Chemotherapy of Invasive Thymoma By Adriano Fornasiero, Otello Daniele, Cristina Ghiotto, Francesco Sartori, Federico Rea, Mario Piazza, Luciano Fiore-Donati, Paolo Morandi, Savina M.L. Aversa, Adriano Paccagnella, Giovanni L. Pappagallo, and Mario V. Fiorentino Thirty-two patients with stage III or IV invasive thymoma (14 women and 18 men; median age, 40 years) were treated at the Padua Medical Oncology Department from 1977 to 1988. All patients received the following chemotherapy in 4-day courses: 50 mg/m' of cisplatin intravenously (IV) and 40 mg/m' of doxorubicin IV on day 1; 0.6 mg/m' of vincristine IV 2 on day 3; and 700 mg/m of cyclophosphamide IV on day 4 (ADOC). The courses were repeated every 3 weeks, and toxic effects were tolerable. The radiologically defined overall clinical response rate (complete plus partial response) was 91% with 47% clinical
INVASIVE
THYMOMAS are relatively rare tumors, representing about 0.2% to 1.5% of all malignancies. The main cause of death is due to locoregional spread and, less frequently, distant metastases. 1-3 Surgery and radiotherapy have so far been the main treatment modalities for invasive thymoma with an overall 5-year survival rate of about 25%.4-7 Chemotherapy has usually been administered only after surgical and/or radiation therapy to patients with unresectable or progressive disease. Combination chemotherapy, particuhave proven larly platinum-containing regimens, 8 -17 disease. invasive in effective be to In this report, the results of a prospective trial of systemic treatment of invasive thymoma in 32 patients (11 of whom have been previously described") are presented. MATERIALS AND METHODS Thirty-two patients with invasive thymoma (14 women, 18 men; median age, 40 years; range, 22 to 64) were treated at our unit from 1977 to 1988. The pathologic classification was adopted according to the dominant cell type: epithelial (E), mixed lympho-epithelial 8 (LE), and lymphocytic. "" All the histologic sections were revised by one pathologist (MP) and immunohistochemical analysis was employed using monoclonal antibodies for epithelial membrane antigens (EMA; Ortho Diagnostic System Inc, Raritan, NJ), leukocyte common antigen (CD,, Dako; Dakopatts, Glostrup, Denmark), and cytokeratin (Dakopatts). A histologic review of cases that were problematic was done in cooperation with another pathologist (LFD).
complete remissions; median time to progression was 11 months (range, 0 to 96) and the median estimated (Kaplan-Meier) progression-free interval was 22 months. Five of the 15 clinical complete remissions were pathologically confirmed at thoracotomy. We believe the ADOC regimen qualifies for adjuvant and preoperative treatment of invasive thymoma due to the high complete response and overall response rates. J Clin Oncol 8:1419-1423. o 1990 by American Society of Clinical Oncology.
Staging Clinical staging included a detailed medical history and physical examination, complete biochemical profile, complete blood count, serum iron, copper, fibrinogen, lactic dehydrogenase, erythrocyte sedimentation rate (as indicators of disease), screening for autoimmune disease, posteroanterior and lateral chest x-rays, chest and abdominal computed tomography (CT) scans, and bronchoscopy. The following classification system according to Masaoka et alzo was adopted: stage I: macroscopically encapsulated and exempt from microscopic capsular invasion; stage II: (A) gross invasion into surrounding fatty tissue or mediastinal pleura, (B) microscopic invasion into capsule; stage III: gross invasion into contiguous structures; stage IV: (A) pleural or pericardial dissemination, (B) lymphogenous or hematogenous metastases. Twelve patients were stage III, 10 were IVA, and 10 were IVB.
Associated Immune Pathologies Four patients exhibited autoimmune conditions: two had myasthenia gravis (electromyogram confirmed), one had progressive systemic sclerosis, and one systemic lupus erythematosus. Patient characteristics are described in Table 1.
From the Divisione di Oncologia Medica, Unith Locale Socio SanitariaN. 21, Padova;Istituto di Clinica Chirurgica I; Istituto di Anatomia Patologica, Universitb di Padova; Istituto di Anatomia Patologica; and Universith di Verona, Italy. Submitted February16, 1989; accepted March 12, 1990. Address reprint requests to Adriano Fornasiero, MD, Divisione di Oncologia Medica, Unith Locale Socio SanitariaN. 21, 35100, Padova,Italy. © 1990 by American Society of ClinicalOncology. 0732-183X/90/0808-0008$3.0/01
Journal of Clinical Oncology, Vol 8, No 8 (August), 1990: pp 1419-1423
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FORNASIERO ET AL 100
Table 1. Patient Characteristics Characteristic
No. of Patients
Sex Male Female Age in years Median (range) Cell type LE E Stage III IVa IVb
18 14 50
40 (22-64)
n
24 8 0
12 10 10
Treatment Modalities All patients were treated with a combination of 50 mg/m2 of cisplatin intravenously (IV) and 40 mg/m2 of doxorubicin IV on day 1, 0.6 mg/m 2 of vincristine IV on day 3, and 700 mg/mz of cyclophosphamide IV on day 4 (ADOC), as previously described." This cycle was repeated every 3 weeks. All patients undergoing at least two therapy cycles were assessable for response. Extent of surgery before treatment varied from complete resection of the tumor bulk in one patient and partial resection in two, to biopsy only after thoracotomy or during mediastinoscopy or CT in the others. Three patients received radiotherapy to the mediastinum as postoperative treatment using opposite anterior and posterior parallel fields, at doses ranging from 40 to 56 Gy. Previous single-agent chemotherapy (cyclophosphamide) had been administered in one patient. Completely resected patients were not treated with ADOC until relapse.
Response Evaluation Complete remission was defined as the disappearance of all clinically and radiologically detectable tumors. Partial remission was defined as a _ 50% decrease in the size of the main measurable or assessable lesions, without an increase in the size of any lesions or the appearance of new lesions. Stable disease was defined as less than 50% regression of measurable or assessable lesions with no new lesions appearing and no deterioration in patient performance. Duration of response and survival was measured from the start of therapy. The probability of complete remission has been related to patient characteristics (ie, age, sex, cell type, stage) using the logistic regression model. 21 The Cox regression model 22 was used to evaluate relationships between progression-free interval plus survival time and the above-mentioned patient characteristics.
RESULTS
Thirty-two patients (14 women, 18 men; median age, 40 years; range, 22 to 64) were treated with the described combination chemotherapy for measurable disease. A median of five courses (range, three to seven) was administered. Fifteen
12
24
36
months
Fig 1. Kaplan-Meier overall survival (32 patients); tick marks indicate censored patients.
patients (47% + 17%) attained a complete remission with ADOC, and 14 patients (44% ± 17%) achieved a partial remission, with an overall CR plus PR rate of 91% ± 10%. Eighteen patients progressed after a major response, with a median time to progression of 11 months (range, 0 to 96) and an estimated (Kaplan-Meier) median freedom-from-progression time of 22 months (Fig 1). Two patients showed stable disease (for 5 and 7 months, respectively), while one patient had disease progression during treatment. Twenty patients died, two without evidence of disease 38 and 27 months, respectively, after the end of chemotherapy: one from chronic obstructive lung disease and another from myocardial infarction. These patients, however, were not censored in the survival analysis. The median time to death was 17 months (range, 5 to 96), with an estimated (KaplanMeier) overall median survival of 15 months (Fig 1). When patient characteristics were analyzed in a multivariate fashion, stage III and the LE cell type were found to affect positively the probability of complete remission, while the achievement of a clinical complete remission was the only factor that influenced survival duration. None of Table 2. Results of Multivariate (Logistic and Cox's Regression) Analyses Variable
Clinical CR Achievement
Duration of Response
Duration of Survival
Male/female Age LE/E Stage III/IV CR/no CR
NS NS P= .030 P = .012 -
NS NS NS NS -
NS NS NS .092 .001
Abbreviation: CR, complete remission.
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1421
CHEMOTHERAPY OF INVASIVE THYMOMA
Fig 2. courses.
A patient exhibiting a pathologically complete remission; (A) x-ray before ADOC chemotherapy, and (B) after four
the variables considered in the analysis were shown to affect independently the duration of a major response (Table 2). Seven patients with clinico-radiologic complete response after ADOC chemotherapy underwent an explorative thoracotomy; a pathologically confirmed complete remission was found in five (Figs 2 and 3). We performed a right thoracotomy with superior lobectomy and removal of the thymic gland in one patient with
Fig 3. courses.
minimal residual disease after five courses of chemotherapy (Fig 4). The histologic examination was negative and only necrotic tissue was found. The ADOC regimen was well tolerated. Nausea, vomiting, and alopecia occurred at various degrees in all patients. Myelosuppression was the major drug-related toxicity: changes from World Health Organization 23 grade 0 at baseline to grade 2 or 3 occurred in 25 and eight patients,
A patient exhibiting a pathologically complete remission; (A) x-ray before ADOC chemotherapy, and (B) after three
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1422
Fig 4.
FORNASIERO ET AL
A patient exhibiting minimal residual disease; (A) x-ray before ADOC chemotherapy, and (B)after five courses.
respectively, for total WBC counts, and to grade 2 in three patients for hemoglobin levels. Renal and cardiac functions remained normal throughout the study; only two patients had a mild increase in serum creatinine.11 DISCUSSION
The treatment of invasive thymoma is usually performed by surgery and radiation therapy. Systemic treatment has generally been administered only to patients with unresectable or progressive disease. A recent review of the literature16 indicates that prednisone and cisplatin are the most active single agents in the treatment of invasive thymoma. Other cytotoxic agents have been used mostly in combination with these two drugs, although it is difficult to demonstrate their additional value. Radiotherapy has been frequently used as postoperative treatment or in nonoperable diseases, although it cannot prevent distant metastases and intrathoracic recurrence outside the radiation field.2 4 These 32 patients treated with the ADOC regimen represent the largest uniformly treated series reported. The encouraging results in the overall response rate (29 of 32 patients respond-
ing, ie, 91%) compare favorably with other reports. Recently, using the combination of doxorubicin, cyclophosphamide, and cisplatin (PAC), Loehrer et al reported good results (80% response in limited thymoma, 60% in extensive disease).17 Despite a high remission rate, however, long-term survival has not been generally achieved. In our series, three of the five patients reported in 1984 are alive and disease-free" with survival beyond 5 years. On the basis of these observations, chemotherapy is now delivered at our center as the primary treatment for thymoma, whereas the surgical approach is applied when maximum response to the ADOC regimen occurs. After resection of residual or suspicious lesions, radiation therapy or further chemotherapy are considered, depending on the histologic findings. 25 Seven patients have entered this preoperative study and a pathologic remission has been obtained in five. The ADOC and PAC chemotherapy regimens show the most efficacy in invasive or metastatic thymoma, and we suggest that trials of early (preoperative) administration of these regimens be extended.
REFERENCES 1. Batata MA, Martini N, Huvos AG, et al: ThymomasClinicopathologic features, therapy and prognosis. Cancer 34:389-396, 1974 2. Salyer WR, Eggleston JC: Thymoma: A clinical and pathological study of 65 cases. Cancer 37:229-249, 1976 3. Verley JM, Hollmann KH: Thymoma: A comparative
study of clinical stages, histologic features, and survival in 200 cases. Cancer 55:1074-1086, 1985 4. Maggi G, Giaccone G, Donadio M, et al: Thymomas: A review of 169 cases with particular reference to results of surgical treatment. Cancer 58:765-776, 1986 5. Ariaiatnan LS, Kalnicki S, Mincer F: The management
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 9, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1423
CHEMOTHERAPY OF INVASIVE THYMOMA of malignant thymoma with radiation therapy. Int J Radiat Oncol Biol Phys 5:77-80, 1979 6. Marks RD, Wallace KM, Pettit HA: Radiation therapy control of 9 patients with malignant thymoma. Cancer 41:117-119, 1978 7. Penn CRH, Hope-Stone HF: The role of radiotherapy in the management of malignant thymoma. Br J Surg 59:7, 1972 8. Boston B: Chemotherapy of invasive thymoma. Cancer 38:49-52, 1976 9. Cocconi G, Boni C, Cuomo A: A long-lasting response to cisplatinum in recurrent malignant thymoma: Case report. Cancer 49:1985-1987, 1982 10. Campbell MG, Pollard R, Al-Sarraf M: A complete response in metastatic malignant thymoma to cis-platinum, doxorubicin and cyclophosphamide. Cancer 98:1315-1317, 1981 11. Fornasiero A, Daniele O, Sperandio P, et al: Chemotherapy of invasive or metastatic thymoma: Report of 11 cases. Cancer Treat Rep 68:1205-1210, 1984 12. Chainian AP, Bhardwaj S, Meyer RJ, et al: Treatment of invasive or metastatic thymoma: Report of eleven cases. Cancer 47:1752-1761, 1981 13. Giaccone G, Musella R, Bertetto O, et al: Cisplatincontaining chemotherapy in the treatment of invasive thymoma: Report of five cases. Cancer Treat Rep 69:695-697, 1985 14. Daugaard G, Hansen HH, Rirth M: Combination chemotherapy for malignant thymoma. Ann Intern Med 99:189-190, 1983
15. Klippstein TH, Mitrov PS, Kochendorfer KJ, et al: Adriamycin and cisplatinum in invasive thymomas. Cancer Chemoth Pharmacol 13:78-81, 1984 16. Hu E, Levine J: Chemotherapy of malignant thymoma. Cancer 57:1101-1104, 1986 17. Loehrer PJ, Perez C, Roth IM, et al: Cisplatin (P) plus Adriamycin (A) plus cyclophosphamide (C) in limited and extensive thymoma: Preliminary results of an intergroup trial. Am Soc Clin Oncol Proc 7:199, 1988 (abstr) 18. Rosai J, Levine GD: Tumors of the thymus, in Atlas of Tumor Pathology, 2nd series, fascicle 13. Washington, DC, Armed Forces Institutes of Pathology, 1976 19. Lattes R: Thymoma and other tumors of the thymus. An analysis of 107 cases. Cancer 15:1224-1260, 1962 20. 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 21. Cox DR: Analysis of Binary Data. London, England, Methuen, 1970 22. Cox DR: Regression models and life tables. J R Stat Soc 34:187-220, 1972 23. Miller AB, Hoogstratten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981 24. Chainian AP, Holland JF, Bhardwaj S: Chemotherapy for malignant thymoma. Ann Intern Med 99:736, 1983 (letter) 25. Fornasiero A, Daniele O, Morandi P, et al: Neoadjuvant chemotherapy in invasive thymoma. Second International Congress on Neo-Adjuvant chemotherapy. Paris, 1988 (abstr US)
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 9, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
INVASIVE
THYMOMAS are relatively rare tumors, representing about 0.2% to 1.5% of all malignancies. The main cause of death is due to locoregional spread and, less frequently, distant metastases. 1-3 Surgery and radiotherapy have so far been the main treatment modalities for invasive thymoma with an overall 5-year survival rate of about 25%.4-7 Chemotherapy has usually been administered only after surgical and/or radiation therapy to patients with unresectable or progressive disease. Combination chemotherapy, particuhave proven larly platinum-containing regimens, 8 -17 disease. invasive in effective be to In this report, the results of a prospective trial of systemic treatment of invasive thymoma in 32 patients (11 of whom have been previously described") are presented. MATERIALS AND METHODS Thirty-two patients with invasive thymoma (14 women, 18 men; median age, 40 years; range, 22 to 64) were treated at our unit from 1977 to 1988. The pathologic classification was adopted according to the dominant cell type: epithelial (E), mixed lympho-epithelial 8 (LE), and lymphocytic. "" All the histologic sections were revised by one pathologist (MP) and immunohistochemical analysis was employed using monoclonal antibodies for epithelial membrane antigens (EMA; Ortho Diagnostic System Inc, Raritan, NJ), leukocyte common antigen (CD,, Dako; Dakopatts, Glostrup, Denmark), and cytokeratin (Dakopatts). A histologic review of cases that were problematic was done in cooperation with another pathologist (LFD).
complete remissions; median time to progression was 11 months (range, 0 to 96) and the median estimated (Kaplan-Meier) progression-free interval was 22 months. Five of the 15 clinical complete remissions were pathologically confirmed at thoracotomy. We believe the ADOC regimen qualifies for adjuvant and preoperative treatment of invasive thymoma due to the high complete response and overall response rates. J Clin Oncol 8:1419-1423. o 1990 by American Society of Clinical Oncology.
Staging Clinical staging included a detailed medical history and physical examination, complete biochemical profile, complete blood count, serum iron, copper, fibrinogen, lactic dehydrogenase, erythrocyte sedimentation rate (as indicators of disease), screening for autoimmune disease, posteroanterior and lateral chest x-rays, chest and abdominal computed tomography (CT) scans, and bronchoscopy. The following classification system according to Masaoka et alzo was adopted: stage I: macroscopically encapsulated and exempt from microscopic capsular invasion; stage II: (A) gross invasion into surrounding fatty tissue or mediastinal pleura, (B) microscopic invasion into capsule; stage III: gross invasion into contiguous structures; stage IV: (A) pleural or pericardial dissemination, (B) lymphogenous or hematogenous metastases. Twelve patients were stage III, 10 were IVA, and 10 were IVB.
Associated Immune Pathologies Four patients exhibited autoimmune conditions: two had myasthenia gravis (electromyogram confirmed), one had progressive systemic sclerosis, and one systemic lupus erythematosus. Patient characteristics are described in Table 1.
From the Divisione di Oncologia Medica, Unith Locale Socio SanitariaN. 21, Padova;Istituto di Clinica Chirurgica I; Istituto di Anatomia Patologica, Universitb di Padova; Istituto di Anatomia Patologica; and Universith di Verona, Italy. Submitted February16, 1989; accepted March 12, 1990. Address reprint requests to Adriano Fornasiero, MD, Divisione di Oncologia Medica, Unith Locale Socio SanitariaN. 21, 35100, Padova,Italy. © 1990 by American Society of ClinicalOncology. 0732-183X/90/0808-0008$3.0/01
Journal of Clinical Oncology, Vol 8, No 8 (August), 1990: pp 1419-1423
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1419
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FORNASIERO ET AL 100
Table 1. Patient Characteristics Characteristic
No. of Patients
Sex Male Female Age in years Median (range) Cell type LE E Stage III IVa IVb
18 14 50
40 (22-64)
n
24 8 0
12 10 10
Treatment Modalities All patients were treated with a combination of 50 mg/m2 of cisplatin intravenously (IV) and 40 mg/m2 of doxorubicin IV on day 1, 0.6 mg/m 2 of vincristine IV on day 3, and 700 mg/mz of cyclophosphamide IV on day 4 (ADOC), as previously described." This cycle was repeated every 3 weeks. All patients undergoing at least two therapy cycles were assessable for response. Extent of surgery before treatment varied from complete resection of the tumor bulk in one patient and partial resection in two, to biopsy only after thoracotomy or during mediastinoscopy or CT in the others. Three patients received radiotherapy to the mediastinum as postoperative treatment using opposite anterior and posterior parallel fields, at doses ranging from 40 to 56 Gy. Previous single-agent chemotherapy (cyclophosphamide) had been administered in one patient. Completely resected patients were not treated with ADOC until relapse.
Response Evaluation Complete remission was defined as the disappearance of all clinically and radiologically detectable tumors. Partial remission was defined as a _ 50% decrease in the size of the main measurable or assessable lesions, without an increase in the size of any lesions or the appearance of new lesions. Stable disease was defined as less than 50% regression of measurable or assessable lesions with no new lesions appearing and no deterioration in patient performance. Duration of response and survival was measured from the start of therapy. The probability of complete remission has been related to patient characteristics (ie, age, sex, cell type, stage) using the logistic regression model. 21 The Cox regression model 22 was used to evaluate relationships between progression-free interval plus survival time and the above-mentioned patient characteristics.
RESULTS
Thirty-two patients (14 women, 18 men; median age, 40 years; range, 22 to 64) were treated with the described combination chemotherapy for measurable disease. A median of five courses (range, three to seven) was administered. Fifteen
12
24
36
months
Fig 1. Kaplan-Meier overall survival (32 patients); tick marks indicate censored patients.
patients (47% + 17%) attained a complete remission with ADOC, and 14 patients (44% ± 17%) achieved a partial remission, with an overall CR plus PR rate of 91% ± 10%. Eighteen patients progressed after a major response, with a median time to progression of 11 months (range, 0 to 96) and an estimated (Kaplan-Meier) median freedom-from-progression time of 22 months (Fig 1). Two patients showed stable disease (for 5 and 7 months, respectively), while one patient had disease progression during treatment. Twenty patients died, two without evidence of disease 38 and 27 months, respectively, after the end of chemotherapy: one from chronic obstructive lung disease and another from myocardial infarction. These patients, however, were not censored in the survival analysis. The median time to death was 17 months (range, 5 to 96), with an estimated (KaplanMeier) overall median survival of 15 months (Fig 1). When patient characteristics were analyzed in a multivariate fashion, stage III and the LE cell type were found to affect positively the probability of complete remission, while the achievement of a clinical complete remission was the only factor that influenced survival duration. None of Table 2. Results of Multivariate (Logistic and Cox's Regression) Analyses Variable
Clinical CR Achievement
Duration of Response
Duration of Survival
Male/female Age LE/E Stage III/IV CR/no CR
NS NS P= .030 P = .012 -
NS NS NS NS -
NS NS NS .092 .001
Abbreviation: CR, complete remission.
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CHEMOTHERAPY OF INVASIVE THYMOMA
Fig 2. courses.
A patient exhibiting a pathologically complete remission; (A) x-ray before ADOC chemotherapy, and (B) after four
the variables considered in the analysis were shown to affect independently the duration of a major response (Table 2). Seven patients with clinico-radiologic complete response after ADOC chemotherapy underwent an explorative thoracotomy; a pathologically confirmed complete remission was found in five (Figs 2 and 3). We performed a right thoracotomy with superior lobectomy and removal of the thymic gland in one patient with
Fig 3. courses.
minimal residual disease after five courses of chemotherapy (Fig 4). The histologic examination was negative and only necrotic tissue was found. The ADOC regimen was well tolerated. Nausea, vomiting, and alopecia occurred at various degrees in all patients. Myelosuppression was the major drug-related toxicity: changes from World Health Organization 23 grade 0 at baseline to grade 2 or 3 occurred in 25 and eight patients,
A patient exhibiting a pathologically complete remission; (A) x-ray before ADOC chemotherapy, and (B) after three
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1422
Fig 4.
FORNASIERO ET AL
A patient exhibiting minimal residual disease; (A) x-ray before ADOC chemotherapy, and (B)after five courses.
respectively, for total WBC counts, and to grade 2 in three patients for hemoglobin levels. Renal and cardiac functions remained normal throughout the study; only two patients had a mild increase in serum creatinine.11 DISCUSSION
The treatment of invasive thymoma is usually performed by surgery and radiation therapy. Systemic treatment has generally been administered only to patients with unresectable or progressive disease. A recent review of the literature16 indicates that prednisone and cisplatin are the most active single agents in the treatment of invasive thymoma. Other cytotoxic agents have been used mostly in combination with these two drugs, although it is difficult to demonstrate their additional value. Radiotherapy has been frequently used as postoperative treatment or in nonoperable diseases, although it cannot prevent distant metastases and intrathoracic recurrence outside the radiation field.2 4 These 32 patients treated with the ADOC regimen represent the largest uniformly treated series reported. The encouraging results in the overall response rate (29 of 32 patients respond-
ing, ie, 91%) compare favorably with other reports. Recently, using the combination of doxorubicin, cyclophosphamide, and cisplatin (PAC), Loehrer et al reported good results (80% response in limited thymoma, 60% in extensive disease).17 Despite a high remission rate, however, long-term survival has not been generally achieved. In our series, three of the five patients reported in 1984 are alive and disease-free" with survival beyond 5 years. On the basis of these observations, chemotherapy is now delivered at our center as the primary treatment for thymoma, whereas the surgical approach is applied when maximum response to the ADOC regimen occurs. After resection of residual or suspicious lesions, radiation therapy or further chemotherapy are considered, depending on the histologic findings. 25 Seven patients have entered this preoperative study and a pathologic remission has been obtained in five. The ADOC and PAC chemotherapy regimens show the most efficacy in invasive or metastatic thymoma, and we suggest that trials of early (preoperative) administration of these regimens be extended.
REFERENCES 1. Batata MA, Martini N, Huvos AG, et al: ThymomasClinicopathologic features, therapy and prognosis. Cancer 34:389-396, 1974 2. Salyer WR, Eggleston JC: Thymoma: A clinical and pathological study of 65 cases. Cancer 37:229-249, 1976 3. Verley JM, Hollmann KH: Thymoma: A comparative
study of clinical stages, histologic features, and survival in 200 cases. Cancer 55:1074-1086, 1985 4. Maggi G, Giaccone G, Donadio M, et al: Thymomas: A review of 169 cases with particular reference to results of surgical treatment. Cancer 58:765-776, 1986 5. Ariaiatnan LS, Kalnicki S, Mincer F: The management
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 9, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1423
CHEMOTHERAPY OF INVASIVE THYMOMA of malignant thymoma with radiation therapy. Int J Radiat Oncol Biol Phys 5:77-80, 1979 6. Marks RD, Wallace KM, Pettit HA: Radiation therapy control of 9 patients with malignant thymoma. Cancer 41:117-119, 1978 7. Penn CRH, Hope-Stone HF: The role of radiotherapy in the management of malignant thymoma. Br J Surg 59:7, 1972 8. Boston B: Chemotherapy of invasive thymoma. Cancer 38:49-52, 1976 9. Cocconi G, Boni C, Cuomo A: A long-lasting response to cisplatinum in recurrent malignant thymoma: Case report. Cancer 49:1985-1987, 1982 10. Campbell MG, Pollard R, Al-Sarraf M: A complete response in metastatic malignant thymoma to cis-platinum, doxorubicin and cyclophosphamide. Cancer 98:1315-1317, 1981 11. Fornasiero A, Daniele O, Sperandio P, et al: Chemotherapy of invasive or metastatic thymoma: Report of 11 cases. Cancer Treat Rep 68:1205-1210, 1984 12. Chainian AP, Bhardwaj S, Meyer RJ, et al: Treatment of invasive or metastatic thymoma: Report of eleven cases. Cancer 47:1752-1761, 1981 13. Giaccone G, Musella R, Bertetto O, et al: Cisplatincontaining chemotherapy in the treatment of invasive thymoma: Report of five cases. Cancer Treat Rep 69:695-697, 1985 14. Daugaard G, Hansen HH, Rirth M: Combination chemotherapy for malignant thymoma. Ann Intern Med 99:189-190, 1983
15. Klippstein TH, Mitrov PS, Kochendorfer KJ, et al: Adriamycin and cisplatinum in invasive thymomas. Cancer Chemoth Pharmacol 13:78-81, 1984 16. Hu E, Levine J: Chemotherapy of malignant thymoma. Cancer 57:1101-1104, 1986 17. Loehrer PJ, Perez C, Roth IM, et al: Cisplatin (P) plus Adriamycin (A) plus cyclophosphamide (C) in limited and extensive thymoma: Preliminary results of an intergroup trial. Am Soc Clin Oncol Proc 7:199, 1988 (abstr) 18. Rosai J, Levine GD: Tumors of the thymus, in Atlas of Tumor Pathology, 2nd series, fascicle 13. Washington, DC, Armed Forces Institutes of Pathology, 1976 19. Lattes R: Thymoma and other tumors of the thymus. An analysis of 107 cases. Cancer 15:1224-1260, 1962 20. 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 21. Cox DR: Analysis of Binary Data. London, England, Methuen, 1970 22. Cox DR: Regression models and life tables. J R Stat Soc 34:187-220, 1972 23. Miller AB, Hoogstratten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981 24. Chainian AP, Holland JF, Bhardwaj S: Chemotherapy for malignant thymoma. Ann Intern Med 99:736, 1983 (letter) 25. Fornasiero A, Daniele O, Morandi P, et al: Neoadjuvant chemotherapy in invasive thymoma. Second International Congress on Neo-Adjuvant chemotherapy. Paris, 1988 (abstr US)
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