Japanese Journal of Clinical Oncology

INTRODUCTION

There is a general consensus that surgery is the treatment of first choice for thymomas and many authors have recommended complete resection whenever possible (1-3). In completely resected Masaoka stage I (noninvasive) tumors, routine postoperative irradiation has not been recommended because the incidence of relapse has been reported to be low even without postoperative irradiation (4,5). On the other hand, in completely resected stage II and III (invasive) tumors, postoperative mediastinal irradiation has been routinely recommended to prevent local relapse (5,6). However, a controversy exists concerning optimal postoperative radiation therapy for tumors at these stages (4,7). Some authors have reported low relapse rates with the use of postoperative mediastinal irradiation and pointed out its efficacy (5,6). Others have found that postoperative mediastinal irradiation might be insufficient because relapses of pleural dissemination sometimes occurred remote from the initial tumor site even in stage II tumors (4,8) Therefore, this study was conducted to assess the efficacy of routine adjuvant mediastinal irradiation in patients with completely resected invasive thymoma.

PATIENTS AND METHODS

Between 1981 and 1996, 24 patients with nondisseminated invasive thymoma were treated with surgery and subsequent radiation therapy at the Department of Radiology, University of the Ryukyus Hospital or National Okinawa Hospital. Three patients who had partial resection at thoracotomy were excluded from this study. The remaining 21 patients, all of whom had undergone macroscopically complete resection, were analyzed retrospectively (Table 1). Ages ranged from 6 to 69 years (median: 53 years) and 17 patients were male and four female. On presentation, there was an asymptomatic mass on chest X-ray in 13 patients, symptoms of mediastinal compression, such as chest pain and dyspnea, in four patients, myasthenia gravis in three patients and symptoms of both mediastinal compression and myasthenia gravis in one patient.

The tumors were classified into lymphocytic type (n = 7), mixed type (n = 6) and epithelial type (n = 8). Patients presenting a pathological diagnosis of thymic carcinoma were excluded from this study. Clinical staging was based on the surgical and pathological criteria described by Masaoka et al. (9) The criteria used in this study were as follows:

Stage I:	Macroscopically completely encapsulated and no microscopic capsular invasion.
Stage II:	1. Macroscopic invasion into surrounding fatty tissue or mediastinal pleura.
	2. Microscopic invasion into the capsule.
Stage III:	Macroscopic invasion into neighboring organs (pericardium, great vessels or lung).
Stage IVa:	Pleural or pericardial dissemination of thymoma.
Stage IVb:	Lymphogenous or hematogenous metastases.

The distribution of patients according to stage was 14 stage II and seven stage III. Pleural invasion by the tumor was also assessed. This was based on microscopic invasion to the mediastinal pleura. Nine patients had pleural invasion by the tumor.

Radiation therapy was administered with a ⁶⁰Co teletherapy unit or a 6 or 10 MV linear accelerator (⁶⁰Co teletherapy unit: patient Nos 1, 2, 3, 15 and 16). The mediastinal irradiation fields can be classified as having two patterns: 13 patients were treated with localized fields that covered the primary tumor bed with margins of about 1-2 cm and eight patients were treated with whole mediastinal fields including the primary tumor bed, with the upper margin at the thoracic inlet and the lower margin at the diaphragmatic crurae. Patients were treated with anteroposterior opposed fields with the spinal cord dose limited to 45 Gy in all cases (to 41.4 Gy at the whole mediastinal field). Two anterior wedged portals or off-cord oblique opposed portals were used to boost the anterior mediastinum to higher doses. The supraclavicular fossa was not included in the irradiated field in any of the patients. The total dose to the primary tumor was 40-61 Gy (median: 52 Gy). Daily fraction sizes of 1.8-2.0 Gy 5 days per week were mostly used. However, patient No. 18, aged 6, received a total dose of 40 Gy, namely anteroposterior opposed fields (20.8 Gy) and two anterior wedged fields (19.2 Gy), with a daily fraction size of 1.6 Gy, in order to reduce the chance of later complications.

Table 1. Clinical summary of patients with completely resected invasive thymoma following radiation therapy

Patient No.	Age (years)	Gender	Histological classification	MG	Mediastinal compression	Masaoka clinical	Pleural invasion stage	Irradiated dose (Gy)	Irradiated field	Site of first relapse	Prognosis
1	47	M	M	-	+	2	-	40	L	-	NED (202 mo)
2	59	M	M	+	-	2	-	50	L	-	NED (187 mo)
3	59	F	Ly	-	-	2	-	52	L	-	NED (171 mo)
4	33	M	E	+	-	2	-	50	L	-	NED (141 mo)
5	59	M	M	-	-	2	-	50	L	-	NED (135 mo)
6	53	M	Ly	-	-	2	-	61	WM + B	-	NED (50 mo)
7	56	M	E	-	-	2	-	61	WM + B	-	NED (48 mo)
8	55	M	Ly	-	-	2	-	60	WM + B	-	NED (48 mo)
9	69	M	Ly	-	-	2	-	56	L	-	DWD (20 mo)
10	42	M	E	-	+	2	-	60	L	-	NED (38 mo)
11	45	F	Ly	-	-	2	-	50.4	WM + B	-	NED (38 mo)
12	52	M	E	-	-	2	-	51.2	WM + B	-	NED (34 mo)
13	68	F	M	+	+	2	+	51.3	L	Pleura	DOD (50 mo)
14	53	M	Ly	-	-	2	+	45	WM + B	-	NED (84 mo)
15	69	F	M	-	-	3	+	60	L	-	DWD (36 mo)
16	48	M	E	-	-	3	+	42	L	Pleura, marginal	DOD (157 mo)
17	60	M	E	-	-	3	+	60	L	Pleura, SF	DOD (30 mo)
18	6	M	E	-	-	3	+	40	L	-	NED (122 mo)
19	33	M	Ly	-	-	3	+	60	L	Pleura	AWD (115 mo)
20	43	M	M	+	-	3	+	55.8	WM + B	Pleura	AWD (39 mo)
21	65	M	E	-	+	3	+	53.2	WM + B	-	NED (29 mo)

M, mixed; E, epithelial; Ly, lymphocytic; MG, myasthenia gravis; L, localized; WM, whole mediastinal; B, boost; SF, supraclavicular fossa; NED, no evidence of disease; DWD, dead without disease; DOD, dead of disease; AWD, alive with disease; mo, months.

No patients received chemotherapy during the initial treatment.

Since patients with invasive thymomas often develop intrathoracic relapse remote from the initial tumor site (4,8), relapses at intrathoracic lesions were analyzed in this study. Intrathoracic failure was defined as the appearance of a tumor at an intrathoracic lesion, such as the mediastinum, pleura, pericardium or lung. In order to assess the prognostic factors for intrathoracic control, the data were analyzed with respect to age, gender, histological classification, mediastinal compression, myasthenia gravis, Masaoka stage, pleural invasion, irradiated dose and irradiated field.

The median follow-up time of the 16 living patients was 67 months (range: 29-202 months) and no patients were lost to follow-up. All living patients were followed up with thoracic computed tomography. Overall survival and intrathoracic control rates were calculated actuarially according to the Kaplan-Meier method (10) and were measured from the day of surgery. Differences between groups were estimated using the generalized Wilcoxon test (11). Multivariate analysis was performed using the Cox regression model (12). A probability level of 0.05 was chosen for statistical significance. Statistical analysis was performed using the SPSS 6.1 software package.

RESULTS

Five of 21 (24%) patients died during the period of this analysis. Three patients died of thymoma and two died without any sign of clinical relapse (due to renal failure and glioblastoma, respectively). The 5- and 10-year actuarial overall survival rates in all patients were both 77%. Fig. 1 presents the actuarial overall survival curves according to Masaoka stage. The 5-year actuarial overall survival rates were 81% for stage II and 67% for stage III. There was no significant statistical difference between these groups.

Figure 1. Actuarial overall survival rates according to Masaoka stage.

Relapse of thymoma was observed in five of 21 patients (Nos 13, 16, 17, 19 and 20). All five patients had relapse of pleural dissemination remote from the irradiated field at the first relapse. Three patients (Nos 13, 19 and 20) had relapse of ipsilateral pleural dissemination only at the first relapse. Two patients (Nos 16 and 17) had relapses not only of ipsilateral pleural dissemination but also at other sites simultaneously at the first relapse (patient No. 16, marginal field relapse at mediastinum; patient No. 17, supraclavicular fossa). There was no relapse within the irradiated field in any patient.

Patterns of intrathoracic relapse were analyzed with respect to the mode of radiation therapy (irradiated dose and irradiated field). Table 2 shows the incidence and sites of intrathoracic relapse according to the irradiated dose. There was no in-field relapse and no dose-response relationship was seen in intrathoracic control. Table 3 presents the incidence and sites of intrathoracic relapse according to the irradiated field. Out-field relapses (pleural disseminations) were observed both in patients with localized irradiation and those with whole mediastinal irradiation.

The 5- and 10-year actuarial intrathoracic control rates in all patients were 84% and 66%, respectively. Table 4 presents the univariate analysis of various potential prognostic factors for intrathoracic control. In the analysis, pleural invasion had a statistically significant impact on intrathoracic control (P = 0.01). Table 5 presents the incidence and sites of intrathoracic relapses according to the presence of pleural invasion. Five of nine (56%) patients with pleural invasion had relapse of pleural dissemination outside the irradiated field, while 0 of 12 (0%) patients without pleural invasion had any relapse. Fig. 2 shows the intrathoracic control according to the presence of pleural invasion. The 5- and 10-year actuarial intrathoracic control rates in patients with pleural invasion were 62% and 31%, respectively. On the other hand, in the multivariate analysis, no factors reached statistical significance.

Four of 21 (19%) patients (Nos 7, 8, 9 and 20) developed symptomatic radiation pneumonitis requiring steroids (three, whole mediastinum and boost field; one, localized field). The radiation doses to the primary tumor were more than 55 Gy in these four patients. Patient No. 18, who was given radiation therapy at the age of 6, is at present 16 and in good health without treatment-related complications. No patient died due to side effects or complications resulting from treatment.

Table 2. Incidence and sites of intrathoracic relapses according to the irradiated dose

Irradiated dose (Gy)	Site of relapse		Overall
	In-field	Out-field
[le]50 (n = 7)	0	1	1/7 (14%)
>50 (n = 14)	0	4	4/1 (29%)
Total (n = 21)	0	5	5/21 (24%)

Table 3. Incidence and sites of intathoracic relapses according to the irradiated field

Irradiated field	Site of relapse		Overall
	In-field	Out-field
Localized (n = 13)	0	4	4/13 (31%)
WM + B (n = 8)	0	1	1/8 (13%)
Total (n = 21)	0	5	5/21 (24%)

WM, whole mediastinal; B, boost.

Figure 2. Actuarial intrathoracic control rates according to the presence of pleural invasion.

Table 4. Univariate analysis of various potential prognostic factors in patients with completely resected invasive thymoma following postoperative irradiation

Prognostic factor	IC		p value
	5-year rate (%)	10-year rate (%)
Age (years)
[le]50	88	53
>50	84	84	0.42
Gender
Male	87	65
Female	75	75	0.95
Histological classification
Lymphocytic	100	67
Mixed	63	63
Epithelial	88	58	0.51
Mediastinal compression
Yes	80	80
No	86	61	0.72
Myasthenia gravis
Present	50	50
Absent	94	67	0.10
Masaoka stage
II	93	93
III	64	21	0.08
Pleural invasion
Yes	62	31
No	100	100	0.01
Total dose (Gy)
[le]50	86	86
>50	75	37	0.11
Irradiated field involved	84	63
Whole mediastinal + boost	83	83	0.58

IC, intrathoracic control.

Table 5. Incidence and sites of intathoracic relapses according to the presence of plural invasion

Pleural invasion	Site of relapse		Overall
	In-field	Out-field
Invasion (+) (n = 9)	0	5	5/9 (56%)
Invasion (-) (n = 12)	0	0	0/12 (0%)
Total (n = 21)	0	5	5/21 (24%)

DISCUSSION

Invasive thymomas tend to recur within the thoracic cavity and poor prognosis has been observed in patients who experience relapse (2,5). The most common pattern of failure in completely resected invasive thymoma following mediastinal irradiation has been reported to be pleural dissemination (4,9). However, it might be difficult to predict the risk of relapse of pleural dissemination by Masaoka stage alone because relapses sometimes occur even in stage II tumors (4,8). One reason for these results may be an equivocal classification of local tumor invasion (particularly stage II), which has been recognized as the major factor in thymoma (4,13,14). Therefore, additional prognostic factors based on local tumor invasion may be needed to devise valid recommendations for prophylactic treatment of pleural-based relapse.

In this study, the sites of first relapse all involved pleural dissemination and pleural invasion had a statistically significant impact on intrathoracic control in univariate analysis. In patients without pleural invasion, no relapse was seen following mediastinal irradiation. These results suggest that invasive thymomas without pleural invasion might be localized disease with a lesser risk of pleural dissemination and that mediastinal irradiation would be effective in preventing relapse. Dose-response in irradiation of thymoma has not been clearly established. With regard to total dose, most authors recommend a dose of 40-50 Gy after complete resection (2,7,15). In our series, no in-field relapse was observed and no dose-response relationship was seen in the intrathoracic control. A dose of 40-50 Gy appeared to be appropriate after complete resection.

However, in patients with pleural invasion, five of nine (56%) patients had relapse of pleural dissemination (stage II, 1/2; stage III, 4/7). Haniuda et al. reported that of 80 completely resected thymoma patients, 12 of 13 (92%) cases developed relapse of pleural dissemination and that in stage II and III patients with pleural invasion, six of 15 (40%) relapses occurred even with mediastinal irradiation (stage II, 3/5; stage III, 3/10) (4). Our results also indicated that there was a significant difference with regard to intrathoracic relapse according to pleural invasion. These results suggest that some patients with pleural invasion already had latent microscopic pleural dissemination at the time of surgical treatment, even though they were classified as stage II. In such patients where pleural invasion is seen, the mediastinal irradiation may have only a limited effect. Not merely localized field irradiation, but even whole mediastinal irradiation might be insufficient to prevent pleural-based relapse because it can cover only a part of the pleura.

In order to reduce the risk of intrathoracic relapse, some authors have advocated the use of prophylactic pleural and pulmonary irradiation (8,13). Uematsu et al. reported that except for in elderly patients, entire hemithorax irradiation following complete resection appears to be safe and feasible and can reduce intrathoracic relapse in stage II and III tumors (8). Once established in patients with advanced cases, chemotherapy may deserve evaluation for completely resected invasive thymoma patients (7). However, these prophylactic measures should be tested in properly randomized trials restricted to patients who are considered to be at high risk of pleural-based relapse.

From these views and findings, we concluded that pleural invasion might be predictive of pleural-based relapse for completely resected invasive thymoma. In patients without pleural invasion, the tumor might be localized disease with a lesser risk of pleural dissemination and postoperative mediastinal irradiation would be sufficient to prevent relapse. On the other hand, in patients with pleural invasion, there is some possibility of occult dissemination at or before the time of surgery. Therefore, additional treatment, such as prophylactic pleural and pulmonary irradiation, would be required to prevent pleural-based relapse. It may be appropriate to divide Masaoka stage II into two categories according to the existence and the extent of pleural invasion. However, this study was retrospective, with a small number of patients. Furthermore, the findings in this study were obtained only by univariate analysis. Therefore, further prospective studies should be undertaken with a greater number of subjects.

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Received April 1, 1999; accepted July 9, 1999
For reprints and all correspondence: Kazuhiko Ogawa, Department of Radiology, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa, 903-0215, Japan. E-mail: kogawa{at}med.u-ryukyu.ac.jp

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