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Radiotherapy for Stage I seminoma testis: Results of treatment and complications
Radiotherapy and Oncology, 6 (1986) 115-120 Elsevier
115
RTO 00233
Radiotherapy for Stage I seminoma testis: Results of treatment and complications C. H a m i l t o n , A. H o r w i c h , D. E a s t o n a n d M . J. P e c k h a m * Institute o f Cancer Research and The Royal Marsden Hospital, London and Surrey, U.K.
(Received 5 September 1985, revision received24 December 1985, accepted 20 January 1986)
Key words: Seminoma;Radiotherapy, Results, Morbidity
Summary The results of treatment by infradiaphragmatic lymph node irradiation and orchiectomy in 232 patients with Stage I testicular seminoma seen between 1963 and 1983 are reported. O f this group, only five (2%) patients relapsed and none died from seminoma. Contralateral testicular tumours occurred in 12 patients and five developed second non-testicular malignancies. The acute and late morbidity of radiotherapy was low although 15 patients developed peptic ulceration. There was a significant association between prior abdominal surgery and a history of dyspepsia with ensuing peptic ulceration. Future management policy is discussed on the basis of these observations.
Introduction The results of treatment by orchiectomy and radiotherapy for Stage I testicular seminoma are excellent with cure rates exceeding 90% [1,2,6,13,14,16]. These results may reflect the radiosensitivity of seminoma and the consequent high probability of eradicating occult tumour, on the other hand, they may also be attributable to a low incidence o f retroperitoneal lymph node metastases. Limited data from lymphadenectomy series suggest that less than 10% of patients with clinical Stage I seminoma have histologically positive nodes [7]. A policy of
surveillance after orchiectomy has been pursued successfully in non-seminomatous testicular germcell tumour patients [10,11] and it is appropriate to consider whether a similar approach would be justifiable in seminoma, particularly in view o f the high cure rates now achievable in advanced disease with chemotherapy [12]. In this report we analyse the results of treatment and the complications of lymph node irradiation in patients with Stage I seminoma as a basis for considering the appropriateness of surveillance as a management policy.
Patients and methods * Address for correspondence: Professor M. J. Peckham, Testicular Tumour Unit, The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM 2 5PX. U.K.
A total of 232 patients with clinical Stage I seminoma receiving para-aortic and ipsilateral pelvic
0167-8140/86/$03.50 9 1986 Elsevier SciencePublishers B.V. (BiomedicalDivision)
116
Radiotherapy
908070-
60Number of patients
50 40 302010O-
[ .....
10-19
2 0 - 29
30-39
40-49
50-59
60-69
70-79
Age ( y e a r s )
Fig. 1. Age distribution of Stage I testicular seminoma patients (Royal Marsden Hospital 1963-1983). lymph node irradiation following orchiectomy between 1963 and 1983 are included in the study. Details were obtained from patients records. It is our policy to maintain regular follow-up on all patients referred to the Unit. Patients have been followed for 12 months to 20 years (median 7 years). The age range was 19 to 70 years, mean 39 years (Fig. 1). All patients had a histologically verified diagnosis of pure seminoma. The tumour was right-sided in 140 (61%) of patients, left-sided in 90 (38%) and occurred as bilateral synchronous presentations in two patients. Eighteen patients (8%) had a history of maldescent and in six this was bilateral. Of the 12 patients with unilateral maldescent, tumour occurred in the contralateral normally descended testis in four.
Staging and staging classification Between 1963 and 1977 staging included chest radiographs, lymphography, intravenous urography and liver function tests. CT scanning became available in 1977 and was employed on a selective basis. Serum human chorionic gonadotrophin and alpha-fetoprotein titres were routinely assayed after 1973. The Royal Marsden Hospital staging classification was employed [8]. Stage I disease is defined as tumour confined to the testis with no evidence of metastases after clinical staging.
Details of radiotherapy have been published elsewhere [9]. Treatment was by equally weighted opposed anterior and posterior fields extending from D 1 0 / l l to the mid-obturator foramen. The paraaortic field was wide enough to cover nodes opacified at lymphography and extended laterally to the renal hila. Inferiorly the field was shaped to include the ipsilateral pelvic lymph nodes, the point of inflexion between the para-aortic and pelvic area being at the lower border of L5 medially and the transverse process of L4 laterally. The remaining testis was protected by 1 cm thick lead cups. If there had been a scrotal incision (39 patients; 17%) scrotal involvement by tumour or a history o f orchidopexy, the ipsilateral scrotal sac was irradiated using 250 kV X-rays with a lead cut-out to protect the contralateral testis. In these cases the pelvic field was extended down to include the inguinal nodes. The para-aortic and pelvic nodes were irradiated with 6-8 MeV photons delivering mid-plane doses of the order of 30 Gy in 3-3.5 weeks. In earlier years there was some variation o f dose employed and the anterior and posterior fields were not routinely treated each day. In latter years the tumour dose has been 30 Gy in 15 fractions over 21 days with anterior and posterior fields treated each day.
Statistical methods Survival rates were calculated using the KaplanMeier method [5].
Results
As shown in Table I, only 5 of 232 patients (2%) relapsed and there were no deaths from seminoma. Actuarial survival rates at 5 and 10 years were 99 and 94%, respectively. The time from orchiectomy to relapse was 10, 12, 21, 44 and 60 months (Fig. 2). The sites of relapse and outcome of salvage treatment which was successful in all five patients is summarized in Table II.
117 TABLE I Clinical Stage I testicular seminoma: outcome of treatment by orchiectomy and infradiaphragmatic lymph node irradiation (The Royal Marsden Hospital 1963-1983). Total patients
Number relapsing"
Deaths from seminoma
Deaths from teratomab
Deaths from other causes
232
5
0
2
10
a Actuarial 5 and 10 year survival rates are 99 and 94%, respectively. b Non-seminomatous germ-cell tumour.
Causes of death and second malignancy I n the t o t a l g r o u p there were 12 d e a t h s as s h o w n in T a b l e III. Bilateral testicular t u m o u r s o c c u r r e d in 12 cases; s e m i n o m a in 7; m i x e d s e m i n o m a / t e r a t o m a in one a n d t e r a t o m a in 4. T h e interval b e t w e e n first a n d s e c o n d t u m o u r s r a n g e d f r o m zero ( s y n c h r o n ous t u m o u r s ) to 6 years (Fig. 2). In one o f the seven
I 0 0 ~ tst .."" 80 tt
Cumulative percentage of r e l a p s e or second tumours
' 40
20
t
i
0
.,:
..'"" 210
.-'"'"""
..'"'"'""'"" ~
R e l a p s e (5 p a t i e n t s )
_ _ _ Contralateral lesticular t u r n o u t (12 patients) Non-testicular malignancy " . . . . (5 p a t i e n t s )
I I 80/ I I I I 40 60 100 120 140 160 Time after orchidectomy (months)
i 180
I 200
Fig. 2. Time between orchidectomy and diagnosis of relapse, contralateral testicular tumour or non-testicular malignancy in Stage I seminoma (Royal Marsden Hospital 1963-1983).
p a t i e n t s with b i l a t e r a l s e m i n o m a s the t u m o u r s a p p e a r e d s y n c h r o n o u s l y . This p a t i e n t received inverted Y - i r r a d i a t i o n a n d is disease-free at 4 years. O f the six p a t i e n t s with m e t a c h r o n o u s b i l a t e r a l semin o m a s all h a d Stage I disease w h e n r e s t a g e d after the s e c o n d o r c h i e c t o m y . T w o p a t i e n t s have been o b s e r v e d a n d have n o t r e l a p s e d a n d f o u r received f u r t h e r r a d i o t h e r a p y to the i p s i l a t e r a l pelvic nodes. One irradiated patient developed disseminated t u m o u r which at a u t o p s y p r o v e d to be t e r a t o m a . T h e o t h e r s are disease-free at 8, 14 a n d 15 years. The patient who developed a contralateral mixed s e m i n o m a / t e r a t o m a is b e i n g o b s e r v e d a n d is well. O f the f o u r p a t i e n t s w h o d e v e l o p e d t e r a t o m a t o u s s e c o n d t u m o u r s one r e l a p s e d w i t h m e d i a s t i n a l a n d p u l m o n a r y m e t a s t a s e s a n d has been s a l v a g e d with platinum-containing chemotherapy. A second p a t i e n t r a p i d l y d i s s e m i n a t e d a n d d i e d p r i o r to the e r a o f effective c h e m o t h e r a p y .
TABLE II Clinical Stage I testicular seminoma treated by orchiectomy and lymph node irradiation: sites of relapse and outcome of salvage treatment (The Royal Marsden Hospital 1963-1983). Site of relapse
Time to relapse after start of radiotherapy (mths)
Treatment of relapse
Outcome from time of relapse
Lung Left supraclavicular nodes Mediastinal nodes Lung/pleura Mediastinal, supraclavicular and axilla nodes
44 60 12 10 21
Lobectomy Radiotherapy Radiotherapy Chemotherapy Chemotherapy
Disease-free Disease-free Disease-free Disease-free Disease-free
" Lost to follow-up 7 years ago.
at at at at at
11 years 1 yea# 11 years 2 years 2 years
118 TABLE III
TABLE IV
Clinical Stage I testicular seminoma: causes of death in patients treated by orchiectomy and lymph node irradiation (The Royal Marsden Hospital 1963-1983).
Clinical Stage I testicular seminoma treated by orchiectomy and lymph node irradiation: influence of prior surgery and dyspepsia on the development of peptic ulceration (The Royal Marsden Hospital 1963-1983).
Cause of death
Contralateral non-seminomatous germ-cell testicular tumour Myocardial infarction Chronic bronchitis Peritonitis Cerebrovascular accident Non-testicular malignancy
Time from presentation (yrs)
1, 6 5, 8, 9 8, 10 10 12 5, 8, 19
Factor
Peptic ulceration
p Value
Prior abdominal surgery No prior abdominal surgery
5/27 (19%) 10/205 (5~
0.02
Prior history of dyspepsia No prior history of dyspepsia
4/10 (40%)
< 0.001
11/222 (5%)
Discussion
Five patients developed second non-testicular malignancies as follows: acute myeloid leukaemia at 7 years, pancreatic cancer at 2 years, gastric cancer at 16 years, prostatic cancer at 12 years and a carcinoma of the buccal mucosa at 8 years (Fig. 2). The expected number of tumours based on agestandardized national incidence rates is 5.2.
Peptic ulceration following radiotherapy Symptoms compatible with peptic ulceration occurred in 15 patients. In 13 the diagnosis was established by barium studies which showed a duodenal ulcer in 11 patients, gastric in one and gastric and duodenal ulceration in a further patient. In all 15 patients the pain was described as severe and in five patients symptomatology persisted for more than one year. Twelve patients were treated medically and three came to surgery, one of whom developed pyloric stenosis and died of peritonitis post-operatively. There was no apparent association between the appearance of this complication and total dose, dose per fraction, overall time or number of fields treated each day. Of the 25 patients who had moderate or severe acute gastrointestinal toxicity, seven developed peptic ulceration. As shown in Table IV, prior abdominal surgery or a history of dyspepsia strongly predisposed the patient to subsequent peptic ulceration.
Post-orchiectomy lymph node irradiation in seminoma is based on the assumption that a proportion of patients with clinical Stage I disease will have occult metastases in the draining lymph nodes. The stage distribution at presentation of patients with testicular seminoma shows that more than 70% have Stage I disease indicating that this tumour type has a low propensity for spread. Limited data from lymph node dissection adds support to this contention. In the series of Stage I patients undergoing surgery reported by Maier et al. [7], only 8% proved to have histologically demonstrable metastases. Since in this era patients were not investigated by lymphography and CT scanning it is possible that this figure could be even lower. It is likely therefore that the large majority of Stage I patients receiving post-orchiectomy radiotherapy do so unnecessarily. Furthermore, if the small proportion of patients relapsing after radiotherapy (2% in the present series) represent part of the population with occult metastases (approximately 8 %), then the cure rate with radiotherapy or clinical Stage I patients with metastatic disease may be of the order of 60-70%. The tumour dose for small-size metastases of seminoma is unknown, but may be lower than the dose of 30 Gy employed in the present series. With doses of this order late morbidity is rarely a problem although our results suggest that there may be
119 an increased risk of peptic ulceration particularly in patients with a history of dyspepsia. However, it is difficult to be sure of the aetiological role of irradiation in this context and there are not comparable control series with which the incidence of peptic ulceration can be compared. Five second nontesticular malignancies were observed in the present series but there was no evidence that this represented an increased risk over the expected number of cancers in an unirradiated population. Hay et al. [3] in a study of 547 testicular tumour patients treated with radiotherapy between 1950 and 1969 found 51 second malignancies of which 7 were testicular. The incidence of second non-testicular cancers was significantly increased compared with the expected rate. The difference in incidence of second non-testicular tumours in the series of Hay et al. [3] and in the present series (8 and 2%, respectively) is likely to be explained by the longer observation period in the Edinburgh study. During the first 5 years after radiotherapy most second tumours are testicular, as shown in Fig. 2. As reported by Hay et al. [3], the second period during which there is a significant increase in observed compared with expected rates of malignancy is attributable to non-testicular tumours and occurs between 15 and 19 years. The relapse rate observed in the present study is closely similar to that recently reported by Schultz et al. [13] who described 13 treatment failures (3%) in 424 Stage I seminoma patients treated by orchiectomy and radiotherapy between 1976 and 1980 in Denmark. In the Danish series 5/8 relapses were non-seminomatous and 2 of the 8 cases with seminoma metastases died of their disease. In the present series all Stage I patients relapsing after radiotherapy were successfully salvaged and there has been no death attributable to metastatic seminoma. Given the high degree of effectiveness of platinum-containing chemotherapy in advanced seminoma, the salvage of relapsing patients after irradiation or in a surveillance study should rarely be associated with treatment failure [12]. The appearance of second testicular tumours is a well-documented phenomenon and unlikely to be related to radiotherapy since similar patterns are observed in patients treated surgically for non-seminomatous
tumours and in patients undergoing surveillance. The question arises as to whether radiotherapy after orchiectomy can be abandoned in favour of a policy of close surveillance, as has been conducted successfully for non-seminomatous germ-cell tumours [10,11]. Surveillance in non-seminomatous tumours is facilitated by the generally short interval between orchiectomy and the appearance of metastatic tumour in relapsing patients and by employing alpha-fetoprotein and human chorionic gonadotrophin as tumour markers. As shown in the present study, the time interval between orchiectomy and diagnosis of metastases in the five patients who relapsed ranged from 0 to 60 months. Three relapses occurred within the first 2 years and it is possible that the intervals in the remaining two patients might have been shorter if current imaging techniques including CT scans had been available. Until recently, there has been an absence of reliable tumour markers for seminoma, although a proportion produce human chorionic gonadotrophin and more recent studies have demonstrated that placental alkaline phosphatase levels are elevated in patients with demonstrable metastatic tumour [4,17]. However, the value of placental alkaline phosphatase in longitudinal studies particulary in the surveillance of Stage I disease, remains to be established. In our view the routine treatment of choice for patients with Stage I seminoma is radiotherapy and surveillance should be regarded as a clinical research exercise to be conducted in centres where close monitoring can be assured, where modern imaging facilities are readily available and where placental alkaline phosphatase assays can be carried out. Certainly, if the reliability of the patients' attendance is in doubt radiotherapy should be given. On the other hand, if there is a prior history of peptic ulceration a policy of surveillance will avoid the risks of producing an exacerbation by radiotherapy. Furthermore, when issues of fertility are at stake then the ommission of radiotherapy should also be considered. This includes those situations where according to traditional practice the treatment field is extended inferiorly to include the inguinal nodes and where the ipsilateral scrotal sac is irradiated, for example, after scrotal orchiectomy,
120 t r a n s c r o t a l biopsy or p r i o r orchidopexy. A l t h o u g h fertility m a y be recovered after scrotal i r r a d i a t i o n this is a n u n c o m m o n event a n d the large m a j o r i t y o f patients are sterilised. W e have previously reported that in patients treated with a linear accelerator in w h o m the fields do n o t extend below the ipsilateral o b t u r a t o r f o r a m e n the r a d i a t i o n dose to the c o n t r a l a t e r a l testis (0.33-0.52 Gy) is c o m p a t i b l e with recovery o f spermatogenesis [15]. H o w e v e r , w h e n scrotal a n d i n g u i n a l i r r a d i a t i o n are e m p l o y e d the dose to the c o n t r a l a t e r a l testis is s u b s t a n t i a l l y higher (0.75-1.38 G y ) a n d p e r m a n e n t a z o o s p e r m i a is likely to occur. Since the p r o p o r t i o n o f clinical Stage I s e m i n o m a patients h a r b o u r i n g occult metastases is u n k n o w n a n d data b e a r i n g o n this p o i n t are extremely scanty, we felt it justifiable in 1983 to initiate a surveillance study, to better define the n a t u r a l history o f Stage I s e m i n o m a a n d provide a firm basis for future practice. So far, 46 patients have been entered into the study, two relapses have occurred b o t h in the r e t r o p e r i t o n e u m a n d b o t h patients are in complete remission following i n f r a d i a p h r a g m a t i c i r r a d i a t i o n . A l t h o u g h b o t h relapses have occurred w i t h i n one year o f orchiectomy, longer o b s e r v a t i o n times in larger n u m b e r s of patients will be necessary before the p r o p o r t i o n o f p a t i e n t s with occult metastases can be identified with confidence. Details o f the s e m i n o m a surveillance study will be p u b l i s h e d in due course.
Acknowledgements We are grateful to Julie Butcher for p r e p a r i n g the m a n u s c r i p t a n d J u d y Nicholls a n d G i l l i a n Jay for their help in a s s e m b l i n g the clinical data.
References I Caiman, F. M. B., Peckham, M. J. and Hendry, W. F. The pattern of spread and treatment of metastases in testicular seminoma. Br. J. Urol. 51: 154-160, 1979. 2 Earle, J. D., Bagshaw, M. A. and Kaplan, H. S. Supervoltage radiation therapy of testicular tumours. Am. J. Roentgenol. 117: 653-661, 1973.
3 Hay, J. H., Duncan, W. and Kerr, G. R. Subsequent malignancies in patients irradiated for testicular tumours. Br. J. Radiol. 57: 597-602, 1984. 4 Horwich, A., Tucker, D. F. and Peckham, M. J. Placental alkaline phosphatase as a tumour marker in seminoma using the HI7E2 monoclonal antibody assay. Br. J. Cancer 51: 625-629, 1985. 5 Kaplan, E. L. and Meier, P. Non-parametric estimation from incomplete observations. J. Am. Stat. Assoc. 457-481, 1958. 6 Maier, J. G. and Sulak, M. H. Radiation therapy in malignant testis tumours 1. Seminoma. Cancer 32: 1212-1216, 1973. 7 Maier, J. G., Sulak, M. H. and Mittemeyer, B.T. Seminoma of the testis: analysis of treatment success and failure. Am. J. Roentgenol. 102: 596-602, 1968. 8 Peckham, M. J. Testicular tumours: investigation and staging: general aspects and staging classification. In: The Management of Testicular Tumours, pp. 89-101. Editor M. J. Peckham. Edward Arnold Ltd., London, 1981. 9 Peckham, M. J. (Ed.) Serninoma testis. In: The Management of Testicular Tumours, pp. 134-151. Editor: M. J. Peckham. Edward Arnold Ltd., London, 1981. 10 Peckham, M. J., Barrett, A., Horwich, A. and Hendry, W. F. Orchiectomy alone for Stage I testicular non-seminoma. Br. J. Urol 55: 754-759, 1983. I 1 Peckham, M. J., Barrett, A., Husband, J. E. and Hendry, W. F. Orchidectomy alone in testicular Stage I non-seminomatous germ-cell tumours. Lancet II: 678-680, 1982. 12 Peckham, M. J., Horwich, A. and Hendry, W. F. Advanced seminoma: treatment with cis-platin based chemotherapy or carboplatin (JM8). Br. J. Cancer 52:7 14, 1985. 13 Schultz, H. P., Von der Maase, H., Rorth, M., Pedersen, M., Sandberg Nielsen, E., Walbom-Jorgensen S. and DATECA Study Group. Testicular seminoma in Denmark 1976-1980: results of treatment Acta Radiol. Oncol. Radiat. Phys. Biol. 23: Fasc 4, 263 270, 1984. 14 Thomas, G. M., Rider, W. D., Dembo, A. J., Cummings, B. J., Gospodarowicz, M., Hawkins, N. V., Herman, J. G. and Keen, C. W. Seminoma of the testis. Results of treatment and patterns of failure after radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 8: 165-174, 1982. 15 Thomas, P. R. M., Mansfield, M. D., Hendry, W. F. and Peckham, M. J. The implications of scrotal interference for the preservation of spermatogenesis in the management of testicular tumours. Br. J. Surgery 64:352 354, 1977. 16 Van der Werf-Messing, B. Radiotherapeutic treatment of testicular tumours. Int. J. Radiat. Oncol. Biol. Phys. 1: 235-248, 1976. 17 Wahren, B., Holmgren, P. A. and Stigbrand, T. Placental alkaline phosphatase, alphafetoprotein and carcino embryonic antigen in testicular tumour tissue typing by means of cytologic smears. Int. J. Cancer 24: 749-753, 1979.
115
RTO 00233
Radiotherapy for Stage I seminoma testis: Results of treatment and complications C. H a m i l t o n , A. H o r w i c h , D. E a s t o n a n d M . J. P e c k h a m * Institute o f Cancer Research and The Royal Marsden Hospital, London and Surrey, U.K.
(Received 5 September 1985, revision received24 December 1985, accepted 20 January 1986)
Key words: Seminoma;Radiotherapy, Results, Morbidity
Summary The results of treatment by infradiaphragmatic lymph node irradiation and orchiectomy in 232 patients with Stage I testicular seminoma seen between 1963 and 1983 are reported. O f this group, only five (2%) patients relapsed and none died from seminoma. Contralateral testicular tumours occurred in 12 patients and five developed second non-testicular malignancies. The acute and late morbidity of radiotherapy was low although 15 patients developed peptic ulceration. There was a significant association between prior abdominal surgery and a history of dyspepsia with ensuing peptic ulceration. Future management policy is discussed on the basis of these observations.
Introduction The results of treatment by orchiectomy and radiotherapy for Stage I testicular seminoma are excellent with cure rates exceeding 90% [1,2,6,13,14,16]. These results may reflect the radiosensitivity of seminoma and the consequent high probability of eradicating occult tumour, on the other hand, they may also be attributable to a low incidence o f retroperitoneal lymph node metastases. Limited data from lymphadenectomy series suggest that less than 10% of patients with clinical Stage I seminoma have histologically positive nodes [7]. A policy of
surveillance after orchiectomy has been pursued successfully in non-seminomatous testicular germcell tumour patients [10,11] and it is appropriate to consider whether a similar approach would be justifiable in seminoma, particularly in view o f the high cure rates now achievable in advanced disease with chemotherapy [12]. In this report we analyse the results of treatment and the complications of lymph node irradiation in patients with Stage I seminoma as a basis for considering the appropriateness of surveillance as a management policy.
Patients and methods * Address for correspondence: Professor M. J. Peckham, Testicular Tumour Unit, The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM 2 5PX. U.K.
A total of 232 patients with clinical Stage I seminoma receiving para-aortic and ipsilateral pelvic
0167-8140/86/$03.50 9 1986 Elsevier SciencePublishers B.V. (BiomedicalDivision)
116
Radiotherapy
908070-
60Number of patients
50 40 302010O-
[ .....
10-19
2 0 - 29
30-39
40-49
50-59
60-69
70-79
Age ( y e a r s )
Fig. 1. Age distribution of Stage I testicular seminoma patients (Royal Marsden Hospital 1963-1983). lymph node irradiation following orchiectomy between 1963 and 1983 are included in the study. Details were obtained from patients records. It is our policy to maintain regular follow-up on all patients referred to the Unit. Patients have been followed for 12 months to 20 years (median 7 years). The age range was 19 to 70 years, mean 39 years (Fig. 1). All patients had a histologically verified diagnosis of pure seminoma. The tumour was right-sided in 140 (61%) of patients, left-sided in 90 (38%) and occurred as bilateral synchronous presentations in two patients. Eighteen patients (8%) had a history of maldescent and in six this was bilateral. Of the 12 patients with unilateral maldescent, tumour occurred in the contralateral normally descended testis in four.
Staging and staging classification Between 1963 and 1977 staging included chest radiographs, lymphography, intravenous urography and liver function tests. CT scanning became available in 1977 and was employed on a selective basis. Serum human chorionic gonadotrophin and alpha-fetoprotein titres were routinely assayed after 1973. The Royal Marsden Hospital staging classification was employed [8]. Stage I disease is defined as tumour confined to the testis with no evidence of metastases after clinical staging.
Details of radiotherapy have been published elsewhere [9]. Treatment was by equally weighted opposed anterior and posterior fields extending from D 1 0 / l l to the mid-obturator foramen. The paraaortic field was wide enough to cover nodes opacified at lymphography and extended laterally to the renal hila. Inferiorly the field was shaped to include the ipsilateral pelvic lymph nodes, the point of inflexion between the para-aortic and pelvic area being at the lower border of L5 medially and the transverse process of L4 laterally. The remaining testis was protected by 1 cm thick lead cups. If there had been a scrotal incision (39 patients; 17%) scrotal involvement by tumour or a history o f orchidopexy, the ipsilateral scrotal sac was irradiated using 250 kV X-rays with a lead cut-out to protect the contralateral testis. In these cases the pelvic field was extended down to include the inguinal nodes. The para-aortic and pelvic nodes were irradiated with 6-8 MeV photons delivering mid-plane doses of the order of 30 Gy in 3-3.5 weeks. In earlier years there was some variation o f dose employed and the anterior and posterior fields were not routinely treated each day. In latter years the tumour dose has been 30 Gy in 15 fractions over 21 days with anterior and posterior fields treated each day.
Statistical methods Survival rates were calculated using the KaplanMeier method [5].
Results
As shown in Table I, only 5 of 232 patients (2%) relapsed and there were no deaths from seminoma. Actuarial survival rates at 5 and 10 years were 99 and 94%, respectively. The time from orchiectomy to relapse was 10, 12, 21, 44 and 60 months (Fig. 2). The sites of relapse and outcome of salvage treatment which was successful in all five patients is summarized in Table II.
117 TABLE I Clinical Stage I testicular seminoma: outcome of treatment by orchiectomy and infradiaphragmatic lymph node irradiation (The Royal Marsden Hospital 1963-1983). Total patients
Number relapsing"
Deaths from seminoma
Deaths from teratomab
Deaths from other causes
232
5
0
2
10
a Actuarial 5 and 10 year survival rates are 99 and 94%, respectively. b Non-seminomatous germ-cell tumour.
Causes of death and second malignancy I n the t o t a l g r o u p there were 12 d e a t h s as s h o w n in T a b l e III. Bilateral testicular t u m o u r s o c c u r r e d in 12 cases; s e m i n o m a in 7; m i x e d s e m i n o m a / t e r a t o m a in one a n d t e r a t o m a in 4. T h e interval b e t w e e n first a n d s e c o n d t u m o u r s r a n g e d f r o m zero ( s y n c h r o n ous t u m o u r s ) to 6 years (Fig. 2). In one o f the seven
I 0 0 ~ tst .."" 80 tt
Cumulative percentage of r e l a p s e or second tumours
' 40
20
t
i
0
.,:
..'"" 210
.-'"'"""
..'"'"'""'"" ~
R e l a p s e (5 p a t i e n t s )
_ _ _ Contralateral lesticular t u r n o u t (12 patients) Non-testicular malignancy " . . . . (5 p a t i e n t s )
I I 80/ I I I I 40 60 100 120 140 160 Time after orchidectomy (months)
i 180
I 200
Fig. 2. Time between orchidectomy and diagnosis of relapse, contralateral testicular tumour or non-testicular malignancy in Stage I seminoma (Royal Marsden Hospital 1963-1983).
p a t i e n t s with b i l a t e r a l s e m i n o m a s the t u m o u r s a p p e a r e d s y n c h r o n o u s l y . This p a t i e n t received inverted Y - i r r a d i a t i o n a n d is disease-free at 4 years. O f the six p a t i e n t s with m e t a c h r o n o u s b i l a t e r a l semin o m a s all h a d Stage I disease w h e n r e s t a g e d after the s e c o n d o r c h i e c t o m y . T w o p a t i e n t s have been o b s e r v e d a n d have n o t r e l a p s e d a n d f o u r received f u r t h e r r a d i o t h e r a p y to the i p s i l a t e r a l pelvic nodes. One irradiated patient developed disseminated t u m o u r which at a u t o p s y p r o v e d to be t e r a t o m a . T h e o t h e r s are disease-free at 8, 14 a n d 15 years. The patient who developed a contralateral mixed s e m i n o m a / t e r a t o m a is b e i n g o b s e r v e d a n d is well. O f the f o u r p a t i e n t s w h o d e v e l o p e d t e r a t o m a t o u s s e c o n d t u m o u r s one r e l a p s e d w i t h m e d i a s t i n a l a n d p u l m o n a r y m e t a s t a s e s a n d has been s a l v a g e d with platinum-containing chemotherapy. A second p a t i e n t r a p i d l y d i s s e m i n a t e d a n d d i e d p r i o r to the e r a o f effective c h e m o t h e r a p y .
TABLE II Clinical Stage I testicular seminoma treated by orchiectomy and lymph node irradiation: sites of relapse and outcome of salvage treatment (The Royal Marsden Hospital 1963-1983). Site of relapse
Time to relapse after start of radiotherapy (mths)
Treatment of relapse
Outcome from time of relapse
Lung Left supraclavicular nodes Mediastinal nodes Lung/pleura Mediastinal, supraclavicular and axilla nodes
44 60 12 10 21
Lobectomy Radiotherapy Radiotherapy Chemotherapy Chemotherapy
Disease-free Disease-free Disease-free Disease-free Disease-free
" Lost to follow-up 7 years ago.
at at at at at
11 years 1 yea# 11 years 2 years 2 years
118 TABLE III
TABLE IV
Clinical Stage I testicular seminoma: causes of death in patients treated by orchiectomy and lymph node irradiation (The Royal Marsden Hospital 1963-1983).
Clinical Stage I testicular seminoma treated by orchiectomy and lymph node irradiation: influence of prior surgery and dyspepsia on the development of peptic ulceration (The Royal Marsden Hospital 1963-1983).
Cause of death
Contralateral non-seminomatous germ-cell testicular tumour Myocardial infarction Chronic bronchitis Peritonitis Cerebrovascular accident Non-testicular malignancy
Time from presentation (yrs)
1, 6 5, 8, 9 8, 10 10 12 5, 8, 19
Factor
Peptic ulceration
p Value
Prior abdominal surgery No prior abdominal surgery
5/27 (19%) 10/205 (5~
0.02
Prior history of dyspepsia No prior history of dyspepsia
4/10 (40%)
< 0.001
11/222 (5%)
Discussion
Five patients developed second non-testicular malignancies as follows: acute myeloid leukaemia at 7 years, pancreatic cancer at 2 years, gastric cancer at 16 years, prostatic cancer at 12 years and a carcinoma of the buccal mucosa at 8 years (Fig. 2). The expected number of tumours based on agestandardized national incidence rates is 5.2.
Peptic ulceration following radiotherapy Symptoms compatible with peptic ulceration occurred in 15 patients. In 13 the diagnosis was established by barium studies which showed a duodenal ulcer in 11 patients, gastric in one and gastric and duodenal ulceration in a further patient. In all 15 patients the pain was described as severe and in five patients symptomatology persisted for more than one year. Twelve patients were treated medically and three came to surgery, one of whom developed pyloric stenosis and died of peritonitis post-operatively. There was no apparent association between the appearance of this complication and total dose, dose per fraction, overall time or number of fields treated each day. Of the 25 patients who had moderate or severe acute gastrointestinal toxicity, seven developed peptic ulceration. As shown in Table IV, prior abdominal surgery or a history of dyspepsia strongly predisposed the patient to subsequent peptic ulceration.
Post-orchiectomy lymph node irradiation in seminoma is based on the assumption that a proportion of patients with clinical Stage I disease will have occult metastases in the draining lymph nodes. The stage distribution at presentation of patients with testicular seminoma shows that more than 70% have Stage I disease indicating that this tumour type has a low propensity for spread. Limited data from lymph node dissection adds support to this contention. In the series of Stage I patients undergoing surgery reported by Maier et al. [7], only 8% proved to have histologically demonstrable metastases. Since in this era patients were not investigated by lymphography and CT scanning it is possible that this figure could be even lower. It is likely therefore that the large majority of Stage I patients receiving post-orchiectomy radiotherapy do so unnecessarily. Furthermore, if the small proportion of patients relapsing after radiotherapy (2% in the present series) represent part of the population with occult metastases (approximately 8 %), then the cure rate with radiotherapy or clinical Stage I patients with metastatic disease may be of the order of 60-70%. The tumour dose for small-size metastases of seminoma is unknown, but may be lower than the dose of 30 Gy employed in the present series. With doses of this order late morbidity is rarely a problem although our results suggest that there may be
119 an increased risk of peptic ulceration particularly in patients with a history of dyspepsia. However, it is difficult to be sure of the aetiological role of irradiation in this context and there are not comparable control series with which the incidence of peptic ulceration can be compared. Five second nontesticular malignancies were observed in the present series but there was no evidence that this represented an increased risk over the expected number of cancers in an unirradiated population. Hay et al. [3] in a study of 547 testicular tumour patients treated with radiotherapy between 1950 and 1969 found 51 second malignancies of which 7 were testicular. The incidence of second non-testicular cancers was significantly increased compared with the expected rate. The difference in incidence of second non-testicular tumours in the series of Hay et al. [3] and in the present series (8 and 2%, respectively) is likely to be explained by the longer observation period in the Edinburgh study. During the first 5 years after radiotherapy most second tumours are testicular, as shown in Fig. 2. As reported by Hay et al. [3], the second period during which there is a significant increase in observed compared with expected rates of malignancy is attributable to non-testicular tumours and occurs between 15 and 19 years. The relapse rate observed in the present study is closely similar to that recently reported by Schultz et al. [13] who described 13 treatment failures (3%) in 424 Stage I seminoma patients treated by orchiectomy and radiotherapy between 1976 and 1980 in Denmark. In the Danish series 5/8 relapses were non-seminomatous and 2 of the 8 cases with seminoma metastases died of their disease. In the present series all Stage I patients relapsing after radiotherapy were successfully salvaged and there has been no death attributable to metastatic seminoma. Given the high degree of effectiveness of platinum-containing chemotherapy in advanced seminoma, the salvage of relapsing patients after irradiation or in a surveillance study should rarely be associated with treatment failure [12]. The appearance of second testicular tumours is a well-documented phenomenon and unlikely to be related to radiotherapy since similar patterns are observed in patients treated surgically for non-seminomatous
tumours and in patients undergoing surveillance. The question arises as to whether radiotherapy after orchiectomy can be abandoned in favour of a policy of close surveillance, as has been conducted successfully for non-seminomatous germ-cell tumours [10,11]. Surveillance in non-seminomatous tumours is facilitated by the generally short interval between orchiectomy and the appearance of metastatic tumour in relapsing patients and by employing alpha-fetoprotein and human chorionic gonadotrophin as tumour markers. As shown in the present study, the time interval between orchiectomy and diagnosis of metastases in the five patients who relapsed ranged from 0 to 60 months. Three relapses occurred within the first 2 years and it is possible that the intervals in the remaining two patients might have been shorter if current imaging techniques including CT scans had been available. Until recently, there has been an absence of reliable tumour markers for seminoma, although a proportion produce human chorionic gonadotrophin and more recent studies have demonstrated that placental alkaline phosphatase levels are elevated in patients with demonstrable metastatic tumour [4,17]. However, the value of placental alkaline phosphatase in longitudinal studies particulary in the surveillance of Stage I disease, remains to be established. In our view the routine treatment of choice for patients with Stage I seminoma is radiotherapy and surveillance should be regarded as a clinical research exercise to be conducted in centres where close monitoring can be assured, where modern imaging facilities are readily available and where placental alkaline phosphatase assays can be carried out. Certainly, if the reliability of the patients' attendance is in doubt radiotherapy should be given. On the other hand, if there is a prior history of peptic ulceration a policy of surveillance will avoid the risks of producing an exacerbation by radiotherapy. Furthermore, when issues of fertility are at stake then the ommission of radiotherapy should also be considered. This includes those situations where according to traditional practice the treatment field is extended inferiorly to include the inguinal nodes and where the ipsilateral scrotal sac is irradiated, for example, after scrotal orchiectomy,
120 t r a n s c r o t a l biopsy or p r i o r orchidopexy. A l t h o u g h fertility m a y be recovered after scrotal i r r a d i a t i o n this is a n u n c o m m o n event a n d the large m a j o r i t y o f patients are sterilised. W e have previously reported that in patients treated with a linear accelerator in w h o m the fields do n o t extend below the ipsilateral o b t u r a t o r f o r a m e n the r a d i a t i o n dose to the c o n t r a l a t e r a l testis (0.33-0.52 Gy) is c o m p a t i b l e with recovery o f spermatogenesis [15]. H o w e v e r , w h e n scrotal a n d i n g u i n a l i r r a d i a t i o n are e m p l o y e d the dose to the c o n t r a l a t e r a l testis is s u b s t a n t i a l l y higher (0.75-1.38 G y ) a n d p e r m a n e n t a z o o s p e r m i a is likely to occur. Since the p r o p o r t i o n o f clinical Stage I s e m i n o m a patients h a r b o u r i n g occult metastases is u n k n o w n a n d data b e a r i n g o n this p o i n t are extremely scanty, we felt it justifiable in 1983 to initiate a surveillance study, to better define the n a t u r a l history o f Stage I s e m i n o m a a n d provide a firm basis for future practice. So far, 46 patients have been entered into the study, two relapses have occurred b o t h in the r e t r o p e r i t o n e u m a n d b o t h patients are in complete remission following i n f r a d i a p h r a g m a t i c i r r a d i a t i o n . A l t h o u g h b o t h relapses have occurred w i t h i n one year o f orchiectomy, longer o b s e r v a t i o n times in larger n u m b e r s of patients will be necessary before the p r o p o r t i o n o f p a t i e n t s with occult metastases can be identified with confidence. Details o f the s e m i n o m a surveillance study will be p u b l i s h e d in due course.
Acknowledgements We are grateful to Julie Butcher for p r e p a r i n g the m a n u s c r i p t a n d J u d y Nicholls a n d G i l l i a n Jay for their help in a s s e m b l i n g the clinical data.
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