Aims of the Study
The purpose of this clinical study is to investigate the clinical feasibility and effective benefit of off-line PET for quality assurance of scanned proton and carbon ion beam therapy for a large patient population.
The specific aims are to
1) Acquire PET/CT scan data on patients undergoing external beam ion therapy for a representative population of different tumour sites in order to be able to conclude which patients might in future benefit from PET/CT monitoring.
2) Analyze these data to determine the accuracy with which the beam range can be monitored and the actually delivered dose can be estimated.
3) Analyze these data (acquired during at least three fractions at the beginning, the middle and the end of the regular treatment course) to determine whether quantitative changes of the PET signal after delivery of the same treatment fraction dose can be indicators of physiological modifications connected to tumour response.
4) Assess the possibility of using PET/CT monitoring for quality assurance and adaptive strategies in scanned ion beam therapy.
Procedure to be evaluated
The PET/CT scanner to be used is a CE-labelled medical product (Siemens Biograph mCT 40). The procedure will include acquisition of a control CT for anatomical reference as well as list-mode detection of the β+-activity resulting from the standard therapeutic irradiation. The CT scan is performed for patient position verification as well as monitoring of anatomical changes during the course of radiotherapy and is considered standard of care. Therefore, no trial specific CT imaging will be acquired and patients will not be exposed to additional experimental doses of ionizing radiation. The PET signal to be measured is a by-product of the therapeutic ion beam irradiation, hence no additional radioactive tracer is administered to the patient. The treatment position will be reproduced at the PET/CT scanner using the same immobilization equipment used for the therapeutic irradiation, which is compatible with standard diagnostic CT and PET imaging.
The activity levels to be expected in the study are orders of magnitude lower than in the typical operation condition of the commercial PET device, which is designed for application to nuclear medicine tracer imaging. Therefore, the PET data acquisition will be performed in one single bed position and last over 30 minutes to collect sufficient counting statistics for imaging, following the same clinical protocol reported by other investigators in previous clinical trials in USA [6, 10]. After the first clinical data will be collected, the available iterative reconstruction schemes of the PET scanner will be applied and the resulting images will be compared in order to identify the optimal image reconstruction settings for optimal imaging performances at the expected low statistics levels. The so identified optimal image reconstruction settings will be applied to process all the clinical data acquired in this study.
The reconstructed PET images co-registered to the control CT (using the CE-labelled software provided by the manufacturer) will be finally analysed in comparison to the planned treatment to infer information on the correctness of the actually delivered therapeutic irradiation. An additional comparison with an expected β+-activity distribution will be pursued .
Therapeutic and Diagnostic Modes of Action
By taking part in the MIRANDA study patients are offered the possibility to determine the applied dose more precisely, since by using the PET/CT for monitoring the activation produced by the particle beam can be visualized. The potential benefit for the future of radiotherapy is to implement PET/CT in clinical routine for dose monitoring possibly providing a useful tool for necessary corrections in treatment planning or patient positioning (adaptive particle therapy).
Side effects and risks as well as potential additional exposures during study treatment
The β+-activity is induced by the therapeutic irradiation; therefore, no additional exposure of the patient is required for the PET measurements. To carry out the investigation with accurate anatomical co-registration, this study is performed using a PET/CT. The additional control CT enables the researchers to explore also anatomical modifications compared to the initial imaging data acquired for treatment planning. These control CTs are performed on a regular basis during the course of precision radiotherapy for verification of patient positioning and to monitor any anatomical changes to the tumor and to normal tissue. Therefore, these CT scans can be considered standard of care, and patients will not be exposed to any additional ionizing radiation.
This study will cause the prolongation of the selected treatment sessions, because of the time needed for the transport of the patient to the remote PET/CT scanner (about 5 min) and for the PET/CT acquisition (about 30 min). The latter is mainly determined by the required 30 minutes of PET acquisition, being the CT imaging typically completed in less than 1 min.
Open, mono-centric, non-randomized, prospective study to evaluate PET-CT monitoring after particle therapy for position verification, dose deposition monitoring and for the implementation of adaptive strategies for particle therapy
The patient is treated at the Heidelberger Ionenstrahl Therapiezentrum (HIT) with protons or carbon ions.
During the radiotherapeutic treatment patient positioning and anatomy is verified using validated radiological imaging such as cone beam CT, X-ray or conventional CT (Reference-Imaging as described above).
The patient is at least 18 years of age and is able to give informed consent.
The patient has been informed about the aims and the content of the study.
Within the study protocol, no additional radiological imaging techniques will be performed. Therefore, the patient will not be exposed to any additional irradiation.
No informed consent to take part in the study.
Medical reasons that impair the patients from being in the supine position for the data acquisition time, e.g. pain.
Non-compliance of the patient.
A patient fulfilling the inclusion criteria will be informed about the background of this study and will be offered participation. Thereafter, an information brochure about the study will be handed out to the patient, and the patients will be instructed about the study plan and procedures. Thereafter, the patient can give informed consent. This informed consent will be documented in a written form (signature on informed consent form).
After the patient has given informed consent, patients are included into the study. The study will include procedures as follows:
a. Right after a regular treatment fraction the patient will be transferred to the PET/CT scanner located on the same floor within few meters distance from the treatment sites in the HIT building.
b. A PET/CT scan will be taken. For this examination the patient will remain fixated in the immobilization device used during treatment delivery. The average acquisition time will be in the order of 30 minutes.
The procedure will be repeated for a total of at least three treatment fractions, one being selected in the first week of treatment, one in the middle of the treatment period and one during the last week of therapy.
The study will cause prolongation of the selected treatment sessions due to the transport to the remote PET/CT scanner (about 5 min) and the PET/CT acquisition (about 30 min). All subsequent data analysis will be performed without interaction with the patient.
The data will be pseudonymized and analysed.
No concomitant treatment is part of the study protocol.
Criteria for withdrawal
General withdrawal criteria for the study
There are no general withdrawal criteria for the study protocol
Feasibility and value of post-radiation PET imaging for verification of therapeutic ion beam delivery should be validated for different organ regions. Therefore, different analysis groups will be evaluated including tumors of the brain, skull base, head and neck region, upper gastrointestinal tract (upper GI), lower gastrointestinal tract (lower GI), prostate and pelvic region. For optimal calculations and verification, 30 patients per anatomic region will be analyzed. This amounts to a total patient number of 240 patients.
After acquisition of the data, correlation of the measured activity with the acquired CT imaging for patient position and anatomy will be performed. Additionally, correlation with the calculated dose plan within the Siemens Treatment Planning System (TPS) will be performed. Potential correction vectors consisting of positional changes will be determined based on the newly acquired activity images and the imaging that had been done for treatment planning.
Correlation of the measured activity level with the applied dose and pattern of RBE-values (relative biological effectiveness) determined during the biological treatment planning for particle therapy will be performed.
As activity and dose are known to be different physical quantities, an additional calculation of the expected β+-activity distribution will be pursued, provided that the computational tool used for this purpose is verified to deliver a corresponding calculation of dose distribution in agreement with the certified clinical TPS.
To assess whether the calculated dose and activity distribution are different from the measured activity corresponding to the applied dose distribution, a t-test as a one-sample location test can be used („is the difference different from zero").
Ethical and legal aspects
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and documentation of this trial, are designed to ensure that all persons involved in the trial follow the guidelines of Good Clinical Practice (GCP) and the ethical principles described in the applicable version of the Declaration of Helsinki (2008 Version of the Declaration of Helsinki, adopted at the 59th WMA General Assembly, Seoul, October 2008), as well as in accordance with the „Berufsordnung für Ärztinnen und Ärzte der Landesärztekammer Baden-Württemberg"in the most recent version.
The trial will be carried out in adhering to local legal and regulatory requirements.
The study plan was submitted to the Institutional Review Board (IRB)/independent Ethics Committee (EC) of the Medical Faculty Heidelberg, and official approval was obtained.
Participation of a patient in this study is voluntary. A subject may voluntarily discontinue participation in this study at any time at their own request. Before study entry, patients will be informed by the written information brochure as well as in orally about the planned procedures within this study, especially about potential benefit for their health or potential risks. Informed consent will be documented by the patient's signature on the informed consent form.
All patients will be informed prior to initiation of study treatment concerning the aims of the study, especially with respect to any risks or side effects of the treatment, as well as the potential use of study participation for the overall treatment course. Informed consent will be documented as written informed consent by signature on the informed consent sheet. If the subject withdraws from the trial and also withdraws consent for disclosure of future information, no further evaluations should be performed, and no additional data should be collected. In all cases, the reason for withdrawal must be recorded. In case of withdrawal of a subject at his/her own request, the reason should be asked for as extensively as possible and documented. All data acquired within this study will be deleted, except if the patients allows for further evaluation of the data and inclusion into the final analysis.
The data obtained in the course of the trial will be treated pursuant to the Federal Data Protection Law (Bundesdatenschutz- bzw. Landesdatenschutzgesetz, BDSG, LDSG).
Trial findings stored on a computer will be stored in accordance with local data protection law and will be handled in strictest confidence. For protection of these data, organizational procedures are implemented to prevent distribution of data to unauthorized persons. The appropriate regulations of local data legislation will be fulfilled in its entirety.
No third party will have access to the patient data.