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© 1999 American Society for Clinical Oncology Treatment of Invasive Thymoma With Single-Agent IfosfamideFrom the Departments of Oncology and Surgery, Guy's Hospital, and the Brook Hospital, London; the Royal Devon and Exeter Hospital, Exeter; the Royal Sussex Hospital, Brighton; and Pembury Hospital, Turnbridge Wells, England. Address reprint requests to M.S. Highley, MD, Department of Cancer Medicine, Ninewells Hospital, Dundee DD1 9SY, United Kingdom.
PURPOSE: To evaluate single-agent ifosfamide in the treatment of invasive thymoma. PATIENTS AND METHODS: Fifteen patients (eight male and seven female) with histologically confirmed invasive thymoma were treated. The median age was 48 years (range, 23 to 76 years). Four patients had stage III disease, seven patients had stage IVa disease, and four patients had stage IVb disease. The most common histologic type was lymphoepithelial. Seven patients had received prior treatment, including one patient who received chemotherapy. Ifosfamide 1.5 g/m2 was given on days 1 to 5, with mesna as a uroprotector. RESULTS: Thirteen patients were assessable for response. Five complete responses (38.5%; 95% confidence interval [CI], 17.7% to 64.5%) and one partial response (7.7%; 95% CI, 1.4% to 33.3%) were seen. The median duration of complete response was 66+ months (range, 25 to 87 months), and the estimated survival rate 5 years after ifosfamide treatment was 57% (SE, 32% to 79%). The most frequent toxicities were nausea, vomiting, and leucopenia, but these were well tolerated. CONCLUSION: Single-agent ifosfamide possesses significant activity against invasive thymoma and is comparable to currently used combination regimens. The inclusion of ifosfamide in combination therapy, particularly in place of cyclophosphamide in regimens such as cisplatin, doxorubicin, and cyclophosphamide, needs to be evaluated.
THYMOMAS ARE RARE mediastinal tumors that comprise 0.2% to 1.5% of all malignancies, although they are the most common primary anterior mediastinal tumors that occur in adults.1 They are associated with a variety of autoimmune conditions, particularly myasthenia gravis. The strongest prognostic factor is the extent of local invasion at the time of diagnosis. Most thymomas are encapsulated or noninvasive at the time of presentation, and complete surgical excision is adequate treatment. However, the tumor exhibits locally invasive or metastatic behavior in approximately one third of patients; for these patients, radiotherapy alone is not sufficient. In the study of Curran et al,2 nine of 20 patients (45%) with stage III thymoma that was biopsied or subtotally resected before postoperative radiotherapy developed recurrences within 5 years, four within the mediastinum and five in the lungs, pleura, or bones. Entire hemithorax irradiation can delay recurrent disease in the pleura but does not prolong survival.3,4 Chemotherapy is an essential treatment modality in patients with stage III and IV disease, and an increased number of publications on this aspect of management have appeared in the last 10 years. The rarity and long natural history of thymoma dictated that the first indications of the effectiveness of chemotherapy emerged from case reports. A review of the early data, published in 1986, suggests that cisplatin (five responses in five cases) and corticosteroids (11 responses in 13 cases) were the most active single agents, and that the activity of single-agent alkylators is poor.5 However, in a subsequent prospective clinical trial of cisplatin 50 mg/m2 every 3 weeks, only modest activity was described, with a partial response rate of two of 20 (10%) and a 2-year survival rate of 39%.6 There are little data concerning the activity of ifosfamide in thymoma. A subjective improvement was reported in one of two patients treated with single-agent ifosfamide in 1975.7 The use of ifosfamide combined with cisplatin, or methotrexate and etoposide, as second-line therapy after the initial failure of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP plus bleomycin, respectively, was unsuccessful.8 The regimens of etoposide and ifosfamide, and etoposide, ifosfamide, and cisplatin (VIP) similarly failed to produce responses in two and three patients, respectively, all of whom had experienced disease progression after cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC), although two patients who received VIP remained stable for 2 and 6 months.9 We report our experience of single-agent ifosfamide in invasive thymoma.
Between July 1984 and July 1996, 15 patients (eight male and seven female) with histologically proven stage III or IV invasive thymoma received single-agent ifosfamide. All patients had an Eastern Cooperative Oncology Group performance status of 0 to 2, and although not part of a phase II study, were evaluated prospectively. Two patients with thymic carcinoma were also treated but were analyzed separately. Before chemotherapy, a full physical examination, blood count, biochemical screen, chest x-ray, and a computed tomography (CT) scan of the thorax were performed. If indicated on clinical or biochemical grounds, isotope bone scans (with confirmatory x-rays) and ultrasound or CT scans of the liver were assessed. Thoracotomy was not routinely undertaken before chemotherapy. The staging criteria of Masaoka et al10 were used. Two different regimens of ifosfamide administration were used, and mesna was given as a sulfhydryl group donator to prevent urothelial toxicity. Fourteen patients, including those with thymic carcinoma, received 400 mg of mesna as an intravenous bolus, ifosfamide 1.5 g/m2 in 500 mL of 0.9% NaCl over 30 minutes, and then mesna 1.0 g/m2 in 1,000 mL of 0.9% NaCl infused over 7.5 hours daily on days 1 to 5. Three patients received 2 g of mesna as an intravenous bolus followed by ifosfamide 1.5 g/m2 and mesna 1.5 g/m2 in 3,000 mL of 5% dextrose/0.9% NaCl over 24 hours on days 1 to 5; mesna 1.5 g/m2 in 3,000 mL of 5% dextrose/0.9% NaCl over 24 hours was then continued throughout days 6 to 8. In all patients, cycles were administered every 3 weeks. The blood count, biochemical screen, and chest x-ray were repeated before each cycle of treatment, and the chest CT scan was repeated after every third cycle. Nadir counts were not performed routinely. Toxicity was assessed after each course of chemotherapy and graded according to World Health Organization criteria.11 Each patient received at least two cycles of ifosfamide; treatment was continued for up to nine cycles in responding or stable patients and in those with residual disease after initial surgery. A complete response was defined as the disappearance of all objective evidence of disease, and a partial response was defined as a 50% or greater reduction in the sum of the products of perpendicular diameters of measurable lesions for at least 4 weeks. A 25% or greater increase in the sum of the products of perpendicular diameters of measurable disease or the appearance of new lesions was recorded as progressive disease. Survival was measured from the date of the first cycle of ifosfamide to the date of death (from all causes) or the last date when the patient was known to be alive. Duration of response was taken from the date of first documented response until the date of relapse or death. All patient characteristics are listed in Tables 1 and 2. The median age of those with invasive thymoma was 48 years (range, 23 to 76 years). Four patients had stage III, seven patients had stage IVa, and four patients had stage IVb invasive thymoma. The histologic classification of Rosai and Levine was used12; the most common type was lymphoepithelial (53.3%), with the epithelial (33.3%) and lymphoid (13.3%) varieties occurring less frequently. The most common presenting features were superior vena cava obstruction (SVCO), dyspnea, and chest pain. Two patients had associated systemic syndromes. Patient no. 12 presented with red cell aplasia and a hemoglobin of 5.8 g/dL, whereas patient no. 13 had a history of well-controlled myasthenia gravis and insulin-dependent diabetes mellitus. Four patients had been treated with surgery before ifosfamide therapy, one had received prior surgery with radiotherapy, and one patient had been given radiotherapy alone. Only one patient had been pretreated with chemotherapy (cisplatin and etoposide).
Thirteen patients with invasive thymoma were assessable for response. Five complete responses (38.5%; 95% confidence interval [CI], 17.7% to 64.5%) and one partial response (7.7%; 95% CI, 1.4% to 33.3%) were obtained, with an overall response rate of 46.2% (95% CI, 23.2% to 70.9%). Of the complete responders, patient no. 2 had a radiologic partial response after three cycles of ifosfamide (Fig 1); the residual mass was removed, shown not to contain viable tumor, and a further three cycles of ifosfamide were administered. Patient no. 3 died from bronchopneumonia in clinical and radiologic complete remission; an autopsy was not performed. Patient no. 4 presented with SVCO caused by a stage III thymoma, which was subtotally resected. Nine cycles of ifosfamide were administered for residual disease documented on CT scan, and a complete response was documented after three cycles. Patient no. 6 suffered mediastinal progression 66 months after responding to ifosfamide. She then received four cycles of cisplatin, resulting in a minor response of the mediastinal mass, which was subsequently excised together with pericardium containing deposits of thymoma. Two months after surgery, she developed cardiac tamponade necessitating a pericardiotomy; no malignant cells were seen in the pericardial fluid, reaccumulation of which has not occurred, and she remains well 22 months later. Patient no. 7 underwent initial difficult subtotal resection of a thymoma invading the pericardium, great vessels, and tissues in the root of the neck, and 6 days later ifosfamide was started for significant residual disease. His complete response extended for 68 months and was terminated by the development of a soft tissue mass anterior to the right hilum; he was re-treated with two further cycles of ifosfamide and achieved a partial response. This was followed by radical radiation therapy (55 Gy in 30 fractions). He remains in partial remission. One partial response was seen. Patient no. 8 remains well 30 months after commencing ifosfamide, although his chest x-ray and CT scan show a widened but stable mediastinum. For technical reasons, excision is not possible. The median duration of complete response is 66+ months (range, 25 to 87 months), and the median duration of overall response is 57+ months (range, 25 to 87 months).
Ifosfamide activity was also observed in three other patients with thymoma who were not included in the response analysis. In two, ifosfamide was started soon after radiotherapy or platinum-based treatment, and it was not possible to assess its contribution. From tissue obtained at mediastinoscopy in patient no. 1, a secondary adenocarcinoma was initially diagnosed, and radiotherapy was given (21 Gy in seven fractions over 10 days). However, review of the histology showed a thymoma, and single-agent ifosfamide was commenced 2 weeks after completion of radiotherapy. The SVCO resolved after one cycle, and the subsequent clinical complete response was confirmed at surgery. The diagnosis in patient no. 5 was at first uncertain and was determined to be possibly a lymphoma on the basis of mediastinoscopy and bone marrow examination, but a germ cell tumor could not be excluded. Three courses of empirical cisplatin and etoposide were administered, resulting in a minor response of the mediastinal mass. A further detailed assessment of the histology, however, showed a lymphoid thymoma, and ifosfamide was substituted. After three cycles, the SVCO resolved, the bone marrow infiltration was cleared, and the tumor mass was reduced by more than 50%. Thymectomy was performed after the fourth cycle, and one microscopic focus of viable tumor was found. A further five courses of ifosfamide were given. The patient remains in radiologic complete remission 135 months after diagnosis. The third case, patient no. 9, entered a partial remission after the first cycle of ifosfamide but progressed after the fourth and, therefore, was regarded as having progressive disease. She died shortly after one cycle of cisplatin and etoposide. Five patients with thymoma achieved stable disease during ifosfamide treatment. Patient no. 10 subsequently achieved a partial response of 3 months' duration with cisplatin, doxorubicin, and cyclophosphamide combination chemotherapy, whereas patient no. 11 entered a partial remission of 70+ months after further treatment with cisplatin, etoposide, and radiotherapy. A subtotal excision of a thymic mass invading the right lung and pleura of patient no. 12 was followed 1 month later by five cycles of ifosfamide, during which the residuum remained unchanged, but no further RBC transfusions were required. Radiotherapy was then administered and stability maintained for 37 months. After debulking a thymoma surrounding the left brachiocephalic vein and left phrenic nerve, six cycles of ifosfamide were given to patient no.13, resulting in 17 months of stable disease before radiotherapy was required for disease progression. Patient no. 14 presented with a large mediastinal mass. At surgery, this was found to be encasing the left brachiocephalic vein and infiltrating the pericardium and upper lobe of the left lung. Subtotal resection was followed by 40 Gy of radiotherapy in 20 fractions over 4 weeks to residual disease. Nine months later, the patient developed extensive bilateral pleural metastases with tumor involving the left lung, and ifosfamide was commenced. Patient no. 15 progressed through ifosfamide but attained a partial response with radiotherapy that lasted 3 months.
For patients with invasive thymoma, the 2- and 5-year Kaplan-Meier survival rates after ifosfamide therapy were 73% (SE, 48% to 89%) and 57% (SE, 32% to 79%) respectively, with a median survival of 51+ months (Fig 2). Survival was not significantly influenced by the histologic type or stage of the thymoma, the largest differences being between stages III and IVa (5-year survival of 100% v 40%; log-rank test
Two patients with thymic carcinoma were treated. Patient no. 16 remained static through five cycles of ifosfamide; his treatment was then changed to cisplatin 100 mg/m2 every 3 weeks, and he received three cycles with continued stable disease. He showed radiologic signs of slow disease progression 8 months after starting ifosfamide; after 11 months of further observation, prednisolone was commenced, with resolution of a pleural effusion and stability of mediastinal and hilar masses. Patient no. 17 had stable disease after three cycles of ifosfamide but experienced disease progression after a further cycle, and cisplatin 100 mg/m2 every 3 weeks was initiated.
Toxicity
Patient no. 1 developed dyspnea on exertion after the second cycle of ifosfamide. Respiratory function tests at this time showed a transfer factor of 75% of the predicted value, which fell to 55% after the fourth course. A CT scan showed an alteration in the lung values suggestive of pulmonary fibrosis in an area corresponding to the radiation fields. The ifosfamide was discontinued because of the risk of enhancing the radiation reaction, and the patient proceeded to thoracotomy. A subsequent CT scan showed complete resolution of the lung changes, and 9 months after the last cycle of ifosfamide, the respiratory function tests returned to the predicted normal values.
Previous accounts of single-agent alkylators in invasive thymoma have been restricted to small series of case reports. The early use of nitrogen mustard produced mixed results,13,14 although Wilkins et al15 described responses in the two patients treated in their study. Consecutive chlorambucil and cyclophosphamide both failed to produce a response,16 and in a later report, unresponsiveness to single-agent chlorambucil and nitrogen mustard was described.17 Alkylators, mainly cyclophosphamide, have also been used in multiple-agent regimens, including CHOP, the basis of most early combinations. Goldel et al8 administered CHOP or CHOP/bleomycin to 13 patients as first-line chemotherapy, and five complete responses were observed. Three complete responses and one partial response were achieved in six patients using cyclophosphamide, vincristine, and prednisone (COP), or COP and procarbazine (COPP), and in two additional patients, alternating COPP/cisplatin, vinblastine, and bleomycin was administered with one complete response. Two additional investigations of CHOP, both involving three patients, led to three complete responses in one study3 and one complete and one partial response in the other.18 Evans et al19 reported partial responses to COPP in four of five patients, and after the administration of a combination of cyclophosphamide, lomustine, and vincristine, with or without prednisolone, four complete responses and one partial response in nine patients were observed by Daugaard et al.20 The contribution of cyclophosphamide is difficult to assess in these regimens, as high-dose corticosteroids were also administered. There have been multiple case reports of responses to corticosteroids, including activity in chemotherapy- and radiotherapy-resistant disease. In one series of 18 patients, 14 (77%) responded to corticosteroids alone.21 The true effectiveness of corticosteroids has been questioned; they may have no activity against malignant epithelial cells and exert only a lympholytic effect.22 Combination regimens containing alkylating agents without corticosteroids have also been used. Boston17 found transient responses to nitrogen mustard, vincristine, procarbazine, and vinblastine, and a complete response to cyclophosphamide and doxorubicin lasting more than 13 months has been described.23 The combination of cyclophosphamide, doxorubicin, and vincristine has been used successfully; one article reported two complete responses of 7 and 8 months duration,24 and a second reported two complete and three partial responses among five patients.25 More recently, the successful collective use of cisplatin, doxorubicin, and cyclophosphamide in ovarian and non–small-cell lung cancers and the growing experience of these agents in thymoma has led to larger studies of this combination. Loehrer et al,22 in association with the Southeastern Cancer Study Group, Southwest Oncology Group, and Eastern Cooperative Oncology Group, has pioneered the regimen of cisplatin 50 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (PAC) in thymoma. PAC was administered at three weekly intervals to 30 assessable patients with extensive disease or with limited disease that had progressed after radiotherapy. None of the patients had received prior chemotherapy. Three complete and 12 partial responses were seen, with an overall response rate of 50%. The median duration of response was 11.8 months, median survival was 37.7 months, and the 2- and 5-year survival rates were 64.5% and 32%, respectively. In a second study, the use of PAC followed by radiotherapy in 23 assessable patients with limited, but unresectable thymoma was investigated.26 Patients had not received previous chemotherapy or mediastinal radiotherapy. There were five complete and 11 partial responses after PAC, leading to an overall response rate of 69.6%. A further improvement was seen in five patients after radiotherapy. All patients with objective responses progressed within 2 years of chemotherapy. The median survival was 93 months, and the 5-year survival rate 52.5%. The most frequent toxicity was myelosuppression. Three of 26 patients who were assessable for toxicity developed cardiovascular disturbances after PAC, and there was one case of radiation pneumonitis, although such side effects are also seen after radiotherapy alone. In another study, cisplatin (80 mg/m2 on day 1), doxorubicin (45 mg/m2 on day 1), and cyclophosphamide (800 mg/m2 on day 1) were combined with etoposide (80 mg/m2 on days 1 to 3) and administered with granulocyte colony-stimulating factor. Six partial responses but no complete responses were seen in 14 patients with thymoma or thymic carcinoma.27 Fornasiero et al9 have used the ADOC regimen comprising cisplatin 50 mg/m2 and doxorubicin 40 mg/m2 on day 1, vincristine 0.6 mg/m2 on day 3, and cyclophosphamide 700 mg/m2 on day 4 every 3 weeks. In 37 patients with stage III or IV disease, the complete response rate was 43%, with an overall response of 91.8%. The median survival was 15 months (range, 5 to 96+ months). The median duration of complete response was 27 months (range, 3 to 96+ months), and median duration of partial response was 9.5 months (range, 2 to 30 months). The main toxicity was nausea/vomiting. Chemotherapy, until recently confined to the treatment of metastatic disease or local recurrence after radiotherapy and surgery, is now used in the neoadjuvant setting, emphasizing the increasing importance of this modality of treatment. As a result, easier, less extensive surgical resections are necessary and smaller radiotherapy fields can be used. Berruti et al28 treated six patients with stage III or IVa invasive thymoma using four or five cycles of ADOC. Five showed partial responses and underwent radical surgery followed by two additional cycles of ADOC. Rea et al29 used three to five cycles of the same regimen in 16 patients, 13 of whom had stage III and three of whom had stage IVa disease, observing seven complete and nine partial responses. Eleven patients, including all those with a complete remission, underwent a radical resection, and five underwent a partial resection. No residual tumor was found histologically in five patients, who received an additional three cycles of chemotherapy; the remainder, with residual disease, received radiotherapy. One of the patients who was free of disease at operation died after 5 years, whereas five of those found to have microscopic disease subsequently relapsed: three locally, one in the liver, and one in bone. The median survival was 66 months and the 3-year survival was 70%. A prospective phase II study in patients with stage III or IVa disease has recently been initiated at the M.D. Anderson Cancer Center using three cycles of induction PAC plus prednisolone.30 A preliminary report describes 12 treated patients, eight of whom subsequently had a complete resection, with two achieving a pathologic complete remission. Our results show that single-agent ifosfamide has significant activity in invasive thymoma, with a complete response rate of 38.5% and an overall response rate of 46.2%; this compares favorably with single-agent cisplatin. Moreover, the complete responses to ifosfamide have proved durable, with a median duration of 66+ months (range, 25 to 87 months). The median survival has not yet been reached, but the estimated 2- and 5-year survivals are 73% and 57%, respectively. The two patients with thymic carcinoma did not respond. The treatment was well tolerated, with acceptable toxicity. The response rate obtained with single-agent ifosfamide is comparable to that of PAC in patients with extensive or relapsed thymoma (46% v 50%), although the median duration of overall response (57+ months v 11.8 months) and median survival (51+ months v 37.7 months), are longer.22 Moreover, single-agent ifosfamide, like PAC, shows a trend to lower response rates but extended duration of response and survival compared with ADOC (response rate, 91.8%; median duration of overall response, 12 months; median survival, 12.5 months). The development of a complete response was the most important factor influencing survival, a feature also found with ADOC.31 The preliminary results of a prospective study of four cycles of VIP (cisplatin 20 mg/m2/d, ifosfamide 1.2 g/m2/d, and etoposide 75 mg/m2/d on days 1 to 4) administered every 3 weeks in advanced thymoma have recently been published.32 Six of 14 patients (43%) entered a partial remission and eight remained stable. There was some concern regarding toxicity, and the authors concluded that these initial results cast doubt on the use of VIP as standard first-line therapy. The place of chemotherapy in the management of this disease is becoming clearer, and further investigation of the role of ifosfamide in combination chemotherapy regimens, particularly as an alternative to the inclusion of cyclophosphamide, is warranted. The use of the cisplatin, doxorubicin, and ifosfamide combination is one example, but such studies need to be performed in a multi-institutional setting.
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Curran WJ, Kornstein MJ, Brooks JJ, et al: Invasive thymoma: The role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 6:1722-1727, 1988 3. Uematsu M, Kondu M: A proposal for treatment of invasive thymoma. Cancer 58:1979-1984, 1986[Medline] 4. Uematsu M, Yoshida H, Kondo M, et al: Entire hemithorax irradiation following complete resection in patients with stage II-III invasive thymoma. Int J Radiat Oncol Biol Phys 35:357-360, 1996[Medline] 5. Hu E Levine J: Chemotherapy of malignant thymoma: Case report and review of the literature. Cancer 57:1101-1104, 1986[Medline] 6. Bonomi PD, Finklestein D, Aisner S, et al: EST 2582: Phase II trial of cisplatin in metastatic or recurrent thymoma. Am J Clin Oncol 16:342-345, 1993[Medline] 7. Dabrowska W: Results of chemotherapy in patients with thymoma according to the records at the Institute of Oncology in Warsaw in the years 1958-1973. Nowotwory 25:107-113, 1975[Medline] 8. Goldel N, Boning L, Fredrik A, et al: Chemotherapy of invasive thymoma: A retrospective study of 22 cases. Cancer 63:1493-1500, 1989[Medline] 9. Fornasiero A, Daniele O, Ghiotto C, et al: Chemotherapy for invasive thymoma. Cancer 68:30-33, 1991[Medline] 10. Masaoka A, Monden Y, Nakahara K, et al: Follow-up study of thymomas with special references to their clinical stages. Cancer 48:2485-2492, 1981[Medline] 11. World Health Organization: WHO handbook for reporting results of cancer treatment. Geneva, Switzerland, World Health Organization, WHO offset publication 48, 1979 12. Rosai J, Levine GD: Tumors of the thymus. Washington, DC, Armed Forces Institute of Pathology, 1976 13. Effler DB, McCormack LJ: Thymic neoplasms. J Thorac Surg 31:60-82, 1956 14. Lattes R: Thymoma and other tumors of the thymus. Cancer 15:1224-1260, 1962 15. Wilkins EW Jr Edmunds LH Jr Castleman B: Cases of thymoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg 52:322-330, 1966[Medline] 16. Mottet NK: Malignant thymoma. Am J Clin Path 41:61-71, 1964[Medline] 17. Boston B: Chemotherapy of invasive thymoma. Cancer 38:49-52, 1976[Medline] 18. Späth G, Inniger R, Huth Ch, et al: Thymome: Eine retrospektive Studie über 48 Fälle. Chirurg 58:529-536, 1987[Medline] 19. Evans WK, Thompson DM, Simpson WJ, et al: Combination chemotherapy in invasive thymoma: Role of COPP. Cancer 46:1523-1527, 1980[Medline] 20. Daugaard G, Hansen HH, Rirth M: Combination chemotherapy for malignant thymoma. Ann Intern Med 99:189-190, 1983 21. Kirkove C, Berghmans J, Noel H, et al: Dramatic response of recurrent invasive thymoma to high doses of corticosteroids. Clin Oncol 4:64-66, 1992
22.
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. J Clin Oncol 12:1164-1168, 1994 23. Butler WM, Diehl LF, Taylor HG, et al: Metastatic thymoma with myasthenia gravis. Cancer 50:419-422, 1982[Medline]
24.
Loehrer PJ, Bonomi P, Goldman S, et al: Remission of invasive thymoma due to chemotherapy. Chest 87:377-380, 1985 25. Kosmidis PA, Iliopoulos E, Pentea S: Combination chemotherapy with cyclophosphamide, adriamycin, and vincristine in malignant thymoma and myasthenia gravis. Cancer 61:1736-1740, 1988[Medline] 26. 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 15:3093-3099, 1997[Abstract]
27.
Oshita F, Kasai T, Kurata T, et al: Intensive chemotherapy with cisplatin, doxorubicin, cyclophosphamide, etoposide and granulocyte colony-stimulating factor for advanced thymoma or thymic cancer: Preliminary results. Jpn J Clin Oncol 25:208-212, 1995
28.
Berruti A, Borasio P, Roncari A, et al: Neoadjuvant chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide (ADOC) in invasive thymomas: Results in six patients. Ann Oncol 4:429-431, 1993 29. Rea F, Sartori F, Loy M, et al: Chemotherapy and operation for invasive thymoma. Cardiovasc Surg 106:543-549, 1993 30. Komaki R, Putnam JB Jr Shin DM, et al: Thymic neoplasms. Curr Opin Oncol 9:156-160, 1997[Medline] 31. Fornasiero A, Daniele O, Ghiotto C, et al: Chemotherapy of invasive thymoma. J Clin Oncol 8:1419-1423, 1990[Abstract] 32. Loehrer PJ, Jiroutek M, Aisner S, et al: Phase II trial of etoposide (V), ifosfamide (I) plus cisplatin (P) in patients with advanced thymoma (T) or thymic carcinoma (TC): Preliminary results from an ECOG coordinated intergroup trial. Proc Am Soc Clin Oncol 17:30a, 1998 (abstr 47) Submitted October 7, 1998; accepted April 22, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 = 2.981; P = .0842), and between lymphoepithelial and epithelial histologies (5-year survival of 70% v 20%; log-rank test 
