ARTFORCE (“Adaptive and innovative Radiation Treatment FOR improving Cancer patients treatment outcomE”), a consortium of top clinical centers and small and medium-sized enterprises (SME’s) in Europe aimed at improving outcomes and reducing the clinical and economic burden of treatment for non-small cell lung and advanced head and neck cancers, has released its head and neck cancer clinical trial Periodic Report Summary 2.
Concomitant chemoradiation is the current standard of care for head and neck cancer, and for advanced stage cancer, dose intense multimodality treatment is required, unfortunately with substantial side effects. The ARTFORCE consortium’s objective is to improve outcomes for patients suffering from stage III/IV head and neck cancer by developing predictive rather than prognostic pretreatments and adaptive radiation methodologies featuring state of the art quality control with dose escalation based on pretreatment FDG-PET images.
ARTFORCE hopes to improving the therapeutic ratio between tumor control and normal tissue damage by:
• Redistributing the dose of radiation
• Ensuring 3-D quality control in vivo
• Maximizing the benefit of combined modality treatment
• Disseminating the results to the community by means of exposure throughout the scientific community and development of generally applicable software and tools in combination with commercial partners.
The scientific objectives of the project are to combine beyond state-of-the-art radiation technologies with novel approaches in patient selection based upon specific treatment response predictors.
Redistribution of the radiation dose will be made possible through the use of FDG-PET scans, which can identify the most active areas of a tumor, i.e. the area that should receive the highest dose of radiation instead of conventional homogenous doses. This redistribution can be performed without increase of toxicity. ARTFORCE notes that recently reported radiation accidents in the U.S. demonstrate that quality assurance (QA) is of utmost importance for safe radiation delivery in complex treatments. To assure accurate delivery over time, they will monitor both the patient’s geometry as well as the delivered dose using image-guided adaptive plan modifications and three dimensional (3D) in-vivo dosimetric verification.
This dose redistribution can be executed without increasing the spillover dose to surrounding tissues by assuring accurate radiation delivery. Novel 3-dimensional (3-D) optimized imaging-guided radiation (IGRT) techniques that demand an extra level of quality control are required along with 3-D monitoring and adaptation of the radiation dose to be delivered using repetitive anatomical cone beam CT scans on linear accelerators along with biological imaging by FDG-PET, plus 3-D in vivo portal imaging performed during the course of radiotherapy for quality assurance.
Adaptive Image Guided Radiation Techniques and Quality Assurance developed in this project will allow safe delivery of higher tumor doses in both head and neck and lung cancer patients and is projected to result in at least a 15 percent improvement in local tumor control in patients with head and neck tumors or lung cancer, in turn resulting in improved survival rates and fewer side effects. For non-small lung cancer, this means that by adaptive radiation dose redistribution within the tumor, the local progression free survival will improve after 1 year from 70 percent to 85 percent, which the researchers say should have a direct impact on improvement of survival.
For advanced head and neck cancer, ARTFORCE expects that dose redistribution and adaptive RT to the primary tumor will lead to improvement of locoregional control at two years from 60 to 75 percent. Redistribution of radiation dose will be directed to areas known to be therapy resistant and based upon new treatment planning algorithms developed in this project safe delivery of the higher radiation dose requires top level accuracy, therefore, new quality assurance methods for sophisticated high tech radiation procedures are implemented.
To develop and implement three dimensional (3-D) in-vivo dosimetry as an integrated quality assurance (QA) procedure for accurately verifying dose delivery applicable to all the major teletherapy systems in the EU, ARTFORCE have designed a method for calibrating the on-board cone-beam CT imager currently installed on linear accelerators. This step is necessary for accurate dose verification measurements. This verification can be performed using the software developed in this work package but users/clinics may also use the CBCT calibration procedure for a quick recalculation of the dose distribution inside the new anatomy derived from the CBCT in their own treatment planning system. The calibration procedure and validation of this method has been done, and this tool, combined with cone beam CT scans of the day, is able to not only detect errors in beam delivery, but also monitor the effect of patients’ shape changes and impact on the patient’s critical structures.
ARTFORCE says a combination of the drugs Cisplatin and Cetuximab has been shown to improve local control and survival, but both drugs have severe side effects, and cisplatin is only effective in a fraction of patients — ones who have tumors sensitive to cisplatin. Additionally, Cetuximab is expensive, and has been shown to be useful only in tumors in which high concentrations of the drug can be incorporated. Consequently, there is an urgent need for careful selection of the patients to receive treatment with this drug combination. For this purpose, cetuximab uptake will be estimated by imaging tumor uptake with 89Zr labelled cetuximab, while cisplatin-sensitive tumors can be selected by biomarkers that predict the cisplatin response, genetic profiles and HPV status, making it possible to minimize toxicity and reduce treatment cost while avoiding unnecessary treatment of non-sensitive patients.
These treatment innovations will be studied in randomized phase II clinical trials in top European institutes, followed by phase III trials outside this proposal.
The ARTFORCE Periodic Report Summary 2 notes that to date, 22 patients have been randomized and treated according this protocol in three centers. However, they report that unfortunately Merck announced that it was no longer willing to provide cetuximab free of charge after May 2014, which necessitated a significant adaptation of the protocol. An amended protocol V6.0 (with the same number of randomized patients) has been approved by the medical ethical committee in The Netherlands, and ARTFORCE expects approval to follow swiftly in the other participating centers and that patient accrual will increase.
The participating institutes of this project and the SME’s involved have extensive experience and have played leading roles in development of combined modality treatments for both head and neck cancer and lung cancer. They are experienced in adaptive IGRT and stereotactic radiotherapy as well as the novel quality assurance methods, and their knowledge of molecular predictive assays will benefit the project. The European Society for Therapeutic Radiology Oncology (ESTRO) will play a major role in the dissemination of the project results through its network and will be instrumental in organizing educational events on these topics, PhD student exchange programs and research fellowships with regard to the work within the ARTFORCE project, whose starting date was April 1, 2011 and projected date of closure will be in April 2016.
For more information, visit:
ARTFORCE Head and Neck Study Periodic Report Summary 2:
The European Society for Therapeutic Radiology Oncology (ESTRO)