THYMOMA- TREATMENT

Thymoma

Stage I and Stage II Thymoma

Excellent long-term survival can be obtained following complete surgical excision for a pathologic stage I thymoma. There appears to be no benefit to adjuvant radiation therapy following complete resection of encapsulated noninvasive tumors.[1,2] For patients with stage II thymomas with pathologically demonstrated capsular invasion, adjuvant radiation therapy following complete surgical excision has been considered a standard of care despite the lack of prospective clinical trials.[3,4]

Most studies use 40 Gy to 70 Gy with standard fractionation scheme (1.8–2.0 Gy/fraction). Some, but not all, retrospective clinical studies show improved local control and survival with the addition of postoperative radiation therapy (PORT).[5-8][Level of evidence: 3iiiDiv] More recent retrospective studies have found no outcome difference in patients treated with or without PORT following complete resection of the thymic tumor.[8-12]

In the largest series reported to date, data was obtained from 1,320 Japanese patients.[8] The Masaoka clinical stage was found to correlate well with prognosis of thymoma and thymic carcinoma. Patients with stage I thymoma were treated with surgery only, and patients with stage II thymoma underwent surgery and additional radiation therapy. Prophylactic mediastinal radiation therapy did not appear to prevent local recurrences effectively in patients with totally resected stage II thymoma.

The role and risks of adjuvant radiation therapy for patients with completely resected stage II thymomas need further study. To avoid the potential morbidity and costs associated with thoracic radiation, PORT may be reserved for stage II patients where adjacent organs are within a few millimeters or involve of the surgical margin as determined by both pathological and intraoperative findings.

Operable or Potentially Operable Stage III and Stage IVA Thymoma

Stage III thymoma may be difficult to identify prior to surgery as subtle invasion to the adjacent organs may only be identified at the time of mediastinal exploration. Such patients often receive aggressive surgical resection including wide surgical margins with consideration of adjuvant radiation therapy. Invasion of local organs can be apparent on pretreatment computed tomographic imaging. Such patients may be offered combined modality treatment with chemotherapy followed by surgery and/or radiation therapy.[13-20] The optimal strategy for induction therapy, which minimizes operative morbidity and mortality and optimizes resectability rates and ultimately survival, currently remains unknown.

Two large series have reported outcomes. In the first study, data was obtained from 1,320 Japanese patients.[8] The Masaoka clinical stage was found to correlate well with prognosis of thymoma and thymic carcinoma. Patients with stage III thymoma underwent surgery and additional radiation therapy. Patients with stage IV thymoma were treated with radiation therapy or chemotherapy. For patients with stage III or stage IV thymoma, the 5-year survival rates were 93% for patients treated with total resection, 64% for patients treated with subtotal resection, and 36% for patients whose disease was inoperable. Prophylactic mediastinal radiation therapy did not appear to prevent local recurrences effectively in patients with totally resected stage III thymoma. Adjuvant therapy including radiation or chemotherapy did not appear to improve the prognosis in patients with totally resected stage III or stage IV thymoma.[8]

In the second study, 1,334 patients diagnosed and treated between 1973 and 2005 were identified in a SEER database. At a relatively short median follow-up of 65 months, radiation therapy did not appear to increase the risk of cardiac mortality or secondary malignancy. Routine use of PORT did not appear to improve long-term survival.[20]

Most invasive thymomas have been found to be relatively sensitive to cisplatin-based combination chemotherapy regimens. The combinations that follow have reported objective response rates from 79% to 100% with subsequent resectability rates ranging between 36% and 69%:[13-19,21]

·         The combination of cisplatin, doxorubicin, and cyclophosphamide (PAC) with or without prednisone.

·         The combination of cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC).

·         The combination of cisplatin, etoposide, and epirubicin.

Long-term survival rates following induction chemotherapy and surgery with or without radiation therapy and consolidation chemotherapy have ranged from 50% at 4 years, 77% at 7 years and, respectively, 86% and 76% for stage III and IV patients at 10 years in different published series.[14,16,17,22]

However, similar results have been reported with preoperative radiation therapy without chemotherapy, particularly if great vessels are involved (5-year overall survival rate of 77% and 10-year OS rate of 59%).[23,24]

An intergroup trial conducted in the United States reported a predicted 5-year OS rate of 52% in 26 patients receiving the PAC chemotherapy regimen followed by radiation therapy without surgery.[18]

The role of surgical debulking for patients with either stage III or stage IVA disease is controversial. Phase II data suggests that prolonged survival can be accomplished with chemotherapy and radiation therapy alone in many patients presenting with locally advanced or even metastatic thymoma.[18] Therefore, the value of surgery may be questioned if complete, or at the very least, near complete extirpation cannot be accomplished.

Standard treatment options for patients with operable disease include the following:

1.     En bloc surgical resection.

2.     PORT may be considered, especially for patients with close or involved surgical margins and for stage III and stage IVA patients.

3.     Induction chemotherapy followed by surgery with or without radiation.

Standard treatment options for patients with inoperable disease (stage III and stage IV with vena caval obstruction, pleural involvement, pericardial implants, etc.) include the following:

1.     Induction chemotherapy followed by surgery or radiation.

2.     Induction chemotherapy followed by surgery and radiation.

3.     Radiation therapy.

4.     Chemotherapy.

Treatment options under clinical evaluation:

Areas of active clinical evaluation for patients with thymoma include the following:

·         New drug regimens.

·         Variation of drug doses in current regimens.

·         New radiation therapy schedules and techniques.

References

1.     Maggi G, Casadio C, Cavallo A, et al.: Thymoma: results of 241 operated cases. Ann Thorac Surg 51 (1): 152-6, 1991. [PUBMED Abstract]

2.     Masaoka A, Monden Y, Nakahara K, et al.: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48 (11): 2485-92, 1981. [PUBMED Abstract]

3.     Pollack A, Komaki R, Cox JD, et al.: Thymoma: treatment and prognosis. Int J Radiat Oncol Biol Phys 23 (5): 1037-43, 1992. [PUBMED Abstract]

4.     Ogawa K, Uno T, Toita T, et al.: Postoperative radiotherapy for patients with completely resected thymoma: a multi-institutional, retrospective review of 103 patients. Cancer 94 (5): 1405-13, 2002. [PUBMED Abstract]

5.     Ariaratnam LS, Kalnicki S, Mincer F, et al.: The management of malignant thymoma with radiation therapy. Int J Radiat Oncol Biol Phys 5 (1): 77-80, 1979. [PUBMED Abstract]

6.     Penn CR, Hope-Stone HF: The role of radiotherapy in the management of malignant thymoma. Br J Surg 59 (7): 533-9, 1972. [PUBMED Abstract]

7.     Curran WJ Jr, Kornstein MJ, Brooks JJ, et al.: Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 6 (11): 1722-7, 1988. [PUBMED Abstract]

8.     Kondo K, Monden Y: Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 76 (3): 878-84; discussion 884-5, 2003. [PUBMED Abstract]

9.     Mangi AA, Wright CD, Allan JS, et al.: Adjuvant radiation therapy for stage II thymoma. Ann Thorac Surg 74 (4): 1033-7, 2002. [PUBMED Abstract]

10.                       Singhal S, Shrager JB, Rosenthal DI, et al.: Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation. Ann Thorac Surg 76 (5): 1635-41; discussion 1641-2, 2003. [PUBMED Abstract]

11.                       Thomas CR, Wright CD, Loehrer PJ: Thymoma: state of the art. J Clin Oncol 17 (7): 2280-9, 1999. [PUBMED Abstract]

12.                       Berman AT, Litzky L, Livolsi V, et al.: Adjuvant radiotherapy for completely resected stage 2 thymoma. Cancer 117 (15): 3502-8, 2011. [PUBMED Abstract]

13.                       Macchiarini P, Chella A, Ducci F, et al.: Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer 68 (4): 706-13, 1991. [PUBMED Abstract]

14.                       Berruti A, Borasio P, Gerbino A, et al.: Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience. Br J Cancer 81 (5): 841-5, 1999. [PUBMED Abstract]

15.                       Rea F, Sartori F, Loy M, et al.: Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 106 (3): 543-9, 1993. [PUBMED Abstract]

16.                       Shin DM, Walsh GL, Komaki R, et al.: A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 129 (2): 100-4, 1998. [PUBMED Abstract]

17.                       Kim ES, Putnam JB, Komaki R, et al.: Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 44 (3): 369-79, 2004. [PUBMED Abstract]

18.                       Loehrer PJ Sr, Chen M, Kim K, et al.: Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 15 (9): 3093-9, 1997. [PUBMED Abstract]

19.                       Loehrer PJ Sr, Kim K, Aisner SC, et al.: Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 12 (6): 1164-8, 1994. [PUBMED Abstract]

20.                       Fernandes AT, Shinohara ET, Guo M, et al.: The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol 5 (9): 1454-60, 2010. [PUBMED Abstract]

21.                       Yokoi K, Matsuguma H, Nakahara R, et al.: Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone. J Thorac Oncol 2 (1): 73-8, 2007. [PUBMED Abstract]

22.                       Lucchi M, Melfi F, Dini P, et al.: Neoadjuvant chemotherapy for stage III and IVA thymomas: a single-institution experience with a long follow-up. J Thorac Oncol 1 (4): 308-13, 2006. [PUBMED Abstract]

23.                       Yagi K, Hirata T, Fukuse T, et al.: Surgical treatment for invasive thymoma, especially when the superior vena cava is invaded. Ann Thorac Surg 61 (2): 521-4, 1996. [PUBMED Abstract]

24.                       Akaogi E, Ohara K, Mitsui K, et al.: Preoperative radiotherapy and surgery for advanced thymoma with invasion to the great vessels. J Surg Oncol 63 (1): 17-22, 1996. [PUBMED Abstract]