State of the art in radiation therapy for thymic malignancies: extended abstract

For patients with thymic malignancies, radiation therapy has an established role as an adjuvant treatment following surgical resection to improve local tumor control and, in select patients, overall survival (OS). Among patients with thymomas, in a National Cancer Database of over 4,000 patients who underwent thymic resections, post-operative radiation therapy (PORT) was associated with longer OS, with the greatest relative benefits for Masaoka stage IIB–III disease and positive margins (1). Similarly, in an International Thymic Malignancy Interest Group (ITMIG) Database analysis of 1,263 patients who underwent R0 resection for stage II–III thymoma, there was an OS benefit from PORT for both stage II (P=0.021) and stage III (P=0.0005) patients (2). With randomized data lacking, these analyses are the most comprehensive reports assessing PORT for thymoma and provide support for its use, particularly in patients at higher risk of recurrence, which has historically included Masaoka stage II patients with R1/R2 resections or with unfavorable histology and larger tumor size (>5 cm) (3), as well as Masaoka stage III and IVA patients. As the American Joint Committee on Cancer (AJCC) staging stage I thymic malignancies include a subset of patients Masaoka stage I, II, and III patients, additional data are needed to better characterize which AJCC stage I patients can benefit from PORT, along with AJCC stage II and III patients (4).

When radiation therapy is being considered, radiation oncologists should communicate closely with surgeons and pathologists to review operative findings to inform target volumes. Target volumes should include the preoperative tumor bed, surgical clips and potential sites of residual disease with margin, whereas prophylactic treatment of the entire mediastinum or supraclavicular region should not be performed. Doses of 45–50.4 Gy should be delivered for R0 patients, whereas doses of 54 and ≥60 Gy should be delivered for R1/R2 patients, respectively.

Adjuvant radiation therapy similarly plays an important role for thymic carcinoma (5,6). A recent analysis of the ITMIG/European Society of Thoracic Surgeons Database found that PORT was associated with an OS benefit (P=0.002), with this benefit statistically significant for advanced stage patients and for those early-stage disease following R1/R2 resections, but not for early-stage patients with R0 resections (7). Recent Appropriate Use Criteria guidelines from the American Radium Society (ARS) recommend adjuvant radiotherapy across disease stages delivered to doses of 45–60 Gy (8).

In patients with unresectable locally-advanced thymic malignancies, radiotherapy to doses of ≥60 Gy to gross disease with margin without elective nodal irradiation should be considered, often in combination with chemotherapy (8-10).

The aforementioned ARS guidelines recommend intensity-modulated radiation therapy (IMRT) or proton therapy as more appropriate than 3D-conformal radiation therapy (3D-CRT) for adjuvant and definitive radiotherapy for thymic tumors (8). These modalities can better protect normal tissues from excess irradiation, thus allowing for a potential reduction in acute and late toxicities. This is particularly important for patients with thymomas, who typically present at a younger age and with a more favorable cancer-specific survival relative to patients with lung cancer and pleural mesothelioma, and are thus at greater risk of late complications like pulmonary fibrosis, major cardiac events, and radiation-induced secondary malignancies. Advanced modalities like IMRT and proton therapy can be particularly advantageous when delivering high doses of definitive radiotherapy for inoperable cases or those with gross residual or recurrent disease, as well as those with a local recurrence after prior radiation therapy.

In a report of 65 patients treated for stage III thymoma who underwent R0 resection, adjuvant 3D-CRT/IMRT improved median OS compared to surgery alone, but adjuvant conventional radiotherapy did not, likely due to higher rates of pneumonitis and cardiac complications reported in patients receiving conventional radiotherapy (11).

Proton therapy can further improve the risk:benefit ratio and reduce dose to critical thoracic normal tissues relative to IMRT (12,13). The 2024 National Comprehensive Cancer Network guidelines for thymic malignancies states, “Compared to IMRT, proton therapy has been shown to improve dosimetry, thus allowing for better sparing of normal organs (lungs, heart, and esophagus) with favorable local control and toxicity” (14). Numerous dosimetric studies have demonstrated that proton therapy can significantly reduce doses to thoracic normal tissues (15,16). Such reductions in dose to the heart can lead to fewer expected major cardiac events with proton therapy relative to IMRT (17). Additionally, by reducing the integral dose to adjacent normal tissues, proton therapy can reduce the risk of developing radiation-induced secondary malignancies (18). The first prospective report of proton therapy in a cohort of 27 patients with high-risk thymic tumors—including patients with thymic carcinomas, gross residual or inoperable disease, and recurrent disease—showed 100% local control at 3 years with no grade ≥3 toxicities, and only 1 grade 2 pneumonitis (4%) (19). Similarly, investigators assessing 30 patients prospectively enrolled in the Proton Collaborative Group or University of Florida Prospective Registries found very low toxicity rates, with the only grade ≥3 toxicity occurring in a patient receiving reirradiation (20). Notably, the lack of exit irradiation dose with proton therapy is particularly favorable in reducing toxicities in the reirradiation setting (21,22).

Advanced radiation modalities are increasingly being employed in the treatment of pleural dissemination or recurrences of thymic malignancies (8). Radiotherapy delivered in ultra-high doses per fraction, termed stereotactic body radiation therapy (SBRT), can provide durable local control of pleural disease and/or metastases, with several institutions reporting excellent local control following SBRT for recurrent pleural mesothelioma (23,24). Such a treatment approach is increasingly being considered for patients with thymic malignancies with pleural metastases, especially those with oligometastatic or oligoprogressive disease (25). Furthermore, intensity-modulated pleural radiation therapy (IMPRINT) delivered to the hemithorax is currently being trialed to treat or prevent pleural dissemination of thymic malignancies (NCT05354570).

Notably, however, there are additional challenges to consider when delivering radiotherapy with advanced modalities, including a need to account for and potentially mitigate respiratory motion and to monitor for anatomical changes during radiotherapy that could affect the radiation dose distribution (26,27), especially for next-generation pencil beam scanning proton therapy (28), underscoring the importance of care being delivered by radiation oncologists with experience managing thymic tumors.

In summary, radiotherapy can improve outcomes in the adjuvant setting for completely resected locally advanced thymic tumors and for early-stage and locally advanced thymic tumors following R1/R2 resections, as well as in the definitive setting for inoperable cases. Radiotherapy has emerging roles for reirradiation and for pleural recurrences or dissemination. To reduce the risks of late complications in patients with thymic malignancies, many of whom have excellent cancer-specific survival, advanced modalities like IMRT and proton therapy should preferentially be utilized for adjuvant and definitive therapy.

Acknowledgments

Funding: This research was funded, in part, through the NIH/NCI Cancer Center Support Grant P30 CA008748.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Malgorzata Szolkowska, Chul Kim, Mohammad Ashraghi, and Claudio Silva) for “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-10/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-10/coif). “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” was commissioned by the editorial office without any funding or sponsorship. C.B.S. reports honorarium from Varian Medical Systems. He is the President of the Board of Directors of the Proton Collaborative Group and the Chair of the NRG Oncology Particle Therapy Work Group. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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