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INTRODUCTION
Approximately 50% of patients with cancer will undergo radiotherapy at some stage of their disease. Current opinion indicates that this figure is more realistically over 60%. Therefore many cancer trials include radiotherapy in the regimen. Data management is often carried out either by personnel without sufficient experience of radiotherapy or personnel with limited knowledge or understanding of the correct procedure of trials. Radiotherapy trials may compare a new technique or a different dose. Often the margin of difference expected is small and therefore accuracy is paramount. The Radiotherapy Technologist (RT) plays a critical role in minimising random and systematic errors, which have a significant impact on the quality of the treatment delivered, and therefore the quality of the data collected and the reliability of the outcome. It is vital that a high level of accuracy, care and attention is applied across a multi centre trial setting to ensure homogeneity of the treatments evaluated in a multi centre setting. These guidelines are aimed at raising awareness of the role of this professional group in achieving these goals. The trial protocol is a written agreement between the subject, the scientific community and the investigator. It explains the background, rationale and objectives of the trial and describes the design, organisation and conditions under which the trial is to be performed. It has been shown that guidelines established by speciality groups will impact positively on the quality of clinical trials. Standard protocols for conducting clinical trials already exist for Medical and Nursing personnel.
The RT is directly responsible for the delivery of the prescribed and planned treatment and therefore the irradiation of the patient. Their role in the reduction of random and systematic errors, as part of a team approach to management is crucial. Errors of either of these types can lead to poor quality treatment, which does not meet the prescription objectives and may adversely affect the prognosis of the patient both in terms of mortality and morbidity. These guidelines, for RTs involved in radiotherapy clinical trials, have been produced to ensure that trial protocols are strictly adhered to and that, therefore, standardisation is achieved. Strict compliance to protocol guidelines is essential.
The guidelines define and clarify, in a logical order, the different steps that must be taken by an RT when co-ordinating or managing patients registered on a randomised trial.
These guidelines have been written in a similar sequence to the master protocol for Phase III studies, to allow deeper understanding of each part of the trial protocol and the role of the RT. Where RTs are also involved in Phase I and Phase II trials, strict criteria must also be adhered to.
Trials carried out with strict compliance to the specified protocols will result in more accurate and reliable data collection. The ultimate beneficiaries will be patients registered on clinical trials across Europe.
Research has shown that patients who participate in a clinical trial, irrespective of the trial arm, have a favourable outcome when compared to similar patients who do not participate in clinical trials. There are several reasons that explain this difference:
1 Patient's who participate meet the eligibility criteria defined by the trial protocol and may therefore have a more favourable prognosis;
2 Patient's who participate in clinical trials are treated in reference institutions, often offering higher standards of care;
3 Patient's and health professionals who participate in clinical trials are in general more highly motivated which might increase the level of attention given.
We are aware that this work is not exhaustive, but hope that the contents will be of help to RTs participating in or co-ordinating clinical trials.
BACKGROUND
Radiotherapy Technologists may be involved in any of the following trials:
1. European multi centre or single centre trials co-ordinated by large trial centres
2. Drug company trials
3. Local departmental trials investigating radiotherapy techniques or equipment
4. Research work undertaken by hospital staff
6. Early Clinical Trials
Phase I, II and III Trials
Phase I trials are the first studies in humans. They are usually not specific to a single tumour site and have an end point based in assessment of toxicity and defining the maximum tolerated dose (MTD) or the recommended safe dose. They are usually small studies conducted in a few selected centres. For ethical reasons they are offered to patients with very advanced disease for whom there is no other treatment option. Primarily they involve cytotoxic agents.
Phase II trials are aimed at assessing the outcome of phase I trials in all tumour types in specific tumour types. The end points are evaluation of the activity of the treatment agent / modality in terms of feasibility, safety and activity. In the first instance preliminary evidence of activity and side effects at a fixed dose are evaluated. Small numbers of patients who have advanced disease are included.
Phase III trials are carried out based on the outcome of phase II trials. They are always randomised controlled trials in a specific disease situation and the end point is efficacy of the treatment. They are usually comparative to assess relative efficacy and also toxicity.
Radiotherapy clinical trials are designed to investigate the following areas:
1. Fractionation regimen and scheduling of treatments
2. Total doses required for cure and palliation
3. Tolerance doses and biological effects
4. Prophylactic irradiation
5. Uniformity of prescription doses
6. Comparison of treatment methods
7. The introduction of new technology - impact and implications
Current Radiotherapy clinical trials include
1. Unconventional fractionation schemes
2. Neo-adjuvant treatment
3. Combined modality treatment
4. Elective
5. Post-operative
6. Radiation sensitisers
7. Radio protectors
8. Management of acute side effects
9. Prevention, reduction of late side effects
10. Curative therapy
The success rate of any clinical trial depends on
1. The compliance of the department to the protocol guidelines
2. The Quality systems within each department
3. Good communication
4. Knowledge of the trial
5. Close liaison by the research radiotherapy technologist with
a) Patients and their families
b) Drug companies
c) Trial centres
d) Oncology staff and personnel from other departments and hospitals
6. Good patient compliance
7. The quality of the protocol
8. The quality of the patient data
9. The motivation and skills of the personnel involved and the infrastructure that is available to support them. Multi disciplinary teamwork is essential for success,
The Role of the Research Radiotherapy Technologist
Work practice and level of professional responsibility taken by RTs varies significantly not only across the member states but also between departments within the individual countries. In preparing this document we consulted widely with representatives from a range of departments with different attitudes to professional practice and levels of responsibility. Within these guidelines we have tried to reflect best practice from each of these settings.
This role has already been established in several centres across Europe. Where it is not a formally acknowledged role we recommend that one member of staff is designated to take responsibility for trial patients on each treatment unit.
All RTs involved in research should be members of a professional organisation that will provide support, education and the opportunity to liaise with other researchers in the area.
An identified research radiotherapy technologist functions as a contact person for all trial queries. This increases communication and understanding and improves relationships between the various departments involved in the trial. It facilitates clearer understanding of the requirements of the trial protocol. It also promotes a more patient centred approach and encourages greater levels of co-operation between all involved personnel in terms of support, side effect management and advice pre, during and post treatment.
As part of the development of an efficient team, staff and student education is essential. The identified RT should arrange presentations to ensure that staff are aware of all aspects of a new trial including the prevention and management of any possible side effects. To facilitate this process it is important that a written summary of the study objectives, design and minimum requirements is drafted by the principal investigator and circulated to all personnel involved in the introduction, management, data collection andquality assurance of the trial.
Meetings will be arranged for each new trial to highlight all the practical aspects of the trial data management. All involved staff will be encouraged to attend with research staff from other affiliated hospitals or departments to exchange ideas and experiences.
Rules Governing Good Clinical Practice (GCP)
A clinical trial is a major undertaking for a department and it requires funding, personnel, facilities, time and effort. Prior to the introduction of any trial it must be ensured that adequate support and the necessary resources are available. Good clinical practice is essential to the successful outcome of a clinical trial.
This includes
1. Ensuring that there is adequate support for the trial so that recruitment will not be a problem
2. Resources such as office space, storage, computer access, telephone and answer phone facilities are available
3. Ensuring that doctors are not involved in competing trials as patients may be eligible for more than one trial and this results in confusion and a decrease in the number of patients registered
4. Maintaining confidentiality
5. Maintaining accurate and complete sets of records for a fifteen year period
6. Obtaining ethical approval from both the Multi Research Ethics Committee and the Local Research Ethics Committee
FEASIBILITY STUDY
Pre trial Evaluation and Protocol Development
An identified radiotherapy technologist should be involved in the planning and writing of protocols to ensure that the techniques described are reproducible and that the trial is logistically possible. The implications for the department and the staff must be considered and the initial feasibility assessment should include
1. The duration of the trial
2. An estimate of the number of patients who would be eligible for registration
3. An estimate of the amount of time required to co-ordinate the trial
4. Whether treatment requires hospitalisation (this is often the case in trials which include chemotherapy)
5. Whether timing of treatment is important (i.e. 2 hours after administration of chemotherapy or 1 hour after the administration of a radiosensitiser or radio protector)
6. Are there additional requirements in terms of planning or treatment technique
7. Will treatment be required at the weekends, bank holidays, service days etc. and will it be possible within the department to meet this requirement
8. Are back up facilities in terms of equipment and plans required or available in the event of a unit breakdown
9. Is rescheduling of machine service dates necessary
10. Are altered working hours necessary. This will also have an impact on personnel other than radiotherapy technologists
11. Are additional investigations and follow ups required and if so how much will these cost and who will provide the resources
12. Are any new skills required e.g. Spirometry, saliva sampling, vital signs monitoring, urine analysis, phlebotomy and if so how will these be resourced
13. What funding is available and will it be adequate
Full liaison between all staff members is necessary to pre-empt difficulties that may arise as a result of the trial
Implementation of the Trial
Once the feasibility study has been carried out the trial can be set up and costed.
1. The costing must be submitted to the relevant personnel i.e. investigator, drug company, clinicaldirectors for their signatures of approval.
2. Ethical committee submissions must be prepared and indemnity for all drug company trials obtained
Any queries raised are responded to ensure that approval to commence recruitment is obtained
Preparation of Trial Documentation
Based on the trial protocol a summary of each trial should be drawn up. This will contain
1. The minimum set of information that is required to check patient eligibility
2. Randomisation criteria
3. Procedure for treatment preparation
4. Details of the treatment technique
5. Patient information sheet
6. Informed Consent document
This summary and attached documentation should be available when the patient attends for their first visit to support recruitment / participation in the trial as everything necessary to inform and consent the patient will be immediately available
The trial and randomisation details should be included with the notes, request sheets and treatment sheets. It is often helpful if the trial protocol can be produced as a condensed guide, with the main aspects highlighted, which can be read quickly and easily. These should be kept with the radiotherapy treatment sheet, the chemotherapy card and in the ward notes and will ensure that all staff involved with the patients are familiar with the protocol.
Radiotherapy Requirements
The RT should produce a trial guide that highlights any trial requirements that are not routine for their department. This will be based on the trial protocol and the specific phase of the treatment prescription and should include information on
1. Patient position
2. Patient data acquisition
3. Volumes of interest
4. Organs at risk
5. Simulator procedure
6. Treatment technique
7. Normal tissue sparing
8. Dose computation
9. Equipment
10. Dose specification
11. Treatment verification
12. Brachytherapy
13. Quality Assurance
Treatment Prescription Defines
1. Dose specification
2. Equipment specification
3. Treatment technique
Treatment Planning
1. Normal tissue Dose compilation
2. Volumes of interest
3. Organs at risk
4. Patient data acquisition
5. Simulation procedure
Treatment Delivery
1. Patient position
Verification
Drug Therapy Requirements
Again based on the trial protocol the RT should produce guidelines on
1. Trial drug supply details
2. Description of the drugs packaging and storage requirements
3. Dose definition and recommended maximum doses
4. Method of administration
Special note should be taken of the relationship with radiation therapy
1. Sequential
2. Alternating
3. Bolus
4. Continuous infusion
5. Hours before / after a radiotherapy fraction
It is essential that the required prophylactic drugs are prescribed and added to the treatment regimen to limit any side effects. These will be altered as necessary for each individual patient as the treatment progresses.
A trial schedule is produced which outlines investigation and treatment dates.
A file containing all current protocols and condensed guides should be readily accessible within the radiotherapy department.
A current list of all patients participating in each trial must be maintained. It should contain the following information
1. Patient's name
2. Patient chart number (if available)
3. Date of birth
4. Trial number
5. Date of randomisation
6. Result of randomisation and the allocated treatment
Additional statistics should indicate the annual recruitment figures per trial and per consultant. There should also be a list of patients who have been invited but have refused participation and an indication of the reason for refusal should be given.
Trial identification stickers should be placed on the front of the patient's radiotherapy notes for ease of identification.
For local studies a set of case report forms should be designed for data collection. A data sheet and database should be set up for entering and analysing this data.
CONDUCTING THE TRIAL
Trial starter packs containing the trial protocol and all relevant investigations and forms required, as part of the trial should be available in all clinics.
Patient trial information sheets should be prepared and a supply of these made available in all clinics. The doctor at the initial consultation can give these to patients.
Informed Consent
Obtaining informed written consent from patients participating in trials is a mandatory inclusion criterion and very time consuming procedure and adequate time must be allocated for its completion.
Patient participation on a trial is voluntary and confidentiality is ensured. It must be stressed to them that refusal to participate will not prejudice their subsequent treatment or care.
Following the requirements of ICH-GCP, all patients must be fully informed on
1. The aims of the study
2. Possible adverse events
3. Procedures and any potential hazards to which he/she may be exposed
4. The mechanism of treatment allocation
5. The strict confidentiality of their personal data
6. That their medical records however may be reviewed for trial purposes by authorised individuals other than their treating physicians
Appointments regarding trial participation should be given to coincide with already scheduled visits and both the doctor and RT should be present. The patient will then have the opportunity to ask any additional questions before making a final decision.
Depending on the centre the RT may or may not be involved in the following areas / aspects of trial management. It is still however, important for the RT to understand all aspects of the clinical trial to ensure full understanding of the trial and patient management and to highlight the aspects which may be important for the patient / clinician or data manager.
Patient Assessment
The RT can make a valuable contribution to the research clinics by carrying out some of the initial investigations and the ongoing assessment both during treatment and at follow up. This saves on valuable consultant time and benefits the patient by providing standardised one-to-one care, consistent continual assessment, time and privacy, immediate medical referral if necessary and fast referral to support services.A patient care plan must be completed. This will contain information on
1. Medical history
2. Previous treatment - surgery, radiotherapy, chemotherapy, hormone therapy, immunotherapy etc.
3. Current medication
4. Symptoms
5. Test results
6. Advice or support given
This care plan can also be used by drug company monitors for source verification of any data recorded on the trial case record forms
Eligibility Criteria/Stratification factors
Pre-treatment assessments and investigations, including physical examination, imaging and laboratory studies, are carried out to determine eligibility. Each protocol has different eligibility criteria designed to exclude patients who may be at an increased risk from the treatment or associated side effects.
Stratifications factors are collected in order to have an equal balance in the treatment groups with regard to potential prognostic factors.
Registration/Randomisation
Following careful verification of eligibility and exclusion criteria and after informed written consent has been obtained the patient is registered/randomised. Patients entered onto EORTC trials are registered/randomised with the EORTC Data Centre through the Internet, available 24hrs/day 7 days/week, or by telephoning the given number from Monday to Friday, from 8.30 am to 05.00 pm and providing the following information on request
1. Institution number
2. Protocol number
3. Step (1 or 2)
4. Name of the responsible physician
5. Identification code of the patient
6. Chart number
7. Birth date
8. Group (for which EORTC group this patient will be randomised)
9. Eligibility criteria / Stratification factors
Trial Evaluation Criteria
The importance of standard evaluation criteria is recognised within all trials to allow comparison of results. These criteria are clearly defined in each trial protocol and include
1. Assessment of the patient's general condition using a performance status scoring system i.e. The WHO or Karnofsky performance status to assess eligibility for trial participation, to stratify patients within treatment groups and to determine treatment efficacy
2. Measuring the extent of the disease using, for example, the TNM classification system giving a precise clinical description and histological classification. The International Union Against Cancer (UICC) publishes a "classification of malignant tumours" widely use d as a staging system for most tumour types.
3. Assessment of the response to treatment based on a set of target lesions, selected before the first treatment is given. (Bi-dimensional disease is measure either clinically or radiologically) The RECIST (Response Evaluation Criteria in Solid Tumours) document provides clear and unambiguous guidelines for response evaluation.
a. Complete Response (CR) - the disappearance of all known disease
b. Partial Response (PR) - A 50% or greater decrease
c. Progressive Disease (PD) - Is a 25% or more increase in disease or the appearance of a new lesion
d. No change (NC) - no change
4. Laboratory, radiological data, treatment, toxicities, adverse events and responses to treatment should all be recorded and reported.
Toxicity Scoring
It is essential that all staff are aware of the anticipated side effects and the approximate time at which these effects will occur. These are highlighted within the trial protocol but it is important that trial guidelines and staff education are put in place to reinforce the information.
Side effects are graded using the recommended toxicity grading system as defined in the protocol. The grading systems must be available at every patient appointment.
Side effects will be reviewed daily by the RT on the treatment unit and at regular intervals by the doctor and, where the system is in place, the identified RT.
Early side effects, up to three months post radiotherapy, are graded using acute toxicity grades. Late side effects are graded using late toxicity grades. The use of Common Toxicity Criteria edited by NCI is recommended for recording toxicity in all clinical trials. Some trials also use the SOMA/LENT scale developed jointly by the RTOG and the EORTC Radiotherapy Group and allowed data acquisition by different methods. (Subjective-Objective-Management-Analytical)
The regular recording of side effects helps to identify trends in toxicity at an early stage. Intervention can therefore be initiated earlier in the treatment process.
The RT must ensure that any prophylactic drugs required as part of the trial protocol to limit known side effects, are added to the treatment regimen.
Dose modification may be required depending on the presence or severity of several treatment related toxicity. Treatment may be continued, increased, discontinued, delayed, reduced by 50% etc.. In some Radiotherapy Departments RTs can dispense a limited range of medications for identified side effects such as nausea, vomiting, diarrhoea, mucositis, dysphagia and erythema.
Reporting of Adverse Events
The efficacy and safety of any new drug has to be proven before it can be licensed for sale. In order to establish the drug's safety profile there has to be objective, consistent and reliable documentation of all adverse events experienced by patients.
An adverse event is any undesirable experience occurring during a clinical trial, whether or not it is considered as related to the experimental product which results in death of the patient, a life threatening event, a permanently disabling event, hospitalisation or prolongation of hospitalisation, congenital abnormality/birth defect and other medically important condition considered as serious and which must be reported to Health Authorities in accordance with the European Union directive(75/619/EEC, Art.29)
Documentation Completion
Accurate and uniform data collection is of critical importance to the success of a clinical trial.
Medical data are transferred onto the appropriate case report forms, which include
1. Randomisation checklist containing a list eligibility criteria and stratifications factors
2. On study form
3. Treatment form (Radiotherapy form, chemotherapy form etc.)
4. Toxicity forms
5. Treatment evaluation/measurement form
6. Off treatment form and or summary form
7. Follow up form
8. Master evaluation form
9. Other specified forms: laboratory form, pathology form, health economics
The EORTC Data Centre has developed a standard operating procedure in respect of the receipt of overdue and missing data. This is the "four warning status" first, final, alarm and lost to follow-up indicates into which category each patient file falls. If the outstanding forms in the alarm category are not received within three weeks your institution will be closed for further registration and randomisation.
Quality of Life
Quality of Life should be 'confidential'. The physician treating the patient should not read the completed Quality of Life questionnaire unless asked to specifically by the patient. In this way the patient is free to write down what he really feels with no influence or undue pressure.
The overall benefit of treatment versus the associated toxicity can only be obtained by careful documentation of quality of life. This is of importance in all instances but particularly so if treatment is given with a palliative intent.
The collection of quality of life data should be concurrent with clinical data collection. It is recommended that patients complete these questionnaires while they are waiting for a clinical assessment. This can aid in the assessment process as it identifies any problems that may have occurred and also reduces their time spent at the hospital.
Diary cards can be used to record the severity of patient's symptoms on a daily basis. Measured pain intensity, pain descriptors or analgesic scores can assess pain.
To ensure compliance and quality control when collecting quality of life data an identified, trained person should be responsible for data collection. Schedules should be produced for each patient so that all staff are aware when forms are due for completion.
Privacy should be afforded to patients when completing these questionnaires
It is important to be aware of the following problems when organising quality of life data collection:
1. Help may be needed with questionnaire completion if the patient has
a) Just received bad news
b) Is very ill
c) Is unable to read or understand the question
In these circumstances research staff may read each question to the patient but must be careful not to bias their answer. This may be time consuming
2. If the questionnaire is too long, repetitive or required too frequently patients may refuse to complete them.
3. Relatives opinions may differ from the patients
4. Some patients have difficulty completing questions which are personal or sensitive
5. Peoples ability and activities alter with age, and therefore some questions may be inappropriate for elderly patients
6. Questions may have different meanings across languages and cultures
7. Patient symptoms may be due to concurrent illness and not their cancer
It is essential to check for missing data. If questions are not completed then the reason must be stated. If they are left blank then it is assumed that they have been missed and they cannot therefore be scored.
If the identified staff member is away for any reason then forms should be left with another member of the clinical staff who will be responsible for ensuring they are completed.
Assessment of the Quality of Life can and should
1. Clarify the views of patients and clinicians when making treatment related decisions
2. Quantify the extent to which levels of psycho social morbidity vary according to treatment regimens, and thus provide a focus for investigating ways in which such morbidity could be reduced
3. Together with cost information help to determine the relative cost-effectiveness of different treatment options
Quality Assurance
It must be stressed that the quality assurance measures are trial dependent and may differ significantly from trial to trial. Given below are some basic guidelines and possibilities. In order to obtain optimal treatment results, quality assurance programmes have to be set up and checks on data, histopathology, equipment, and treatment are required for good quality radiotherapy.
Based on dosimetry comparison of treatment plans, quality assurance programmes aim to detect the incidence and range of deviations. If deviations are found, then corrective actions have to be taken for subsequent patients.
The RT should based on his knowledge of the trial, and his communication ability
1. Organise and assist during site visits when the quality assurance team visit each centre to evaluate the medical and radiotherapy environment and to check the performance of the simulator, megavoltage equipment and planning systems
2. Organise dummy run procedures where a dummy case is planned, following both local policy and the protocol recommendations. This plan is the analysed and a report sent to each local investigator
3. Ensure that in vivo dosimetry is performed. TLDs are sent to each centre with a request to use them for one or several patients during one fraction in accordance with the protocol and to compare the results with the stated value. Any possible deviations are discussed with the local physics department.
4. Assist in individual case reviews by the EORTC. This identifies the quality of performance of member institutions with respect to the accrual of ineligible patients, timeliness and quality of documentation submission and compliance to protocol treatment. Any possible deviations are immediately discussed with the Institutions representatives.
5. Drug Company trials require a trial monitor, case record officer (CRO) to visit each centre every 4-6 weeks to check through each patient's trial case record folder and notes to ensure that each entry can be source verified. Additional visits may be made by independent auditors and the Federal Drug Association (FDA)
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