ESTRO 2024 Congress report
Symposium “Is irradiated volume more important than the dose?”
One of the hot topics in Radiation Oncology nowadays is the impact of irradiated volume, RT doses and its effects on the immune system. This topic was discussed at ESTRO 2024 during the Symposium “Is irradiated volume more important than the dose?” held on Saturday, May 4th.
Prof. Ursula Nestle, from Monchengladbach (Germany), started with a presentation regarding lung cancer and the lessons we can take from here; she started with SBRT for Early-Stage Lung Cancer and how dose escalation has been successful in improving LC (local control) and OS (Overall survival). Unfortunately, this was not the same for LA-NSCLC (Locally Advanced Lung Cancer,) with the disappointing data from RTOG 0617.
Not only do higher doses and bigger RT volumes lead to negative results for both OS and LC for LA-NSCLC but also increase the risk of important cardiotoxicity and even death-related events: this was also observed in the Lung Art study of post-operative mediastinal RT for completely resected pN2 NSCLC.
Therefore, new concepts regarding the target volumes were needed, especially in the Immunotherapy (IO) era; the rationale for CTVs (clinical target volumes) came from traditional concepts of microscopic spread, with the guiding principles of oncologic safety and keeping the risk of outfield recurrence <10%. A very helpful tool in reducing the margins of CTV without compromising too much the oncologic outcome came from modern cancer imaging; for lung cancer, this was explored in the PET-Plan trial, which demonstrated favourable LC with smaller CTVs PET-guided, with safe data regarding outfield recurrences but not impact on OS. RTQAs of the study also demonstrated that OS correlated with exposure of normal tissue to radiation.
In the IO era, after the Pacific study, a new concept of CTVs was needed, for fractionated curative radiotherapy and not only in dose escalation SBRT, with the chance to further evaluate the interaction between IO and target volume modifications.
Prof Udo Gaipl, from UKER (Germany), subsequently showed why immunology matters, with the provocative thought that we should not irradiate the blood pool and uninvolved lymph nodes.
It is well known that RT may stimulate the immune system (with the rationale of combining RT and IO), but it can also have a suppressive effect (such as induction of TGF-beta and increased expression of immune suppressive immune checkpoint molecules); still, it is not known the exact RT dose who may have immunostimulatory or the immunosuppressive effect.
The different radiosensitivity of immunological cells might also play a role: data from pre-clinical studies showed that T cells are more radiosensitive, while myeloid cells seemed to be more radioresistant. Pre-clinical data show that how we delivered the dose might matter: FLASH-RT, with its short-term irradiation of the blood pool, might spare or reduce immune cells to radiation and SFRT (spatial fractionated radiotherapy), with peaks of dose inside the tumour that could increase the release of antigens and trigger immunogenic cell death and tails in which it could be spared immune cells.
It is important to take into account the negative impact of irradiating the lymph nodes since they are the site of development of adaptive immune response against the tumour.
Also, the tumour microenvironment (TME) might differ according to the different tumour locations in the body, with possibly different antigens; for metastatic tumours, RT might also have a more immunological effect when multiple sites are irradiated.
Both RT doses and volumes (especially lymph node volumes) are important but multiple factors played a role, such as tumour TME and blood pool.
Different strategies, like late LN dissection or irradiation, might have to be considered and elucidated, with the arising concept of the adaption of RT to immune therapies.
Highlights of Proffered Papers: latest clinical trials
Sparing blood and immune-rich organs improve the immune system during lung SBRT (NCT04273893)
Krishni Wijesoorija, from the University of Virginia (US), presented findings of optimising SBRT treatment for lung cancer by considering circulating blood-rich and immune-rich organs as organs at risk (OARs), with the aim of reducing the incidence of radiation-induced immunosuppression (RIIS) via a predictive algorithm.
A phase II clinical trial was conducted: 50 pts with early-stage lung cancer suitable for SBRT alone were treated from 2020-2023; pts with baseline absolute lymphocyte count (ALC) <0.5x109 cell/L were excluded. All plans used 6X-FFF Arcs to reduce immune suppression.
Patients were randomised in two arms: standard SBRT planning vs optimisation for RIIS.
Peripheral blood samples were collected at baseline, end of SBRT, at 4 weeks and 6 months after SBRT.
Data from average percentage reduction on integral doses and V5 from the clinically delivered plan were collected (optimised vs standard arm):
- Aorta: 10%, 16.6 %
- Heart: 1.4 %, 27.2 %
- VC (vena cava): 24 %, 43.7 %
- T spine: 48.9 %; 77.5%
- Lymph node stations: 26.1 %, 45.7 %
- Total lung-ITV: 0.6 %, 0.7 %
For both arms, ALC reduction was evaluated: at the end of treatment (26% from baseline in the standard arm vs 11% from baseline in the optimised arm,); at nadir (30% from baseline in the standard arm vs 18% from baseline in the optimised arm); at 6 months (25% from baseline in the standard arm vs 11% from baseline in the optimised arm).
Post-SBRT immune increase and post-SBRT G3 lymphopenia were also evaluated (respectively, 6% in the standard arm vs 32 in the optimised arm, and 16% in the standard arm vs 0 in the optimised arm). ALC was observed to recover fast in the experimental arm.
RIIS was reduced in the experimental arm (relative percentage) at 4 weeks: ALC (38%), WBC (44%), RBC (51%), platelets (44%), monocytes (94%) and neutrophils (50%).
No major differences in treatment-related toxicities were observed between the two arms.
The study demonstrated that is possible to significantly reduce RIIS, with optimisation of RT planning using a predictive algorithm and reducing the dose to blood and immune-rich organs.
Events Free Survival (EFS) and OS results are awaited.
Valeria Dionisi
Radiation Oncologist
Radiation Oncology Department
University and Hospital Trust, Verona, Italy
valeria.dionisi@gmail.com
Member of the ESTRO Lung Focus Group