Radiotherapy and Oncology, 24 (1992) 221-225

© 1992 Elsevier Science Publishers B.V. All rights reserved. 0167-8140/92/$05.00

221

RADION 01017

Aggressive treatment of intrathoracic recurrences of thymoma A l e s s a n d r o U r g e s i a, U g o M o n e t t i a, G i u s e p p e R o s s i a, U m b e r t o R i c a r d i a, G i u l i a n o M a g g i b a n d G i a n Luca Sannazzari a Departments of aRadiation Therapy and b Thoracic Surgery, University of Torino, Torino, Italy

(Received 18 July 1991, revision received 14 January 1992, accepted 31 March 1992)

Key words: Thymoma; Radiotherapy

Summary Between 1974 and 1988, 21 patients with intrathoracic recurrences of thymoma received radiotherapy with radical intent; surgery was always attempted when considered feasible: 11 patients were partially (6 cases) or totally (5 cases) resected before irradiation, while in the other 10 radiotherapy was the only treatment. In 7 cases the recurrence was confined to the anterior mediastinum, 9 had pleural nodules without mediastinal lesions and 5 had both mediastinal and pleural lesions. Mediastinal recurrences were treated by opposed parallel mediastinal fields with 2/3 of the dose delivered through the anterior port: doses ranged between 38 and 44 Gy; a boost of 10-16 Gy was given in patients not radically resected. Pleural nodules were treated with a variety of techniques according to the extent of the lesions. The 7-year survival of the whole group was 70%; 5 patients died: 4 with intrathoracic progression and one with distant metastases. The survival was 74% in the 11 patients having received surgery, either radical or subtotal, and 65 To in the 10 patients treated with radiotherapy alone: the difference is not significant. Patients with Karnofsky index > 70 had a significantly better survival (100%, versus 28%, p = 0.0015). This is a selected series of patients presenting recurrences still amenable to a radical treatment either by surgery and radiotherapy or by, radiotherapy alone: the results confirm that an aggressive approach is warranted in patients in good general conditions with recurrences confined to the mediastinum and/or 1 hemithorax.

Introduction T h y m o m a s are rare neoplasms originating from the epithelial cells o f the thymus [ 15]. The prognosis is correlated mainly with the extent o f disease at diagnosis and the radicality o f surgical exeresis [ 2 - 4 , 1 0 - 1 4 , 1 9 ] . In a majoriiy o f patients surgery or a combination of surgery and radiotherapy can achieve long survivals [ 1,2,6,13 ]. Distant metastases are rare and recurrences are generally confined to the mediastinum, the thoracic serosae or the lung. The appropriate treatment for intrathoracic recurrences is not codified and depends on the extent o f the disease, on previous treatments and on the general condition o f the patient. The purpose o f the present paper is to outline the treatment modalities and the results in a selected series

o f patients with recurrent t h y m o m a suitable for an aggressive approach either by surgery and radiotherapy or by radiotherapy alone.

Patients and methods The records o f all patients who received radiotherapy for recurrences o f t h y m o m a at our Institution between January 1974 and D e c e m b e r 1988 were reviewed; the criteria for inclusion in the present study were: (1) irradiation with radical intent of all k n o w n lesions or (2) post-operative treatment after total or subtotal resection o f recurrence. There were 21 cases fitting these criteria. Nine additional patients received palliative irradiation of symptomatic lesions: they were excluded from the study since radical irradiation was not possi-

Address for correspondence: A. Urgesi, Department of Radiation Therapy, University of Torino, Via Genova 3, 10126, Torino, Italy.

222 ble because of previous mediastinal irradiation (3 cases), distant metastases (2 cases) or extensive invasion of both hemithoraxes (4 cases). Patients presenting with recurrences confined to the pleura were included in the study irrespective of previous mediastinal irradiation at the moment of primary treatment. Recurrences occurred 1 to 9 years after initial treatment which consisted of surgery alone in 16 patients and of surgery followed by post-operative irradiation of the mediastinum (38-46 Gy) in the remaining 5. In 7 cases the recurrence was confined to the anterior mediastinum, in 9 the mediastinum was free of recurrence and only pleural nodules were present (5 of these patients had previously been irradiated on the mediastinum) and in 5 both mediastinal and pleural lesions were present. Surgery was always attempted when considered feasible (11 cases). Reasons for inoperability included invasion of the brachiocephalic trunk (one case), extensive involvement of the mediastinal pleura and pericardium (4 cases) and extensive involvement of the pleural surfaces (5 cases). Thus, in 10 patients radiotherapy was the only treatment at the time of the locoregional recurrence. Table I presents the characteristics of the group of patients who received surgery. Table II presents the characteristics of the 10 patients treated by radiotherapy alone. Radiotherapy was administered with 6°Co or 18 MV photons from a linear accelerator; the mediastinum was irradiated with opposed parallel portals with 2/3 of the dose delivered through the anterior port. Doses ranged

between 38 and 44 Gy in fractions of 1.8-2 Gy, in 45 weeks. A boost of 10-16 Gy was given with oblique wedged anterior fields or single anterior fields combining photons and electrons, in all patients except those who had received total exeresis. Pleural recurrences were treated with a variety of techniques, according to the extent of the lesions: 5 patients with diffuse pleural involvement of 1 hemithorax received a combined photon and electron irradiation of the whole pleural space and of the mediastinum up to a dose of 40 Gy, followed by boosting fields on major lesions; all other patients received single or multiple direct fields, mostly with electrons, on known lesions. Chemotherapy was not used as primary treatment of recurrence in this series; 4 patients received platinum based regimens at the moment of progression of intrathoracic lesions (3 cases) or occurrence of distant metastases (one case). Patients were followed-up in the Departments of Radiation Therapy and Thoracic Surgery; survivals were calculated by the method of Kaplan and Meier [8 ] and the differences between the subgroups were tested by the log-rank test. Results

Eleven patients were operated before radiotherapy: total resection of all known lesions in the mediastinum and pleura was possible in five, while in the other six a subtotal resection was performed. Objective responses were observed in all patients,

TABLE I Characteristics of patients who received surgery prior to irradiation. Case no.

Age (yrs)

Sex

Stage a

Histology

1 2 3 4 5 6

43 32 56 39 29 64

F M M M F F

II II III IVa II III

LE LE E LE L LE

7 8 9 10 11

47 67 43 54 61

M M M F M

III II IVa III III

E L LE LE E

a b ¢ d

KI

PO-RT b

RFI c

Site of relapse

MG d

Type of resection

RT dose Gy

60 60 90 90 60 50

No No Yes Yes No No

18 14 49 32 12 52

No Yes No No Yes No

Total Subtotal Total Subtotal Total Subtotal

40 46 40 48 38 50

100 70 100 60 90

No No Yes No No

73 38 82 19 32

Mediastinum Mediastinum Pleura Pleura Mediastinum Mediastinum + pleura Pleura Mediastinum Pleura Mediastinum Mediastinum

No Yes No Yes Yes

Subtotal Subtotal Total Total Subtotal

50 48 40 38 48

Stage at presentation according to Masaoka (ref. [ 11 ]). Post-operative radiotherapy at the time of primary treatment, Relapse-free interval between primary treatment and recurrence in months. Myasthenia gravis at the moment of treatment of recurrence. E = epithelial; KI = Karnofsky Index; L = lymphocytic, LE = lymphoepithelial.

223 T A B L E II Characteristics o f patients w h o received radiotherapy alone. Case no.

Age (yrs)

Sex

Stage a

Histology

1

54

F

II

LE

2 3

37 32

F M

III II

4 5 6 7

63 43 74 68

F M M F

8

47

9 10

38 71

a b c d

KI

PO-RT b

RF1 c

Site o f relapse

MG ~

R T dose Gy

90

No

37

No

54

LE E

90 60

Yes No

59 22

Yes Yes

48 52

III II IVa II

LE LE L E

90 100 50 60

No No Yes No

49 45 53 76

No Yes No Yes

54 50 48 48

M

III

LE

80

No

12

No

52

F F

lII III

LE L

60 60

No No

56 23

Mediastinum + pleura Pleura Mediastinum + pleura Pleura Pleura Pleura Mediastinum + pleura Mediastinum + pleura Pleura Mediastinum

No Yes

50 48

Stage at presentation according to M a s a o k a (ref. [ l 1 ]). Post-operative radiotherapy at the time of primary treatment. Relapse-free interval between primary treatment and recurrence in m o n t h s . M y a s t h e n i a gravis at the m o m e n t of treatment of recurrence. E = epithelial; KI = K a r n o f s k y Index; L = lymphocytic; L E = lymphoepithelial.

100

both in the surgery + radiotherapy group and in the radiotherapy alone group. Complete remission, however, was difficult to assess as small residual pleural nodules or irregularities of the mediastinal profile after radiotherapy did not always necessarily mean persistence of active disease. The 7 year actuarial survival of the whole group was 70~o. Five patients have died at the moment of this analysis: in 4 cases death was related to the progression of intrathoracic disease, and in one case to distant metastases. Survival was 74~o after surgery + radiotherapy and 65 ~o after radiotherapy alone and the difference was not statistically significant (Fig. 1). The survival of the 9 patients excluded from the study has also been calculated for comparison: median survival was only 26 months and there were no survivors beyond 5 years, indicating that this was a group with really advanced disease. Table III presents an analysis of results as a function of patient characteristics with potential prognostic significance: age, sex, histology and persistence or recurrence of myasthenia gravis did not predict for a different prognosis. The final outcome of patients with mediastinal recurrences was similar to that of patients with pleural recurrences. Patients with lesions involving pleura and mediastinum had a 40 ~o actuarial 7-year survival: although the difference in survival between these patients and those with less extensive disease is

............ i ........................................... i

80-

L-

'~

~02

.D 13

4O

. . . . . . . . . . [61

o 2(? N 20 ~onths

Cro~

40 th~

60 ~nd

80 o~

I00

radioth~r,

120 apU

Fig. 1. Cumulative survival according to treatment: _ _ , all patients . . . . . . , s u r g e r y + r a d i o t h e r a p y , - - - - , radiotherapy alone. N u m b e r s in parentheses indicate patients at risk at. different time intervals.

not significant, there is a trend for worse results (mediastinum + pleura versus mediastinum alone: p = 0.12; mediastinum +pleura versus pleura alone: p = 0.053). The long-term survival was affected by performance status: patients with Karnofsky index > 70 had a significantly better 7-year survival (100 ~o versus 28%, p = 0.015). Tolerance to irradiation was good; subacute radiation reactions in the lung were observed in 7 patients, but all resolved spontaneously and did not require steroids. Some grade of lung fibrosis was present in all cases, however in none was there a severe functional impairment.

224 TABLE III Univariate analysis of prognostic factors. Variable (patients at risk) Age t 50 (10)

% Survival at 7 years

p (log-rank test)

87 54

NS

76 62

NS

81 51 51

NS

Sex Males (11) Females (10)

Histology LE (12) E (5) L (4)

Karnofsky Index >_-70 (11) < 70 (10)

100 28

0.0015

Site of relapse Mediastinum (7) Pleura (9) Mediastinum + pleura (5)

74 77 40

NS

65 79 66

NS

60 77

NS

Type of resection None (10) Subtotal (6) Total (5)

Myasthenia gravis Yes (10) No (11)

E = epithelial; L = lymphocytic; LE = lymphoepithelial.

Discussion

Thymoma is a slowly growing tumor, and long survivals are often observed even in patients in whom the first line treatment has failed to achieve cure [2,9,19]. Surgery is certainly the most important therapeutic tool at the moment of diagnosis; the role of radiotherapy is somewhat less clear [4,17], although the tumor is relatively radiosensitive and most authors believe that post-operative irradiation of invasive thymomas is useful [2,5,7,16,18,20]. The treatment strategy at the moment of relapse is more difficult to define. Some patients are clearly beyond the possibility of radical treatment, either because of distant metastases or because of locally advanced lesions. In these cases significant palliation can be obtained by radiotherapy, but survival cannot be prolonged. Other patients have lim-

ited intrathoracic recurrences involving only the pleural surfaces, or the mediastinum without apparent invasion of the major cardiovascular structures, or involving the mediastinum more extensively, but still without being bulky, so that they can be encompassed in radiotherapy fields of reasonable size. Although these cases can enjoy relatively long survivals even if no treatment is attempted, the disease will sooner or later progress and lead to disturbing symptoms and finally death [ 12]: for this reason we have used an aggressive approach in these situations. Results were satisfactory in patients in good general condition, while any attempt of radical therapy in cases with compromised general status has proven unsuccessful in our experience. Survival at 7 years was only 28% in patients with Karnofsky index below 70. When surgery is feasible it can generally achieve a major debulking or even total resection. In our hands, a subtotal exeresis was obtained in 6 patients and a total resection of all known lesions in five. All patients were then irradiated to prevent further local recurrences and the 7-year survival in these cases was 74%. The results of radical radiotherapy in inoperable patients however were not clearly inferior despite some of these patients had extensive lesions, invading the mediastinum and/or the pleura, that precluded the operability. The relative roles of surgery and radiotherapy are not completely clarified. The use of post-operative radiotherapy after resection of a local recurrence seems logical, however it is not clearly shown that it is necessary. On the other hand, since the results of radiotherapy in inoperable patients were not clearly worse than those of combined treatment, the role of surgery could be questioned. The numbers in this series are small and we feel that it would be unwise to conclude from our results that radiotherapy alone is the treatment of choice for all intrathoracic recurrences of thymorea that can be radically irradiated. It is however important to state that some inoperable patients can enjoy long survivals if radiotherapy at tumoricidal doses is administered to all sites of relapse. This is a selected series: patients fitting the criteria for a radical treatment represent however in our experience a significant proportion of those who are referred for treatment of their relapse. An aggressive approach to these cases can yield long survivals in the majority and should be attempted in all patents whose general conditions are not compromised.

225

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