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The role of radiotherapy (RT) in the treatment of thymoma and thymic carcinoma has been evaluated by many investigators over the past two decades. The low incidence of these neoplasms has limited most published studies to small series spanning long time intervals or extant population-based studies. The exact indications and protocols for the use of RT as a part of the multidisciplinary approach to thymoma and thymic carcinoma are still unclear. However, a review of recent literature shows potential benefits for certain patients based on stage and grade of disease as well as the extent of surgical resection.
Due to the sensitivity of thymoma and thymic carcinoma to radiation therapy, there is much interest in the role of radiotherapy (RT) in the treatment of these rare neoplasms. Although it is the most common anterior mediastinal compartment neoplasm (Figure 1),  low incidence and indolent natural history of the disease have made difficult work of developing definitive recommendations for RT in the multidisciplinary approach to the treatment of thymic neoplasms. In addition, the rapid advances in the delivery of RT make it difficult to evaluate the potential benefit of current treatment practices using data collected over several decades. Currently no domestic randomized prospective clinical trials evaluating the role of adjuvant radiotherapy after complete resection of thymoma or thymic carcinoma have been published. However, retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database as well as multiple small case series show potential for the use of adjuvant RT for the treatment of selected subpopulations of patients with thymoma and thymic carcinoma.
Complete surgical resection provides an 82% 7-year survival rate, while incomplete resection and biopsy alone are associated with 71% and 26% respectively . Therefore, the mainstay of treatment for thymoma and thymic carcinoma without unresectable/metastatic disease has been en bloc resection of the tumor and adjacent involved structures . There is a potential role for both radiotherapy and chemoradiotherapy to prevent recurrence for patients in whom a complete surgical resection is not possible.
Some investigators in the late 1980s recommended adjuvant RT for all thymic neoplasms regardless of stage or completeness of resection [4-5]. More recent studies have called this practice into question, and current work is focused on the benefit of RT for patients stratified by tumor stage and resection characteristics. Awad and colleagues performed a longitudinal study of patients with Masaoka stage I thymomas (which are completely encapsulated) who underwent complete resection who were followed for 32 years and found a 2% to 3% recurrence rate , suggesting that adjuvant RT is unlikely to improve the prognosis in this population of patients. Furthermore, the only randomized prospective trial performed to date, a small (n=29) series from Peking Union Medical College, demonstrated no survival benefit to RT (88% 10-year survival) compared to surgery alone (92% 10-year OS) in Masaoka Stage I patients .
Several other investigators also have data to suggest adjuvant RT provides no benefit for localized disease, but potentially benefits Masaoka Stage II and III [8-13] and patients receiving incomplete resections [8, 10, 14]. In higher stage disease, the benefit of adjuvant RT may be more readily detectable. A population-based domestic survival analysis of malignant thymoma analyzing the SEER registry data (n = 599) revealed significant overall survival benefit from adjuvant RT for a population comparable to Masaoka Stage II . In a more recent retrospective study also using SEER registry data (n = 901), whereas adjuvant RT provided no advantage in terms of overall survival for patients with Masaoka stage I thymoma and thymic carcinoma, a significant increase in overall survival was seen in patients with Masaoka Stage II and III disease, especially when surgery was non-extirpative . However, the SEER registry data include is not coded for surgical resection status (R0/R1/R2), use of chemotherapy, consistent histopathologic criteria , radiation dose, number of fractions, or elapsed days in the treatment course . This limits the further refinement of selection criteria that are possible from SEER data. A retrospective study (n = 175) has also corroborated the data from these extant population-based studies .
In addition, there are data from smaller, mostly institutional series to suggest survival benefit via reduction of recurrences both in the field of radiation and secondary distant progression with adjuvant RT [2, 17-19]. Although not statistically significant, a study of 68 patients by Curran et al. showed local recurrence reaches 47% at 5 years in patients with Stages II and III disease after an R0 resection without adjuvant RT whereas no recurrence was noted after the addition on adjuvant RT . Likewise, out of 33 patients receiving adjuvant RT, Urgesi et al. showed no in field recurrences and three out of field recurrences , lending credence to the efficacy of local control with adjuvant management.
However, several contrasting datasets have also been presented, with countervailing findings regarding RT utilization. In one of the largest series to date, Kondo et al. presented international report of >1000 pooled thymoma patients, including 247 Stage II cases, showing no difference between surgery alone and adjuvant RT . A smaller domestic report at the University of Pennsylvania of 167 patients undergoing surgical resection of thymoma showed no benefit from adjuvant RT in margin negative Stage II disease . Several other studies showed no decrease in local or distant recurrence after R0 resection for Stage III thymoma with adjuvant RT [21-24], and Ruffini et al. actually showed worse outcomes with the addition of adjuvant RT . Another recent study of 41 thymoma patients actually showed a significantly longer total survival time in patients with Stage II disease who did not receive adjuvant RT . Likewise, a meta-analysis published in 2009 by Korst et al. utilized data on 592 patients obtained from 13 out of 22 retrospective cohort studies, and showed no benefit of adjuvant RT on recurrence rates after complete resection of stage II and/or III thymic epithelial tumors,. Consequently, the use of radiation remains an area of debate and institutional norms.
Adjuvant RT is widely believed to be the standard of care for residual disease after incomplete resections of Stage III and IV disease, however. Curran and colleagues also showed no mediastinal failures after radiation in 26 patients with Stage III thymomas and 79% recurrence after 5 years without adjuvant RT . Other studies had similar findings with low mediastinal recurrence after treatment with adjuvant RT [17, 19].
Many of the published retrospective studies focus on the benefits of adjuvant RT in terms of survival and recurrence based on stratification by Masaoka stage. More recent studies have focused WHO cell type as a factor in establishing a good candidate group for adjuvant RT. In 2009, Utsumi et al. published a retrospective study of 324 patients who underwent resection of a thymoma in which 119 were treated with adjuvant radiotherapy . When examined based on WHO cell type and Masaoka staging, they showed patients with stage I and II thymoma as well as WHO types A, AB and B1 should not receive adjuvant RT. Also, no significant difference in actuarial disease-specific survival rates were found in patients with stage III and IV disease or WHO cell types B2 and B3 who were and were not treated with adjuvant RT .
Although the dose-response relationship for adjuvant RT is as controversial as the indication(s), RT treatment regimens for thymoma traditionally utilized doses ranging from 30 to 60 Gy in 1.8 to 2.0 Gy fractions, delivered over 3 to 6 weeks [5, 16-18, 21, 29-36]. It was thought that 40-45 Gy is sufficient for control of completely resected or microscopic residual disease , but in a retrospective study of 175 patients, Zhu and colleagues showed increasing the dose slightly to 50 Gy might be beneficial . Their data suggested RT dose >50 Gy is a prognostic factor for 5-year survival, but extending the radiation field prophylactically did not yield greater local control . Zhu and colleagues suggest that at least 50 Gy should be used for unresectable disease, where as other studies show >60 Gy are likely necessary for incompletely resected or gross disease [19, 29]. Sugie and colleagues suggested adjuvant mediastinal RT with 30-40 Gy for Stage II and 50-55 Gy for Stage III prevented local recurrence, and low-dose entire hemithorax irradiation with 11.2 Gy in 7 fractions or 15-16 Gy in 10 fractions after removal of disseminated lesions in the pleura helped to control pleural metastases . Since thymomas have been shown to be sensitive to chemotherapy  as well as radiotherapy, multimodality treatment with preoperative chemotherapy and surgical resection followed by adjuvant RT has been shown to increase resectability and survival in patients with stage III and IV thymomas when compared to surgery alone [35, 40-41]. Cisplatin, alone or in combination with other agents (e.g. cyclophosphamide, doxorubicin, vincristine, prednisone or epirubicin) has demonstrated response rates between 77% and 100% , and pathologic complete response rates between 4% and 31% and R0 resections achievable in 57% to 82% of cases. Cohort survival with these multimodality regimens ranged between 57% and 95%, showing that cisplatin-based neoadjuvant chemotherapy, surgery, and adjuvant RT provides excellent results for those with previously unresectable Stage III and IV disease [35, 40-41].
A regimen of combination chemotherapy and definitive radiotherapy has also provided reasonable results for unresectable thymomas. A prospective, phase II intergroup study reported a prolonged progression-free survival in patients treated with 2 to 4 cycles of cisplatin, doxorubicin and cylcophosphamide plus a total dosage of 54 Gy to the primary tumor and lymph nodes . Patients receiving this combination of therapy had a median survival time of 93 months with a 5-year survival rate of 52.5% . A phase II study of a multidisciplinary approach to the treatment of locally advanced unresectable malignant thymoma showed treatment with three courses of induction chemotherapy, surgical resection, adjuvant RT followed by three courses of consolidation chemotherapy provided a 95% survival rate and a 77% progression-free survival rate at 5 years .
While adjuvant and definitive RT remain the typical norm, neoadjuvant RT, while rarely utilized in the U.S., provides another approach to multidisciplinary management. In addition to neoadjuvant chemotherapy, Onuki et al.  presented an interesting series of Masaoka Stage III thymoma patients (n=21), involving pre-operative radiotherapy of 12-20 Gy in conventional fractionation, followed by surgical resection 1-3 weeks later. The patient’s were then given a median of 40 Gy (range 22-66.8 Gy) post-operatively. The series, while small, evinced impressive survival, with a 5- and 10-year survival of 91% and 78%, respectively. Patients who achieved complete resection fared very well, with a 10-year DFS of 84%.
Adding chemotherapy to neoadjuvant RT, Korst and colleagues are currently recruiting participants for a phase II study investigating the use of preoperative RT with concurrent cisplatin and etoposide in patients with thymoma or thymic carcinoma with significant risk of recurrence shown by x-ray and pathology criteria . In this study, preoperative radiation will begin 24 hours after the initiation of chemotherapy at a dose of 4000 to 4500 cGy at 180-200 cGy per fraction, to volume including thymus and gross tumor with 2-2.5cm margin. 3D-conformational or IMRT techniques will be used to reduce radiation to nearby structures while delivering higher doses to the tumor itself. Adjuvant RT will be administered to selected patients as determined by Masaoka stage at the time of surgery, WHO pathologic type, and completeness of resection. Trials such as these are necessary to determine with exactitude the optimal regimen and sequence of multimodality management, and enrollment of patients is heavily encouraged.
Thymic carcinoma comparatively more rare and aggressive thymic neoplasm than thymoma, with a 5-year survival of 35% . As with thymomas, surgical resection is the cornerstone of treatment. Prognoses are poor due to early metastases to the pleura and lung, bone, brain and liver, as well as mediastinal, cervical and axillary lymph nodes [46-47]. Contrasting opinions exist on the role of RT in a multimodality regimen, and combination with specific chemotherapeutic agents. As with the treatment of thymoma, there is no consensus on an optimum dose or fractionation. Most studies use a total dose ranging from 40 Gy to 70 Gy with daily fractions of 1.8 to 2.0 Gy.
Hsu and colleagues analyzed 26 patients given adjuvant RT and show improved survival and local control with 77% 5-year survival rate, 91% 5-year local control rate, and 57% 5-year distant metastasis-free rate . Radiation dose was found to have a significant association for local control probability in a small series consisting of 27 patients with invasive thymoma and 6 patients with thymic carcinoma . However, Hsu and colleagues also found that, while Masaoka staging was a statistically significant prognostic factor, radiation dose of <60 Gy, 60 Gy, or >60 Gy was not a significant predictor of overall survival rate . Ogawa and colleagues showed 100% control rates in 40 patients with thymic carcinoma who underwent complete resection and adjuvant RT with prescription doses >50 Gy .
In a larger multi-institutional series of 186 thymic carcinoma patients, Kondo and colleagues showed no survival benefit of adjuvant RT after a subtotal resection . 5-year survival probability for patients with R0 disease receiving adjuvant RT was 73.6%, whereas patients receiving adjuvant chemotherapy, adjuvant chemoradiotherapy and no adjuvant therapy had 5-year probabilities of 81.5%, 46.6% and 72.2% respectively . Although heterogeneous chemotherapeutic regimens, radiotherapy dose, and selection bias can provide some explanation for these results, these results are derived from the largest extant retrospective series and should be considered by those who advocate adjuvant radiotherapy or chemoradiotherapy for all cases of thymic carcinoma.
Due to the rarity of thymic carcinomas and subsequent small numbers of patients treated, it has been difficult to assess the effectiveness of chemotherapy. Most series have used cisplatin based regimens similar to those used in the treatment of thymoma [51-53]. If the treatment of thymoma provides any indication, it is reasonable to presume the addition of adjuvant RT to chemotherapy and surgery might provide additional survival benefit. While Magois et al. recently presented a series of 9 patients with stage III and IV thymic carcinoma that showed efficacy of neoadjuvant chemotherapy followed by surgical resection and adjuvant radiotherapy or chemoradiotherapy , others have suggested surgery remains the best initial treatment option for clearly resectable, well-defined disease, and radiotherapy should be added afterwards if indicated by information gained by surgical staging or pathologic study of the surgical specimen [14, 55]. Other studies suggest that neoadjuvant chemo or radiotherapy should be initiated only when thymic carcinoma is thought to be unresectable [49, 56].
Conventional radiotherapy planning typically utilizes anteroposterior/posteroanterior fields, followed by an opposed oblique beam boost, designed to minimize spinal cord dose (Figures 2--4).4). More recently, 3D conformal therapy (Figures 2--4)4) or intensity-modulated radiation therapy (IMRT; Figures 5--8)8) approaches enable markedly increased conformality, potentiating dose escalation and/or reduction of dose to non-target organs at risk (OARs) (Figures 3 and and4).4). When using RT to treat thymoma and thymic carcinoma, the heart, lungs, esophagus and spinal cord are at risk, and should be the prioritized OARs for dose constraint, using reasonable constraints derived from thoracic radiotherapy experience. To minimize pulmonary toxicity a V20 restriction of <30% and mean lung dose <20 Gy are advocated based on lung cancer series, with V13 minimized[57-58]. The entire heart has been purported to tolerate whole heart dose of 35-40 Gy, allowing no more than 1/3 of the myocardium to receive 60 Gy . It is recommended that the whole heart dose, if feasible, be kept less than 30 Gy to prevent coronary arterial disease risk amplification . Cord doses should remain <45 Gy. Although earlier reports found grade 3 and 4 toxicity ranging from 11% to 13% , newer reports suggest a decreased rate of 5% to 10%, potentially due to technical innovations in radiotherapy delivery . Death secondary to complications from RT has been reported in 1% to 13% of cases .
Controversy still exists concerning the role of radiotherapy in the treatment of thymic neoplasms. This controversy is unlikely to be resolved in the near future due to the conflicting conclusions of multiple small series and the lack of a large-scale, prospective, randomized trial. Although such as trial is needed to give a definitive algorithm for treatment, low incidence and indolent course of thymic neoplasms, as well as rapid advancement in the radiotherapy technology currently preclude such a study. Currently, the role of adjuvant radiotherapy in the treatment of thymic neoplasms largely depends on the stage of disease and the extent of the surgical resection. Patients with Stage I or completely resected Stage II disease do not seem to derive any appreciable benefit in terms of survival, local control, or recurrence upon the addition of radiotherapy after surgical resection. Thymic neoplasms with favorable histology such as WHO class A, AB and B1 have also been shown not to benefit from adjuvant RT. In contrast, patients with Stage III and IV disease have high enough recurrence rates that the benefits of radiotherapy as part of multimodality therapy shown in certain studies justify its use despite the existence of some contrary reports. Additionally, patients having undergone a R1 or R2 extirpation may also benefit for adjuvant RT. More data are necessary to establish a radiation dose-response relationship as well as the incidence of toxicity from treatment. It is important to follow patients indefinitely to monitor for signs of recurrence as well as late toxicity from radiation. In conclusion, a large-scale, multi-center randomized, prospective trial is necessary to develop evidence-based treatment algorithms for thymic neoplasms.