Thymoma Treatment & Management

Chemotherapy

A few reports in the literature suggest that thymomas are chemosensitive tumors.^[5] Potential candidates for chemotherapy include approximately one third of the patients with an invasive thymoma that later metastasizes and all patients with stage IV disease. Fornasiero and colleagues reported successful cases and some long-term survivors following the administration of a regimen of cisplatin/vincristine/doxorubicin/cyclophosphamide for incompletely resected invasive thymomas or cases with unresectable disease.^[6] In 32 patients, a 47% complete and 90% overall response rate was noted with a median survival time of 15 months. A trial conducted by the European Organisation for Research and Treatment of Cancer reported that among 16 patients with recurrent or metastatic thymomas, 5 complete remissions and 4 partial remissions were observed. Median survival time in this study was 4.3 years.

Corticosteroids

Case reports have documented the administration of oral glucocorticoids resulting in regression of an invasive thymoma. In one case, the patient showed complete regression to the thymoma and associated symptoms and has remained without radiological recurrence after 12 months.^[7]

Multidisciplinary approach

A multidisciplinary approach to therapy for unresectable thymomas has been advocated.^[8] In one trial conducted by the M.D. Anderson Cancer Center, a treatment regimen consisting of induction chemotherapy (ie, 3 courses of cyclophosphamide, doxorubicin, cisplatin, and prednisone), surgical resection, postoperative radiation therapy, and consolidation chemotherapy (ie, 3 courses of cyclophosphamide, doxorubicin, cisplatin, and prednisone) was tested.^[9]

This study yielded encouraging results. Of 12 patients who underwent this treatment regimen, the disease had a complete response in 3 patients (25%), a partial response in 8 patients (67%), and a minor response in 1 patient (8%). Among 11 of these 12 patients (1 refused surgery), 9 (82%) had complete resections, and 2 (18%) who had been receiving radiation therapy and consolidation chemotherapy had incomplete resections. All 12 patients (100%) are alive at 7 years, and 10 of these patients (73%) are disease-free at 7 years. Therefore, the authors suggest that aggressive multimodal treatment is effective and may be curative in locally advanced, unresectable, malignant thymomas.

A study was conducted by Loehrer et al evaluating the effects of octreotide alone or with prednisone in 38 patients with advanced thymomas that expressed somatostatin receptors (ie, that were octreotide scan positive).^[10] The patients were given 0.5 mg subcutaneously 3 times daily. Four (10.5%) of the 38 patients had a partial response with octreotide treatment alone. In the 21 patients in whom prednisone (0.6 mg/kg daily) was added, 2 complete and 6 partial responses (38%) occurred. Combination therapy resulted in better progression-free survival than octreotide therapy alone. Octreotide therapy may be a valuable treatment to use in cases in which chemotherapy is ineffective.

Initial management in most cases of thymomas is surgical.^[5] Surgical excision provides the histological characteristics of the tumor and provides staging information that is helpful in determining the need for adjuvant therapy. Small and encapsulated thymomas are excised for diagnosis and treatment. In the past, obtaining a preoperative biopsy of large invasive thymomas was shunned for fear of local implantation of tumor cells. Currently, biopsies are performed for these atypical tumors to discover the histology of the tumor and to ascertain its invasive potential.

A single-institution retrospective study was conducted of 5 patients with stage IVA treated with pleuropneumonectomy. The median survival was 86 months, and the Kaplan-Meier survival was 75% at 5 years and 50% at 10 years. There were no operative mortalities in this study. It has been suggested that, in select patients, this approach after a complete resection and neoadjuvant chemotherapy may be promising.^[11]

The prognosis of a person with a thymoma is based on the tumor's gross characteristics at operation, not the histological appearance. Benign tumors are noninvasive and encapsulated. Conversely, malignant tumors are defined by local invasion into the thymic capsule or surrounding tissue. The Masaoka staging system of thymomas is the most commonly accepted system. Although controversy exists pertaining to the use of postoperative radiation for invasive thymomas, the preponderance of evidence indicates that all thymomas, except completely encapsulated stage 1 tumors, benefit from adjuvant radiation therapy.^[12]

Preoperative adjuvant radiation therapy has been used to increase the possibility of complete resection when CT scan suggests a tumor is very large or invasive. Although doses of 30-45 gray (Gy) have been used in this approach, complete responses rarely have been reported. One caveat to this therapy is that the patient is placed at increased risk for radiation pneumonitis because of the large size of ports required to cover the field.

Patients with a preoperative diagnosis of MG and a thymoma should optimize their medical condition prior to surgery by using cholinesterase inhibitors and plasmapheresis if indicated.

Although the preferred approach is a median sternotomy providing adequate exposure of the mediastinal structures and allowing complete removal of the thymus, the cervical approach also is adequate. If the tumor is small and appears readily accessible, perform a total thymectomy with contiguous removal of mediastinal fat. If the tumor is invasive, perform a total thymectomy in addition to en bloc removal of involved pericardium, pleura, lung, phrenic nerve, innominate vein, or superior vena cava. Resect one phrenic nerve; however, if both phrenics are involved, do not resect either nerve, and debulk the area. Clip areas of close margins or residual disease to assist the radiation oncologist in treatment planning.

Controversy about whether biopsy versus subtotal excision is superior for treating unresectable tumors exists. Some studies have supported subtotal excision, while others have shown no difference between the 2 modalities. A generally accepted rule is that patients with invasive or residual disease should receive adjuvant therapy.

Radiation therapy

Adjuvant radiation therapy^[5] in completely or incompletely resected stage III or IV thymomas is considered a standard of care. The use of postoperative radiation therapy in stage II thymomas has been more questionable. Thymomas are indolent tumors that may take at least 10 years to recur; therefore, short-term follow-up will not depict relapses accurately. Furthermore, the gross appearance of tumor invasiveness is subjective, depending on the opinion of the surgeon. In one report at Massachusetts General Hospital, 22% of patients (5 out of 23) with stage II disease developed recurrence, leading to a proposed recommendation that postoperative radiation be instituted in all patients with stage II thymoma.^[13]

In a study conducted by Curran and colleagues, of 21 patients with stage II and III disease who did not undergo postoperative (total resection) radiation therapy, 8 had recurrence in the mediastinum.^[14] The 5 patients who received adjuvant radiation did not have recurrences. A series from Memorial Sloan Kettering Cancer Center, however, showed that adjuvant radiation therapy did not improve survival or decrease recurrence in stage II and III disease.^[15] To reduce the incidence of local relapse, perform postoperative adjuvant radiation therapy in patients without completely encapsulated stage I tumors.

Wu et al performed a retrospective review of 241 patients with thymoma who received radiation therapy following total thymectomy, partial resection, debulking, or biopsy.^[16] The 10-year survival rate was 87% for patients with stage I thymoma, 78.7% for individuals with stage II disease, 57.4% for those with stage III disease, and 24.3% for patients with stage IV thymoma. The authors concluded that surgery and postoperative radiation treatment should be standard care measures for patients with stage II or III thymoma, but that further research was needed to establish whether this is true for stage I disease. The evidence also indicated that female patients, those with early stage thymoma, and patients who underwent surgical extirpation of the neoplasm tended to have a more favorable prognosis.

Relapse after primary therapy for a thymoma may occur after 10-20 years. Therefore, long-term follow-up probably should continue to be performed throughout the patient's life.

Complications (eg, radiation pericarditis, radiation pneumonitis, pulmonary fibrosis) following postoperative radiation therapy have been reported. Clinicians must consider carefully the risk versus benefit ratio of adjuvant radiation therapy because deaths from these complications have been reported.

Prognosis is worse for patients with symptomatic thymomas because these patients are more likely to have a malignant thymoma. The single most important factor predicting the outcome of patients with thymomas is evidence of invasion. Assess histologic characteristics, such as microscopic capsular^[12] invasion. The surgeon should perform a gross inspection. Cellular characteristics are inconsequential because they have no impact on patient treatment. Because of the well-documented propensity for late recurrences, discuss long-term survival in terms of a 10-year follow-up after treatment of the thymoma. A study conducted by the Memorial Sloan Kettering Cancer Center (1995) reported 5-year and 10-year survival rates to corresponding stages of thymomas.^[15]

Thymomas have been associated with the development of second malignancies. In a review of the Surveillance, Epidemiology, and End Results (SEER) database of thymoma cases in the United States (1973-1988), 849 cases were identified, of which 66 were found to have second malignancies. In this study, there was an excess occurrence of non-Hodgkin lymphoma and soft tissue sarcomas but no other specific cancers. Notably, an increase in digestive system cancers (colon/rectum, stomach, esophagus, liver/biliary tract) occurred; however, these increases where not statistically significant.

Table 3. Survival of Thymoma by Stage: The Memorial Sloan Kettering Experience (Open Table in a new window)

With the advent of video-assisted minimally invasive surgery, many of the traditional thoracic procedures have been abandoned. Cases of video-assisted thoracoscopy have been described; however, no long-term results are available. Roviaro et al performed video thoracoscopy on 6 patients with thymomas; however, they did not describe the extent of resection, size of tumor, or stage of tumor, and long-term follow-up data are unavailable.^[17] Kaiser advocated the use of transcervical dissection in conjunction with video thoracoscopy, allowing better exposure.^[18] Mack presented a series of photographs of thymus glands removed using thoracoscopy.^[19] These photographs confirmed the thymus gland can be resected completely by experienced surgeons. Long-term follow-up data are required to determine the true efficacy of this procedure compared with traditional thymectomy.

Studies have investigated the molecular changes in thymomas. In one study, 10 out of 12 thymomas exhibited epidermal growth factor receptor (EGFR) expression. This information would be useful in selecting patients that may benefit from EGFR inhibitors as part of their treatment regimen. Other areas of investigation include apoptosis-related markers, such as p63, a member of the p53 family. p63 was found to be expressed in virtually all thymomas. Further research pertaining to the biology of thymomas will allow more adequate approaches to treatment.