Thymic epithelial tumour radiotherapy in the UK: A survey of current clinical practice.

Significant variation in treatment centre setup and radiotherapy practice for thymic epithelial tumours (TET) was identified through a comprehensive survey of current UK Clinical (Radiation) Oncology practice. Multi-centre collaboration and wider TET specific multidisciplinary team meetings are needed and will be essential for developing expertise in TET radiotherapy.

American Radium Society Appropriate Use Criteria for Radiation Therapy in the Multidisciplinary Management of Thymic Carcinoma.

Importance: Thymic carcinoma is rare, and its oncologic management is controversial due to a paucity of prospective data. For this reason, multidisciplinary consensus guidelines are crucial to guide oncologic management. Objective: To develop expert multidisciplinary consensus guidelines on the management of common presentations of thymic carcinoma. Evidence Review: Case variants spanning the spectrum of stage I to IV thymic carcinoma were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel to address management controversies. A comprehensive review of the English-language medical literature from 1980 to 2021 was performed to inform consensus guidelines. Variants and procedures were evaluated by the panel using modified Delphi methodology. Agreement/consensus was defined as less than or equal to 3 rating points from median. Consensus recommendations were then approved by the ARS Executive Committee and subject to public comment per established ARS procedures. Findings: The ARS Thoracic AUC panel identified 89 relevant references and obtained consensus for all procedures evaluated for thymic carcinoma. Minimally invasive thymectomy was rated as usually inappropriate (regardless of stage) due to the infiltrative nature of thymic carcinomas. There was consensus that conventionally fractionated radiation (1.8-2 Gy daily) to a dose of 45 to 60 Gy adjuvantly and 60 to 66 Gy in the definitive setting is appropriate and that elective nodal irradiation is inappropriate. For radiation technique, the panel recommended use of intensity-modulated radiation therapy or proton therapy (rather than 3-dimensional conformal radiotherapy) to reduce radiation exposure to the heart and lungs. Conclusions and Relevance: The ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of thymic carcinoma, perhaps the most well referenced on the topic.

Evaluation of the role of postoperative radiotherapy in locally invasive thymoma: A propensity-matched study based on the SEER database.

OBJECTIVES: No consensus was reached on the efficacy of postoperative radiotherapy (PORT) in locally invasive thymomas because of the rarity of the thymic epithelial and the variations of study results. Therefore, we aimed to explore the efficacy of PORT in locally invasive thymomas using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Patients diagnosed with thymomas from 2004 to 2016 were identified using the SEER database. Prognostic factors of cancer-specific survival (CSS) and overall survival (OS) were identified using univariate and multivariate Cox regression analyses.Propensity score matching (PSM) was performed to balance the baseline characteristics. RESULTS: A total of 700 eligible patients were identified. After PSM, 262 paired patients were selected from the two groups, those who received or did not receive PORT. Receiving PORT improved CSS and OS before and after PSM. In the matched population, the multivariate analyses showed that tumour invasion into adjacent organs/structures and non-utilisation of PORT were independent poor prognostic factors for CSS, whereas age ≥62 years,tumour invasion into adjacent organs/structures, and non-utilisation of PORT were independently associated with poorer OS. The subgroup analysis revealed that PORT improved CSS and OS in Masaoka-Koga stage III thymoma, but showed no OS benefit in Masaoka-Koga stage IIB thymoma. CONCLUSION: Based on the SEER database, we found that PORT provides a significant survival benefit in Masaoka-Koga stage III thymoma with complete or incomplete resection. The role of PORT in thymoma requires further evaluation.

The value of postoperative radiotherapy in thymoma patients with myasthenia gravis.

INTRODUCTION: Surgery is the first-line treatment for patients with thymoma associated with myasthenia gravis (MG); however, the value of radiotherapy among these patients remains debatable. Herein, we examined the impact of postoperative radiotherapy (PORT) on the efficacy and prognosis of patients with thymoma and MG. METHODS: This retrospective cohort study included 126 patients with thymoma and MG who were enrolled in the Xiangya Hospital clinical database between 2011 and 2021. Demographic and clinical data were collected including sex, age, histologic subtype, Masaoka-Koga staging, primary tumor, lymph node, metastasis (TNM) staging, and therapeutic modalities. To evaluate short-term MG symptom improvement following PORT, we examined changes in the quantitative myasthenia gravis (QMG) scores within 3 months post-treatment. Minimal manifestation status (MMS) was the main endpoint for assessing long-term improvement in MG symptoms. Overall survival (OS) and disease-free survival (DFS) were primary endpoints to determine the impact of PORT on prognosis. RESULTS: Effects of PORT on MG symptoms: QMG scores significantly differed between the non-PORT and PORT groups (χ2 = 6.300, p = 0.012). The median time to achieve MMS was significantly shorter in the PORT group than that in the non-PORT group (2.0 years vs. 4.4 years; p = 0.031). Multivariate analysis revealed that radiotherapy was associated with a reduced time to achieve MMS (hazard ratio [HR] 1.971, 95% confidence interval [CI]:1.102-3.525, p = 0.022). Effects of PORT on DFS and OS: The 10-year OS rate of the entire cohort was 90.5%, whereas OS rates for the PORT and non-PORT groups were 94.4 and 85.1%, respectively. The 5-year DFS rates for the whole cohort, PORT group, and non-PORT group were 89.7, 95.8, and 81.5%, respectively. PORT was associated with improved DFS (HR 0.139, 95% CI: 0.037-0.533, p = 0.004). In the high-risk histologic subgroup (type B2, B3), patients who received PORT had better OS (p = 0.015) and DFS (p = 0.0053) than those who did not receive PORT. PORT was associated with improved DFS (HR 0.232, 95% CI: 0.069-0.782, p = 0.018) in Masaoka-Koga stages II, III, and IV disease. CONCLUSIONS: Overall, our findings indicate that PORT positively impacts thymoma patients with MG, particularly those with a higher histologic subtype and Masaoka-Koga staging.

Failure patterns for thymic carcinoma with completed resection and postoperative radiotherapy.

BACKGROUND AND PURPOSE: We aimed to evaluate the pattern and risk factors of disease failure in patients with thymic carcinoma after complete resection and postoperative radiotherapy (PORT). MATERIALS AND METHODS: We retrospectively analyzed 127 patients with thymic carcinoma who underwent PORT after complete resection between 2003 and 2020 in our center. Data on clinical characteristics and radiation fields were collected. Failure patterns were recorded as locoregional (disease appearing in the tumor bed or regional lymph nodes), pleural, or distant failure (including hematogenous metastasis and nonregional lymph node metastasis). RESULTS: All patients underwent tumor bed irradiation. During a median follow-up period of 64 months, disease failure was observed in 51 patients (40.2 %). The 5-year disease-free survival (DFS) and overall survival rates were 58.9 % and 85.0 %, respectively. The sequence of failure patterns was distant (n = 41, 32.3 %), pleural (n = 28, 22.0 %), and locoregional failure (n = 19, 15.0 %). Of the locoregional failure patients, failures occurred in-field in three patients (2.4 %), marginal failure in one patient (0.8 %), out-of-field failure in nine patients (7.1 %), synchronous in-field and out-of-field failures in two patients (1.6 %), synchronous marginal and out-of-field failures in two patients (1.6 %), and unknown failure fields in two patients (1.6 %). Multivariate analysis showed that Masaoka stage (hazard ratio [HR], 3.88; p = 0.000) and adjuvant chemotherapy (HR, 0.47; p = 0.015) were independent predictors of DFS. CONCLUSION: The most common failure was distant, the Masaoka stage and adjuvant chemotherapy were independent predictors of DFS, and low locoregional failure-supported tumor bed irradiation was sufficient for patients with thymic carcinoma after complete resection.

An Updated Review on Radiation Treatment Management in Thymus Cancers.

This narrative review aims to summarize the currently available evidence for the role of radiation in the treatment of thymus cancers. Thymus cancers are rare, heterogeneous tumors with limited evidence to guide their clinical management. There remains some controversy over the role of radiation in the adjuvant and induction/definitive setting. We performed a systematic search of the MEDLINE/PubMed database, focusing on studies published within the last 30 years. Our search queried "thymoma [OR] thymic carcinoma [AND] radiation" and was limited only to prospective and retrospective studies and metanalyses, omitting books, documents, and reviews. Our search resulted in 174 total references, of which only 31 references were within the scope of interest ranging from 1988 to 2021. For resectable disease, there is prospective evidence to support the avoidance of postoperative radiation (PORT) in completely resected Masaoka stage I thymoma, but there is a lack of prospective evidence guiding the use of PORT in other situations. Several retrospective studies and metanalyses have suggested a benefit with PORT for positive margins and advanced stage disease, although it remains controversial whether PORT is beneficial for all completely resected Masaoka stage II thymoma. For unresectable disease, induction chemotherapy followed by reassessment of resectability is the preferred management. Prospective evidence exists to support the use of induction chemoradiation for patients unable to tolerate anthracycline-based chemotherapy and the use of definitive chemoradiation for those unable to undergo surgery. An effective multidisciplinary approach is the optimal strategy for achieving the best outcomes in patients with thymus cancers.

On the risk of secondary cancer from thymoma radiotherapy.

Objective.This study aims at quantifying the lifetime attributable risk of secondary fatal cancer (LARFAC) to patients receiving adjuvant radiotherapy treatment for thymoma, a neoplasm where cure rates and life expectancy are relatively high, patient age at presentation relatively low and indications for radiotherapy controversial depending on the disease stage.Approach.An anthropomorphic phantom was scanned, organs were contoured and a standard 6 MV 3DCRT treatment plan was produced for thymoma treatment. The phantom was loaded with thermoluminescent dosimeters (TLDs) and treated by linear accelerator per plan. The TLDs were subsequently read for out-of-field dose distribution while in-field dose distribution was obtained from the planning system. Sex and age-specific lifetime radiogenic cancer risk was calculated as the sum of in-field risk and out-of-field risk. The latter risk was estimated using hybrid ICRP 2007 103-BEIR VII tables of organ-specific risks based on the linear-no threshold (LNT) model and applicable at low doses, while the former using mathematical risk models applicable at high doses.Main results.The LARFAC associated with a prescribed dose of 50 Gy to target volume in 25 fractions was in the approximate range of 1%-3%. The risk was higher for young and female patients. The largest contributing organ to this risk were the lungs by far. Using the LNT model inappropriately to calculate risk at therapeutic doses (in-field) would overestimate the risk up to tenfold.Significance.The LARFAC to patient from thymoma radiotherapy was quantified taking into consideration the inapplicability of the LNT model at therapeutic doses. The risk is not negligible; the information may be relevant to patients and clinicians.

Phase II study of S-1 plus cisplatin with concurrent radiotherapy for locally advanced thymic carcinoma: Results of the LOGIK1605/JART-1501 study.

BACKGROUND: Combination chemotherapy is used to treat advanced thymic carcinoma; however, the effects are insufficient. METHODS: Previously untreated patients with unresectable locally advanced thymic carcinoma received two cycles of 80 mg/m2 /day S-1 orally on days 1-14 plus 60 mg/m2 /day cisplatin intravenously on day 1, and concurrent radiotherapy (60 Gy). RESULTS: Three patients were enrolled into the study. Toxicity and survival were assessable in all patients, but the treatment response was only assessable in one patient. The study was terminated because of poor case recruitment. The patients' characteristics were as follows: male/female = 2/1; PS 0/1 = 2/1; median age (range) = 59 (55-72); and stage III/IV = 2/1. The patient in which the treatment response was assessed exhibited SD (response rate: 0%). In both nonevaluable cases, the second course of chemotherapy was judged to be post-protocol treatment because it was delayed by ≥14 days, but a CR and PR were achieved after the end of the study, respectively. G4 leukopenia/neutropenia and G3 febrile neutropenia occurred in one patient each (33%). The median time to tumor progression was 17.6 months, and the 1-, 2-, 3-, and 4-year survival rates were 67, 33, 33, and 33%, respectively. The median overall survival time was not reached, and the 1-, 2-, 3-, and 4-year survival rates were 100, 67, 67, and 67%, respectively. CONCLUSIONS: Although it was difficult to recruit patients, there was a long-term survivor >4 years who appeared to have achieved a CR, indicating that such chemoradiotherapy may be effective against locally advanced thymic carcinoma.

Postoperative radiotherapy for completely resected thymoma: Differing roles in masaoka stage II and stage III disease.

PURPOSE: The efficacy of radiotherapy for treating thymomas is unclear. The goal of this study was to analyze overall survival (OS) and disease-free survival (DFS) among thymoma patients to determine the impact of postoperative radiotherapy (PORT) on thymoma outcomes. METHODS: Recorded cases of thymoma at Xinqiao Hospital were retrospectively analyzed from 1991 to 2019. Data on stage II and III thymomas were extracted from medical records. This study evaluated OS and DFS and compared outcomes between surgery and surgery-plus-radiation groups. The Kaplan-Meier method and Cox regression analysis were used to compare DFS and OS for these groups. RESULTS: Of the 205 patients included in the current study, 142 (69.3%) presented with stage II disease and 63 (30.7%) presented with stage III disease. The median follow-up was 84.3 months. PORT did not statistically significantly improve OS (P = 0.613) and DFS (P = 0.445) in stage II thymoma patients (compared with surgery alone). However, our subgroup analysis showed a statistically significant difference in DFS in patients with stage III thymoma (P = 0.044). CONCLUSION: Although the routine use of postoperative radiotherapy in patients with thymoma does not appear warranted, patients with stage III thymoma may benefit from adjuvant radiation. These findings, if confirmed, will provide valuable information to guide medical decision-making for thymoma treatment.

Adaptive radiation therapy using weekly hypofractionation for thymoma treatment: A retrospective study of 10 rabbits.

Radiation therapy (RT) is being utilized more commonly for rabbit thymomas due to high perioperative mortality rates with surgery. Median overall survival times reported for rabbit thymomas treated with a variety of RT protocols and techniques range from 6 months to greater than 2 years. As thymomas are radiation-responsive tumours and may shrink rapidly after RT, adaptive radiotherapy (ART) is often warranted. The purpose of this single-institution retrospective case series was to investigate the tumour volume reduction during RT, the frequency of replanning during RT, and survival time in rabbit thymomas treated using intensity-modulated/image-guided radiation therapy (IMRT/IGRT) and a weekly hypofractionated protocol delivering a total dose of 30 Gy. Ten rabbits met the inclusion criteria from October 2014 to October 2019. The median progression-free survival was 561 days and the median overall survival was 634 days (range: 322-1118 days). The tumour volume gradually decreased with each RT fraction. On post-hoc analysis, only the first RT fraction was associated with a significant GTV reduction (of more than 50% on average, p < .001). All subsequent RT fractions did not further reduce the GTV significantly (p > .06). Hypofractionated RT using a weekly protocol of 5 fractions of 6 Gy is a reasonable option to treat rabbit thymomas and replanning should be anticipated. The results of this study support the use of RT to rapidly relieve thymoma-induced dyspnoea in rabbits.

A Rare Case of Brain Metastasis of Thymic Carcinoma.

BACKGROUND: Thymic carcinoma is a rare cancer that often metastasizes to the liver and kidneys but rarely to the brain. CASE REPORT: We present a rare case of an 81-year-old woman with multiple cerebellar metastases of thymic carcinoma. She was initially diagnosed with stage IVb thymic carcinoma based on biopsy examination of a lesion in the anterior mediastinum. The patient refused to undergo treatment at the time. Six months later, she presented with gait disturbance and nausea. Contrast-enhanced magnetic resonance imaging revealed multiple cerebellar metastases. She underwent craniotomy and resection of the left cerebellar metastasis. Postoperative histological examination confirmed metastasis of the original thymic carcinoma. The patient underwent additional stereotactic radiotherapy for the cavity of the cerebellar metastasis and the small cerebellar metastatic lesions. Seven months after radiotherapy, she died due to progression of the thymic carcinoma. CONCLUSION: We believe that these findings add important information to the literature on this rare entity.

Outcomes of dogs with thymoma treated with intensity modulated stereotactic body radiation therapy or non-modulated hypofractionated radiation therapy.

Canine thymomas are routinely treated with radiotherapy (RT). In this study, we investigate the response and toxicity of canine thymoma treated with intensity-modulated stereotactic body radiation therapy (SBRT) relative to dogs treated with hypofractionated non-modulated radiation therapy (NMRT). A retrospective study was performed of dogs with thymoma treated with RT (total: n = 15; SBRT: n = 8, NMRT: n = 7). Tumour response was evaluated in six dogs (40%); following SBRT, three dogs (100%) experienced stable disease (SD); following NMRT, one dog (33%) had a PR, and two dogs (67%) had SD. Median PFS was 116 days (range 66-727 days) for the SBRT group and 134 days (range 10-405 days) for the NMRT group. The MST for the SBRT group was 250 days (range 1-727 days) and 155 days (range 10-405 days) for NMRT. Median disease-specific survival was 250 days (range 1-727 days) for the SBRT group and 169 days (range 20-405 days) for the NMRT group. No significant differences in survival data were found between the treatment groups, however the results from the small number of dogs analysed are likely underpowered for statistical comparisons. Reported acute and late side effects were limited to the lungs and heart and were statistically significantly more common in the NMRT (71%) compared to the SBRT group (25%) (p = .04). We suggest similar treatment efficacy may be provided for canine thymoma treated with either approach, but SBRT could provide the clinical benefit of reduced incidence of radiation-induced toxicity and completion of RT in a shorter time frame.

Dosimetric analysis of postoperative radiotherapy for thymoma.

PURPOSE: To compare the dosimetric differences between intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) in the treatment of male and female thymoma. MATERIAL AND METHODS: This single-institutional analysis included 20 patients with thymoma treated with RT between January 2017 and December 2020. Twenty patients were retrospectively planned for IMRT (IMRT1 with an average field angle of 216°, 288°, 0°, 72°,and 144°; IMRT2 with fan-shaped field angles of 280°, 320°, 0°, 40°, and 80°) and VMAT (VMAT1 with two arcs ranging form 280° to 80°,clockwise and then counterclockwise; VMAT2 with two 360° arcs). The plans for all investigated RT modalities were optimized for a prescriptional dose of 50Gy and fractional dose of 2.0Gy. Planning target volume (PTV) and organs-at-risk (OARs: heart, breasts, lungs, spinal cord, and esophagus) dosimetric parameters were compared. RESULTS: All plans met the preparation aims for all the included metrics. There was little difference in the median values of PTV parameters (D2%, D98%, Dmean, homogeneity index[HI], and conformity index [CI]). The CI of the VMAT2 plan was the closest to 1 in both therapy groups. The monitor unit (MU) of IMRT2 and the estimated total delivery time of VMAT1 were the lowest in both therapy groups and were statistically significant. In the male group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) for VMAT1 were the lowest and showed statistical significance. In the female group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) and bilateral breast parameters (Dmean, V5Gy, V10Gy, and V20Gy) of IMRT2 were the lowest and showed statistical significance. CONCLUSIONS: In male thymoma patients undergoing postoperative RT (PORT) treatment, the choice of fan-shaped VMAT may be a better option for protecting the lungs. For female thymoma patients receiving PORT, fan-shaped IMRT can better protect the lungs and breasts. The fan-shaped field performed better than the average and the full arc fields in PORT for thymoma.

Optimal delineation of the clinical target volume for thymomas in the post-resection setting: A multi-center study.

BACKGROUND: The definition of the clinical target volume (CTV) for post-operative radiotherapy (PORT) for thymoma is largely unexplored. The aim of this study was to analyze the difference in CTV delineation between radiation oncologists (RTO) and surgeons. METHODS: This retrospective multi-center study enrolled 31 patients who underwent PORT for a thymoma from five hospitals. Three CTVs were delineated per patient: one CTV by the RTO, one CTV by the surgeon (blinded to the results of the RTO) and a joint CTV after collaboration. Volumes (cm3), Hausdorff distances (HD) and Dice similarity coefficients (DSC) were analyzed. RESULTS: RTO delineated significantly bigger CTVs than surgeons (mean: 93.9 ± 63.1, versus 57.9 ± 61.3 cm3, p = 0.003). Agreement was poor between RO and surgeons, with a low mean DSC (0.34 ± 0.21) and high mean HD of 4.5 (±2.2) cm. Collaborative delineation resulted in significantly smaller volumes compared to RTO (mean 57.1 ± 58.6 cm3, p < 0.001). A mean volume of 18.9 (±38.1) cm3 was included in joint contours, but missed by RTO. Conversely, a mean volume of 55.7 (±39.9) cm3 was included in RTO's delineations, but not in the joint delineations. CONCLUSIONS: To the best of our knowledge, this is the first study investigating CTV definition in thymoma. We demonstrated a significant variability between RTO and surgeons. Joint delineation prompted revisions in smaller CTV as well as favoring the surgeons' judgement, suggesting that surgeons provided relevant insight into other risk areas than RTO. We recommend a multidisciplinary approach to PORT for thymomas in clinical practice.

Radiotherapy-induced tumor lysis syndrome in a dog with thymoma.

A 13-year-old, female, mixed-breed dog with a huge cranial mediastinal mass underwent radiotherapy (RT). On the following day, the dog presented with lethargy and anorexia. Hematological examination revealed elevated levels of blood urea nitrogen, creatinine, inorganic phosphorus, potassium, lactate dehydrogenase, creatine phosphokinase and aspartate aminotransferase, decreased calcium level, and metabolic acidosis. Urine output markedly decreased. The patient recovered with fluid therapy and diuretic therapy; however, died suddenly from an unknown cause 11 days after RT completion. Histopathological examination after necropsy showed thymoma in the cranial mediastinum and extensive tubular necrosis of both kidneys which may be due to RT-induced tumor lysis syndrome (TLS). This report suggests that the risk of TLS should be evaluated in dogs with thymoma who undergo RT.

Invasive thymoma - Which patients benefit from post-operative radiotherapy?

BACKGROUND: The aim of this study is to identify patients with thymoma who should receive post-operative radiotherapy. METHODS: The Surveillance, Epidemiology, and End Results database was queried for stage IIB-IV thymoma patients diagnosed during 1988-2015. We analyzed the prognostic implications of various clinical-pathological factors by comparing the outcomes of those who received surgery with and without post-operative radiotherapy. RESULTS: A total of 1120 patients were identified; 62% received post-operative radiotherapy and 38% underwent surgery alone. In a propensity-matched cohort of 812 patients, no survival difference was seen in World Health Organization A, AB, B1, B2, or B3 tumors with the addition of post-operative radiotherapy to surgery (p>0.05). Post-operative radiotherapy also did not improve survival over surgery alone for tumors ≥ or < less than the 4 cm, 7 cm, 10 cm, and 13 cm cutoffs, all p>0.05. Post-operative radiotherapy was an independent, positive prognostic indicator only in the subgroup with stage III disease and in those receiving chemotherapy in addition to post-operative radiotherapy, both p<0.05. CONCLUSIONS: Patients with stage III thymoma are most likely to benefit from the addition of post-operative radiotherapy to surgical treatments. Tumor size or World Health Organization histology alone should not be criteria for determining the need for post-operative radiotherapy in locally advanced thymoma. Masaoka-Koga stage, which has traditionally been used to help make such decisions, appears to be the most reliable determinant of the use of post-operative radiotherapy.

RADIORYTHMIC: Phase III, Opened, Randomized Study of Postoperative Radiotherapy Versus Surveillance in Stage IIb/III of Masaoka Koga Thymoma after Complete Surgical Resection.

INTRODUCTION: Thymomas are rare intrathoracic malignancies that may be aggressive and difficult to treat. Knowledge and level of evidence for treatment strategies are mainly based on retrospective studies or expert opinion. Currently there is no strong evidence that postoperative radiotherapy after complete resection of localized thymoma is associated with survival benefit in patients. RADIORYTHMIC is a phase III, randomized trial aiming at comparing postoperative radiotherapy versus surveillance after complete resection of Masaoka-Koga stage IIb/III thymoma. Systematic central pathologic review will be performed before patient enrollment as per the RYTHMIC network pathway. PATIENTS AND METHODS: Three hundred fourteen patients will be included; randomization 1:1 will attribute either postoperative radiotherapy (50-54 Gy to the mediastinum using intensity-modulated radiation therapy or proton beam therapy) or surveillance. Stratification criteria include histologic grading (thymoma type A, AB, B1 vs B2, B3), stage, and delivery of preoperative chemotherapy. Patient recruitment will be mainly made through the French RYTHMIC network of 15 expert centers participating in a nationwide multidisciplinary tumor board. Follow-up will last 7 years. The primary endpoint is recurrence-free survival. Secondary objectives include overall survival, assessment of acute and late toxicities, and analysis of prognostic and predictive biomarkers. RESULTS: The first patient will be enrolled in January 2021, with results expected in 2028.