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Ann Thorac Surg 1997;64:1585-1591
© 1997 The Society of Thoracic Surgeons
Departments of Thoracic Surgery and Human Biopathology, University of Rome "La Sapienza," Rome, Italy
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Abstract |
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 TopFootnotes Abstract IntroductionPatients and MethodsResultsCommentReferences |
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Methods. Between 1965 and 1988, we operated on 83 patients with thymoma who did not receive standardized adjuvant therapy. In 1989, on the basis of the retrospective analysis of the data, we started a multimodality therapy protocol and used it for 65 patients. Twelve patients had medullary thymoma (11 stage I and 1 stage II), 13 had mixed type (6 stage I and 7 stage II), and 40 had cortical thymoma (4 stage I, 11 stage II, 12 stage III, and 13 stage IV). We considered three groups. Group I (n = 18 patients), benign thymoma, included stage I and II medullary and stage I mixed thymomas; radical resection with no adjuvant therapy was performed. Group II (n = 22), invasive thymoma, included stage I and II cortical and stage II mixed thymomas; postoperative chemotherapy plus radiotherapy was always administered. Group III (n = 25), malignant thymoma, comprised stage III and IV cortical thymomas and stage III mixed thymomas; resectable stage III lesions were removed, and highly invasive stage III and stage IV lesions underwent biopsy, neoadjuvant chemotherapy, and surgical resection; postoperative chemotherapy and radiotherapy was administered to all patients.
Results. The 8-year survival rate for patients in stages I, II, III, and IV was 95%, 100%, 92%, and 68%, respectively. Patients with medullary thymoma had a 92% 8-year survival rate; those with mixed type, 100%; and those with cortical thymoma, 85%. Group I had an 8-year survival rate of 94%; group II, 100%; and group III, 76%. Survival was compared with that of patients operated on before 1989: differences were not significant for group I; survival improved in group II (100% versus 81%; p = not significant); and group III showed significant improvement (76% versus 43%; p < 0.049).
Conclusions. Multimodality treatment with neoadjuvant chemotherapy and adjuvant chemotherapy plus radiotherapy may improve the results of radical resection and the survival of patients with invasive and malignant thymoma.
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Introduction |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Thymoma displays a remarkable clinical and pathologic polymorphism: it can present as an encapsulated, noninvasive benign lesion or as a highly infiltrative, even metastasizing tumor [1]. The degree of aggressiveness can be predicted by the anatomic and clinical staging [1, 2] and by the histologic classification of Müller-Hermelink and associates [3, 4]. Although there is still controversy about the full effectiveness and the practical application of the latter [5–8], there is evidence in the literature [4, 9, 10] that the differentiation between medullary and cortical thymomas has an impact on the prognosis. There is a wide consensus that surgical intervention is the treatment of choice for thymoma. However, radical resection is not always feasible for invasive and metastasizing lesions (stages III and IVA in the staging of Masaoka and associates [1]), and these tumors should be approached in a multidisciplinary fashion [11]. Chemotherapy or radiotherapy or both can be used either as the first line of therapy to increase the ability to perform a radical resection or after operation to reduce the incidence of recurrence.
To optimize the indication for multimodality therapy, we [12] proposed that thymomas with similar survival rates be divided into three groups on the basis of both clinical stage and histologic subtype. Retrospectively, this grouping has proved to be a better prognostic indicator than clinical stage per se or histology alone. On the basis of these retrospective observations, we have also suggested which groups should receive neoadjuvant therapy, adjuvant therapy, or both following precise guidelines. These guidelines were subsequently applied prospectively in a single treatment arm study. The results of this study are presented here.
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Patients and Methods |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
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On the basis of our retrospective studies, we considered three groups. Group I (n = 18 patients), benign thymoma, included stage I and II medullary and stage I mixed thymomas; radical resection with no adjuvant therapy was performed. Group II (n = 22 patients), invasive thymoma, included stage I and II cortical and stage II mixed thymomas; postoperative chemotherapy and radiotherapy was always administered, even though radical resection was always feasible. Group III (n = 25 patients), malignant thymoma, included stage III and IV cortical thymomas and stage III mixed thymomas; patients with resectable stage III lesions (invasion of the superior vena cava or pericardium or limited invasion of the mediastinal pleura or lung) underwent surgical intervention, and all patients with stage III tumors that were not considered radically resectable at preoperative workup or with highly invasive or metastasizing lesions underwent biopsy and invasive staging (anterior mediastinotomy or video-assisted thoracoscopy), neoadjuvant chemotherapy, and surgical resection; postoperative chemotherapy and radiotherapy was administered to all patients.
Both neoadjuvant and adjuvant chemotherapy included cisplatin (75 to 100 mg/m2 on day 1), epirubicin hydrochloride (100 mg/m2 on day 1), and etoposide (120 mg/m2 on days 1, 3, and 5) repeated every 3 weeks three times before operation and two or three times after operation, depending on the patient's hematologic status. No preoperative radiotherapy was administered.
All the patients with stage I, II, and III thymoma underwent operation through a median sternotomy. In patients with stage IVA lesions, a median sternotomy was used in 10 and a clamshell incision in 3. Patients requiring radiation therapy postoperatively received 30 Gy (radical resection) or 50 Gy (incomplete resection) delivered in 3 or 5 weeks, respectively, with five fractions per week, to the mediastinum or to the residual tumor areas.
The results were compared in terms of ability to perform radical resection, incidence of recurrence, and survival with those of our previous series of 83 patients operated on before 1989 [12] (Table 1
). Survival curves were calculated from the time of operation to death or to last follow-up. Actuarial curves were constructed according to the Kaplan-Meier method [13]. Differences between variables (age, sex, myasthenia gravis, stage, histology, and clinicopathologic group) were analyzed with the 
2 test; comparison between curves was performed by the two-sided log-rank test [14] and the Wilcoxon test. Multivariate analysis was performed according to the Cox proportional hazard model [15].
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Results |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
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All the patients enrolled in the multimodality treatment protocol completed the program. Only 1 patient with stage IV thymoma had a delayed recovery from myelosuppression during postoperative chemotherapy, and the last cycle had to be postponed. Nonhematologic toxicity was usually mild and included stomatitis, alopecia, nausea, and vomiting. There were no infectious complications. Esophagitis developed in 1 patient at the end of postoperative radiotherapy.
Eight of the 12 patients with stage III thymoma received neoadjuvant chemotherapy; the site of infiltration at presentation is listed in Table 2. After chemotherapy, all patients showed radiologic evidence of tumor mass reduction, but only 1 had a complete histologic remission (Fig 1). In addition, true downstaging from stage III to stage II occurred in 2 patients (regression of chest wall invasion and persistence of capsular infiltration). In 2 patients, radiologic evidence of invasion of the great vessels (ascending aorta and main pulmonary artery) was confirmed at anterior mediastinotomy before neoadjuvant chemotherapy. Tumor infiltration was still present at operation and was the reason for nonradical resection in both.
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); the metastases shrank in all patients, and in 2 patients, all metastatic tumor was replaced by fibrosis (from stage IVA to stages III and II). In 3 patients with stage IVA thymoma, the resection was not radical (apical pleura with extrapleural invasion in 1 and extrapleural diaphragmatic and parietal involvement in 2).
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. There were no postoperative deaths. After radical resection, there was only one recurrence (cortical stage IV) in this prospective group of patients, whereas 11 recurrences developed within 8 years after operation in our previous series.
Follow-up (range, 2 to 101 months; mean period, 56 months; and median period, 53 months) was complete for all but 2 patients. Sex, age, and myasthenia did not significantly affect survival. Survival by stage, histology, and clinicopathologic group is shown in Figures 3B, 4B, and 5B, respectively. Overall survival of patients operated on after 1989 was significantly improved compared with our previous series (89% versus 66% at 8 years; p = 0.009) (Fig 6). Survival by stage showed an improvement in this prospective series (Fig 3); there is a significant difference between stages (p = 0.04), but it is much less impressive than the difference seen in the previous series (before 1989) (p = 0.0001). This likely is related to the improved survival of patients in stage III and IV with the multimodality treatment; in fact, stage III has approached stages I and II in terms of survival, and stage IV has dramatically improved.
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). Before 1989, patients with cortical thymoma had a lower survival (50% at 8 years versus 82% for mixed and 78% for medullary; p = 0.01; Wilcoxon = 0.0007); in this study, survival is 85% for patients with cortical lesions, 100% for those with mixed lesions, and 92% for those with medullary thymoma (p = not significant). The survival of patients with cortical thymoma before and after 1989 shows a significant difference (p = 0.004), but the difference for the other two histologic types is not significant. Also the ability to perform a radical resection has improved: 85% of patients with stage III lesions had a radical operation versus 58% before 1989, and 77% of patients with stage IV tumors had a radical resection versus 33.3% before 1989.
Survival curves plotted according to clinicopathologic group confirm the effectiveness of multimodality treatment. Differences in 8-year survival were not significant for group I (94% versus 86% before 1989); survival improved in group II (100% versus 81%; p = 0.09 with a positive trend); and group III showed a significant improvement (76% versus 43%; p = 0.049). After 1989, differences between groups are significant (p = 0.04) but not as much as before 1989 (p < 0.0001), results showing the positive effect of combined treatment. In this study, the survival of group III approaches that of groups I and II (Fig 5).
The multivariate analysis with a first model combining age (greater than or less than 40 years), year of operation (before or after 1989), histology, and staging showed an increased risk for stages III and IV and for age less than 40 years; the risk is significantly decreased for patients operated on after 1989; histology alone is not a significant risk factor. The recombination of the variables in a second model including clinicopathologic grouping indicated that group III (malignant thymoma) has a significantly higher risk; however, the risk is significantly reduced in the series operated on after 1989 (Table 3).
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Comment |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
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The optimal treatment for stage I thymoma is surgical excision without further therapy [2, 9, 10, 12, 23, 24]. For these tumors, radical resection is always feasible, long-term survival approximates 100%, and recurrences are virtually nonexistent. The present study confirms this finding. We include stage II medullary thymomas in this group benign thymoma because invasion is always confined to the capsula and they never recur. On the other hand, we excluded stage I cortical thymoma, which is placed in group II, invasive thymomas. This group includes stage I and II cortical and stage II mixed thymomas because in our experience, each of these tumors can recur. In fact, in our series preceding 1989, we had 11 recurrences: 10 were cortical thymomas (1 stage I, 3 stage II, 2 stage III, and 4 stage IV), and 1 was mixed (stage II). Further, in four instances (one stage I and two stage II cortical and one stage II mixed), the recurrence was a metastatic seeding to the parietal pleura (n = 2) and lung (n = 2). This finding also indicates that thymoma can recur and metastasize independent of the staging of Masaoka and associates [1]. In this group, cure rather than long-term survival should be the aim of treatment. Consequently, we postulated that invasive thymomas (group II) require some adjuvant treatment, even if surgical resection has been radical. In this prospective study, we performed both radiotherapy and chemotherapy; survival has improved (100% versus 81%), though not significantly (p = 0.09), but there were no recurrences. Postoperative radiation therapy has been given to similar patients by others [2, 10, 24]; we believe, however, that chemotherapy should also be administered to prevent hematogenous and lymphatic seeding.
Malignant thymoma (group III) deserves special consideration. Optimal therapy for stages III and IV has still to be defined. Radical resection, postoperative control of residual tumor, and prevention of local and distant recurrence should be pursued if cure rather than prolonged survival is to be achieved. En bloc resection of the primary tumor and the involved structures is certainly one of the keys to success [21, 25, 26]. However, the reported survival for patients with advanced disease is unsatisfactory, even after radical resection (10-year survival rates ranging between 35% and 53%). Furthermore, up to 50% of patients undergoing operation, whether radical or not, will have local recurrence within 5 years [11, 23]. For this reason, adjuvant therapy has been recommended for all invasive lesions [2, 11, 21, 24].
Radiotherapy alone has commonly been administered to the mediastinum and the site of the intrathoracic metastases, but results are controversial. Thymomas are certainly sensitive to radiation treatment [27], but the high incidence of pleural recurrences (up to 39%) [28] and extrathoracic metastases (3% to 37%) [29, 30] despite postoperative radiotherapy suggests the need of more effective adjuvant strategies. Chemotherapy has been successful in patients with distant metastases or local recurrence, and its benefits in earlier stages have been pointed out.
The reported results with neoadjuvant and adjuvant chemotherapy [11] stimulated us to design this prospective, single treatment arm study aimed especially at advanced lesions. We adopted as a base the clinicopathologic groups previously reported by us [12]. In that retrospective study, it appeared evident that cortical thymomas result in a lower survival rate, a higher local aggressiveness, and a greater potential for metastasis (70% were stage III or IVA and only 2%, stage I). Furthermore, cortical thymomas often recur: ten (91%) of 11 recurrences in our previous study were cortical. Our results have been confirmed by others [10].
We therefore decided to administer additional therapy for invasive thymomas, both preoperatively and postoperatively. The acute and chronic toxicity of the regimen was acceptable and similar to that reported by others [11, 18, 31, 32] and did not affect patient compliance or result in major protocol variations. Eight of the 12 patients with stage III thymoma received neoadjuvant chemotherapy; all showed radiologic evidence of tumor mass reduction, although only 1 had complete histologic remission. Surgical exploration confirmed a reduction in the infiltration of the surrounding structures; however, 2 patients had radiologic evidence of invasion of the great vessels prior to neoadjuvant chemotherapy, and this infiltration persisted after treatment. In our experience, true downstaging of stage III thymomas is rare. However, neoadjuvant chemotherapy yields good local control by shrinking the mass and reducing the infiltration. Tough, dense fibrosis usually results; it involves the surrounding structures corresponding to the site of infiltration (lung or superior vena cava and brachiocephalic vein) and makes the dissection difficult. Thus en bloc resection is sometimes required even if true neoplastic invasion is not histologically evident.
All 13 patients with stage IVA lesions underwent neoadjuvant treatment. At operation, 12 had residual tumor, and in 3, the resection was not radical. Also for this stage, we usually obtain a reduction in the volume of the metastases, but in this series, only two tumors could be downstaged to stage II. However, it appears evident from our study that multimodality treatment for stage III and IVA thymoma (malignant thymoma or group III) allowed a significant improvement in terms of radical resection and survival. We agree with others [2] that a longer follow-up is necessary, even though all the recurrences in our previous series occurred within 8 years after operation.
The application of this multimodality approach in our prospective series led to a significant improvement in survival for patients with stages III and IV cortical lesions (malignant thymoma), thus reducing the gap between curves plotted by clinical stage and clinicopathologic group. The difference is now slightly significant (p = 0.049 after 1989 versus p < 0.001 before 1989). It is important to point out that this does not mean that clinicopathologic grouping, staging by the method of Masaoka and colleagues [1], and histologic subtyping lost validity as prognostic factors. On the contrary, our data emphasize that these criteria should be used to screen for patients requiring an aggressive multimodality approach and that with this approach, patients with histologically malignant thymoma or patients in an advanced clinical stage can be offered a chance of cure that approximates that of less aggressive lesions.
In conclusion, we confirm that medullary thymomas are benign tumors with an excellent prognosis, whereas cortical thymomas, whether they are associated with well-differentiated thymic carcinoma or not, are usually invasive. Stage III and IV lesions should be treated aggressively with neoadjuvant and adjuvant therapy. Stage II lesions (cortical and mixed) should also undergo postoperative chemotherapy and radiotherapy. The standardization of this multimodality protocol led to an evident improvement in terms of the rates of radical resection and survival, even though comparison with a retrospective series cannot be considered conclusive. The incidence of recurrence is decreased at this time of follow-up. However, a longer follow-up, a larger series of patients, and possibly a randomized trial are required to draw definitive conclusions.
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Footnotes |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Address reprint requests to Dr Venuta, Cattedra di Chirurgia Toracica, Policlinico Umberto I, University of Rome "La Sapienza", V.le del Policlinico, 00100 Rome, Italy.
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