Radiation-induced toxicity and secondary malignant neoplasms in radiotherapy of intrathoracic tumors

Radiation oncology is essential in the treatment of cancer, with approximately fifty percent of oncology patients undergoing radiotherapy (RT) at some stage of their disease management. Significant progress is being made in the diagnosis, surgical, medical, and radiotherapeutic treatment of cancer. Consequently, an increasing number of cancer patients will live long after undergoing RT. Radiotherapy invariably involves exposure of healthy tissue to ionizing radiation, leading to potential acute and chronic adverse effects and, in some instances, the induction of secondary malignancies. The overall aim of this thesis was to investigate the feasibility of using alternative RT techniques to reduce the calculated risks of radiation-induced toxicity and secondary cancer in the RT of intrathoracic tumors compared to standard RT. Additionally, the thesis aimed to assess the feasibility of cardiac magnetic resonance imaging (CMR) for detecting early radiation-induced cardiac changes in comparison to myocardial perfusion scintigraphy (MPS).

Study I: In this comparative dosimetric analysis, we evaluated the feasibility of proton beam therapy (PBT) against intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in reducing radiation doses to relevant organs at risk (OARs) in the treatment of thymic tumors. Twelve patients who had previously received 3D-CRT were selected. Retrospective IMRT plans and PBT plans were generated for each patient. The dosimetric comparison demonstrated that PBT significantly reduced the mean doses to numerous OARs, such as the heart, lungs, breasts and esophagus. Utilizing the Lyman-Kutcher-Burman (LKB) model for the calculation of normal tissue complication probability (NTCP), we found that PBT plans could reduce the risks of pneumonitis, esophagitis, and myelopathy when compared to 3DCRT and IMRT.

Study II: The goal of the second study was to determine whether myocardial perfusion scintigraphy (MPS) changes in lung cancer patients treated with RT were detectable with late gadolinium enhancement cardiac magnetic resonance imaging (LGE CMR). Twenty-one patients were evaluated before RT and at two and six-month follow-ups. Semi-quantitative methods and the Bull’s-eye-view technique were employed to analyze MPS changes, while LGE CMR studies were examined for visual signs of myocardial damage and cardiac function. The findings indicated that at the six-month follow-up, MPS changes were less pronounced than previously reported, with no visual or functional signs of myocardial damage observed on LGE CMR. The study highlighted the risk of false-positive MPS changes due to attenuation artifacts.

Study III: This study sought to compare the calculated risks of radiation-induced secondary malignant neoplasms (SMNs) among patients treated for thymic tumors with 3D-CRT, IMRT, and PBT. A mechanistic model based on the organ equivalent dose (OED) concept was used to estimate the risks of carcinoma induction. Twelve patients treated with 3D-CRT had alternative IMRT and PBT plans created retrospectively. Considering two mechanistic models – the linearexponential and the plateau models, which represent different cellular repair capabilities – the study concluded that PBT presented a lower risk of SMNs for all OARs compared to 3D-CRT and IMRT, suggesting a potential benefit of PBT in reducing risks for SMNs.

In study IV we aimed to compare the dosimetric outcomes of Volumetric Modulated Arc Therapy (VMAT), PBT, and conventional External Beam Radiation Therapy (cEBRT) in treating thoracic spinal metastases. Results indicated that both VMAT and PBT achieved better target coverage and delivered lower doses to the spinal cord, heart, esophagus, and lungs than cEBRT. Specifically, VMAT provided optimal target coverage, whereas PBT was superior in minimizing doses to vital organs. These findings suggest that VMAT and PBT may offer dosimetric benefits, particularly in palliative scenarios where sparing of specific OARs is especially important.

In conclusion, the cumulative evidence presented in this thesis highlights the potential of advanced radiotherapy techniques, such as PBT and VMAT, to spare various OARs more effectively than traditional methods like cEBRT and 3D-CRT. Across various clinical scenarios, including the treatment of thymic tumors and thoracic spinal metastases, PBT has demonstrated a consistent ability to reduce radiation doses to OARs, thereby reducing the risk of acute and chronic radiation-induced toxicities. The thesis also suggests that PBT could lower the risk of SMNs in RT of thymic tumors, which is a significant consideration for longterm cancer survivorship. Incorporated into the broader conclusions of this thesis, the findings from Study II reinforce the importance of assessing and monitoring cardiac function in patients undergoing radiation therapy for intrathoracic tumors.

List of scientific papers

I. Lideståhl A, Mondlane G, Gubanski M, Lind PA, Siegbahn A. An in silico planning study comparing doses and estimated risk of toxicity in 3D-CRT, IMRT and proton beam therapy of patients with thymic tumours. Phys Med. 2019 Apr;60:120-126.
https://doi.org/10.1016/j.ejmp.2019.03.028

II. Lideståhl, A., Larsson, T., Thorén, L., Brodin, O., & Lind, P. A. Changes on myocardial perfusion scintigraphy and contrastenhanced cardiac magnetic resonance imaging after definitive radiotherapy in patients with lung cancer. Journal of Radiotherapy in Practice. 2021. 21(4), 455-461.
https://doi.org/10.1017/S1460396921000091

III. Lideståhl A, Johansson G, Siegbahn A, Lind PA. Estimated Risk of Radiation-Induced Cancer after Thymoma Treatments with Proton- or X-ray Beams. Cancers (Basel). 2021 Oct 14;13(20):5153.
https://doi.org/10.3390/cancers13205153

IV. Lideståhl A, Fredén E, Siegbahn A, Johansson G, Lind PA. Dosimetric Comparison of Conventional Radiotherapy, Volumetric Modulated Arc Therapy, and Proton Beam Therapy for Palliation of Thoracic Spine Metastases Secondary to Breast or Prostate Cancer. Cancers (Basel). 2023 Dec 7;15(24):5736.
https://doi.org/10.3390/cancers15245736