the doctor or nurse. Who is organising and funding the trial? This trial is being run by the University of Birmingham and is funded by Cancer Research UK. http://www.cancerresearchuk.org/ Who has reviewed the trial? This clinical trial has been reviewed by the Clinical Trials Awards and Advisory Committee and also by an independent Research Ethics Committee. Research Ethics Committees review all research to protect the safety, rights, wellbeing and dignity of patients. Further information and contact details If you have any questions or concerns about your child s disease or this clinical trial, please discuss them with your child s doctor. You may also find it helpful to contact CancerHelp, an information service about cancer and cancer research studies by Cancer Research UK. Freephone: 0808 800 40 40, website: www.cancerhelp.org.uk. Important telephone contact numbers:...... Thank you for reading this information sheet. Version 5.0 19-Feb-2016 Page 11 of 11