Phase II non-randomized study on proton radiotherapy of thymic malignancies

Thymic epithelial tumours (TETs or thymic malignancies) which comprise thymoma
and thymic carcinoma, are rare cancers worldwide. TETs are heterogenous both
morphologically as well as clinically. Thymomas may be associated with a
spectrum of autoimmune conditions, whereas this is rare in thymic carcinomas.
Thymic carcinomas are more prone to distant metastatic spread.
Surgery remains the cornerstone in the management of TETs. Minimally invasive
techniques including thoracoscopic and robotic surgery for early stage disease
are gradually increasing. Chemotherapy, although often with a moderate
response, has a role in downstaging as well as managing more advanced
disease.The role for radiotherapy is a matter of ongoing debate but the use of
postoperative radiotherapy (PORT) after incomplete surgery and/or advanced
stage (III/IV according to Masaoka) is more or less standard. There is
considerably less evidence and weaker consensus for the efficacy of PORT of
stage II patients and the use of it varies worldwide.

Radiotherapy with photons for TET patients has been reported feasible and with
acceptable toxicity. Treatment is generally given with IMRT-technique and doses
in the literature varies between 45 and 60 Gy with 1.8 or 2 Gy/fraction.

Many of the thymoma patients will become long time survivors and thus may
suffer from late toxicities such as radiation induced lung disease (RILD) or
radiation induced heart disease (RIHD). For many years RIHD has been of major
concern when irradiating patients with left-sided breast cancer and Hodgkin*s
disease. It includes a wide range of symptoms such as pericarditis, myocardial
infarction, valvular heart disease and coronary heart disease. Lately this has
become a greater concern when treating thoracic malignancies such as lung and
esophageal cancer. Depending on the good prognosis, there is a strong rationale
as to try to limit the cardiac dose to the thymoma patients.

Radiotherapy with protons have emerged as a potential possibility to achieve
local control and eventually reduce the risk for late toxicity and secondary
tumors. From early on, thymic malignancies was recognized as a group who would
eventually benefit from proton therapy. Treating thoracic malignancies with
protons is cumbersome because of many reasons; tumor and organs at risk motion
may result in interplay effects which compromise dose distribution being one of
them. Movement of mediastinal structures occurs but seems to be minor compared
to the movement in the lung parenchyma and patients with Hodgkins* disease has
been successfully treated with protons. TETs are generally located in close
proximity to the mediastinum. Recent years more and more data have been
published showing superior dose distribution and feasibility regarding toxicity
while treating thymomas with protons. The majority of previous thoracic proton
therapies have been given with passively-scattered technique. At the Skandion
Clinic and at Maastro all patients will be treated with pencil beam scanning
(PBS) with proton energies ranging from 60 to 230 MeV. This technique may
further optimize dose distribution although planning, quality assurance and
motion management is even more crucial.

To investigate te efficacy and the toxicity of protone radiation of thymomas
and thymic carcinomas.

This is a multicentre non-randomized phase II study of proton beam radiotherapy
in patients with thymic epithelial tumours (i.e. thymoma and thymic carcinoma)
in the post-operative setting or in inoperable patients with localized disease.
Patients not willing or for any reason unsuitable to undergo proton treatment
will be asked to participate in a follow-up assessment after the regular photon
treatment in the same manner as the included patients.

Burden:

Patiënts who participate in this study will undergo some extra examinations,
which consist oft:
- 11 QOL questionnaires
- 17 Extra ECG's
- 3 Extra ultrasounds of the heart
- Bloodtest, done by withdrawing an extra tube of blood during a standard blood
withdrawal.


Risks:
- The above mentioned examinations are low-risk