BIGART 2019 – adapting to the future

Once again, an ACTA ONCOLOGICA Symposium was devoted to biological image-guided adaptive radiotherapy (BIGART) and its related activities, and once again, about 200 clinicians and scientists were gathered in Aarhus (Figure 1) to discuss how to progress in radiation oncology and how to use this modality optimally within the multidisciplinary treatment of cancer.

Figure 1. The BIGART 2019 participants.

This year’s symposium, the sixth in a row [1–6], took place back to back with the scientific opening symposium at Danish Centre for Particle Therapy (DCPT), and as a consequence it especially attracted participants with interest in particle therapy.

The BIGART meetings are a unique opportunity for the young and upcoming talented researchers in radiation oncology to meet and discuss with their more experienced senior peers. This is facilitated by a number of travel grants sponsored by Acta Oncologica, and the format of intense poster discussions where new ideas and concepts are scrutinized in lively discussions. The meeting format with all participants in the same room and ample time for discussions in a good social atmosphere facilitates networking and international collaboration across upcoming and experienced proton centers, and it builds a strong platform for European particle therapy.

There is no Acta Oncologica symposium without an issue with associated scientific papers. As a follow up to the previous symposium proceeding [6–54], the papers in this issue of Acta Oncologica reflect the current interest and status of radiation oncology in 2019. When looking back through the previous BIGART meetings, the progress over time is impressive. The BIGART meetings have become a cornerstone in Danish and Nordic oncology, and the activities presented illustrated very well, why Denmark over the last decades has become a global beacon in radiation oncology [55].

The BIGART 2019 topic illustrates the problems and dilemmas, which radiotherapy faces today. One constant goal is to optimize the delivery of treatment in order to be most effective and with a minimal risk of treatment related morbidity. This was highlighted through the many presentations of particle therapy [56–60], and the associated introduction of new delivery concepts such as GRID therapy and FLASH [61]. The latter has received substantial attention recently and will be further explored in the coming years. Whether it will be a substantial contribution to radiotherapy or just another halfhearted approach to overcome hypoxia remains to be seen. At present, the enthusiasm is still high and the topic is likely to be a new fad in experimental radiotherapy [62–65].

Sometimes we talk so much about an issue that we think we know all about it, but in reality, we have very limited knowledge about the importance. Such an issue is the relative biological effectiveness (RBE) of particle therapy, and especially the RBE values for protons in the clinically relevant settings. The previous BIGART 2017 meeting was one of the first occasions where world leaders in the field openly discussed and described their insufficient knowledge in this field [9–11]. It is not enough to declare that we agree that an RBE of 1.1 is not the global correct figure; we must then strive to get the information needed because otherwise, we will over- or underdose patients treated with protons, with the consequential risk for either treatment failure or increased morbidity. This is not only related to dose per fraction and different responses in different tissues, but also the problems related to differential LET along the course of the Bragg peak [12,13]. The issue is now being addressed, but we should be more alert because negligence of the known unknown must never be a cause of unsuccessful treatment. It is an international joint obligation to get the necessary information of particle RBEs in order to secure optimal clinical use of this exiting modality [66].

Several papers addressed normal tissue morbidity, and not least the relationship between objective clinical observations and patient reported outcome measures (PROMs) [67–71]. The patient’s involvement in evaluating the side effects of the treatment is a must, but at the same time the balance between PROM and clinical objective detected side effects should be kept, as we are otherwise unable to modify the treatment in a favorable way for the patients. This is also of major importance for the many attempts to create NTCP models to be used for guidance in treatment planning and risk calculations [72]. There will always be a need for strong clinical data, and the requirements for prospective recorded clinical observations cannot be emphasized enough. Far too many studies are based on retrospective analyses, but true clinical science is best achieved in prospectively designed clinical trials. Such studies were also presented during the meeting [73–75], but more are needed.

While the technical abilities for advanced treatment delivery currently dominates the field of radiation oncology, the importance of utilizing and understanding clinical radiobiology gradually returns to the focus area. This takes place partly through well designed studies where predictive parameters are being applied in order to select the right patients for the right treatment [76–82]. This happens through analyses of risk factors associated with treatment related morbidity, such as cardiovascular problems or risk of radiation induced secondary cancer, and also by focusing on variation in tumor radiosensitivity, such as the influence of human papillomavirus (HPV) positivity related to the irradiation treatment of squamous cell carcinomas [83,84]. The need to link such variation in radiosensitivity with a given radiation treatment, demands a very clear understanding of the irradiated volumes and site of treatment failure [85–88]. Again, such information will have to come from carefully designed prospective studies and the tradition of having large clinical databases in the Nordic countries, is an obvious advantage for this type of analysis. The importance of clinical radiobiology is also gaining renewed interest, not only by the endless discussion of the role of hypoxia and its imaging [37–40,89–91], but even more in the attempt to escalate or de-escalate the tumor dose. In this aspect optimal fractionation is of outmost importance, and (accelerated) hyperfractionation is gaining a renewed justified role to optimize dose escalation [73,84].

Automation and artificial intelligence were highlighted during the meeting. Automatic procedures, which often are based on modeling of past clinical data will be important tools in the future, and radiation oncology is still in the forefront of such development [91–93].

The progress in radiation oncology must always be seen on the background of the multidisciplinary interaction with other cancer treatment modalities and the overall oncological scenario [75,94–96]. Cancer treatment has in recent years been strongly dominated by the modern introduction of immunotherapy and many patients – who also need radiotherapy – are now treated with this modality, although the overall impact still needs to be evaluated in the full cancer patient population. Immuno-radiotherapy is therefore an upcoming activity, and our knowledge of the interaction between radiation and the manipulation of the immune apparatus is of utmost importance. It is somehow strange to see that, while radiation in the 1970s was considered to be a poison for the immune response and consequently, by some, was eagerly abandoned [97,98], it is now marketed as a stimulator of the same response, and immuno-radiotherapy is in some instances considered strongly favorable. Time will tell what is right and wrong in that aspect, but it is interesting to see how attitudes have be altered, although neither the nature of cancers nor the human biology have changed significantly during the last decades. The dominating role of other cancer modalities have, however, placed radiotherapy in a more defensive position and the indication for radiotherapy in the primary curative setting is on a relative decline. To a large extent, this is due to the changed age demographics, where the number of elderly cancer patients is increasing fast, but at the same time they are offered less aggressive treatment, especially when it comes to the adjuvant setting. As an example, many breast cancer patients with low risk tumors are now only treated with primary surgery and the adjuvant use of radiotherapy is abolished due to the risk of side effects, among which cardiac problems in the elderly may become prominent. On the other hand, radiotherapy has found a new role as a prime tool for managing oligometastatic disease [78]. The future will probably see this approach being applied more and more, and it has even been a scientific interface between sophisticated advanced radiotherapy with, e.g., MR-linacs and treatment of metastatic disease [99].

Radiation oncology has much to offer in oncology. Therefore, it should come as no surprise if future radiotherapy on the one hand will become a high tech treatment of specific tumors who possess a local regional problem associated with a high risk of morbidity, and on the other hand, be an activity left for treatment recurrence or metastatic failures. Radiation oncology is not alone in making such decision as it very much depends on the development in other treatment modalities, but we should continue to keep our place in the multidisciplinary approach to cancer, as only by utilizing the full therapeutic armamentarium, can we serve the increasing number of cancer patients in the future.

The development of radiotherapy is indeed in transition and we are eagerly looking forward to seeing the status at the next BIGART Acta Oncologica Symposium in 2021.

Disclosure statement

No potential conflict of interest was reported by the authors.