The prognosis of clinical stage I testicular seminoma is favourable, with cure rates
after orchiectomy and adjuvant radiotherapy of approximately 95% (Zagars and Babaian,
1987; Dosmann and Zagars, 1993; Vallis et al, 1995; Bauman et al, 1998). Traditionally,
the target volume of radiotherapy comprises infradiaphragmatic para-aortic and ipsilateral
iliac lymph nodes (‘hockey-stick’ portals). Para-aortic lymph nodes are the primary
site of testicular lymphatic drainage as has been demonstrated by early lymphangiography
(Busch et al, 1965) and surgical lymphadenectomy studies (Mason et al, 1991). Thus,
limitation of the treatment portals of irradiation to the para-aortic lymphatics may
be sufficient for safe control of retroperitoneal micrometastases in stage I seminoma.
Omitting pelvic radiotherapy carries the potential benefit of reducing scattered radiation
to the contralateral testis, thus minimising the risk of treatment-induced infertility
(Jacobsen et al, 1997). Furthermore, limitation of the treatment portals may reduce
gastrointestinal toxicity as well as the risk of secondary malignancies after treatment
(Travis et al, 1997).
In 1986, Willich et al (1986) reported promising results for limited para-aortic radiotherapy
in stage I seminoma. This report encouraged us to initiate a prospective multicentre
trial in order to further evaluate the potential of small-volume para-aortic irradiation.
The aims of our study were to quantify acute side effects as well as late toxicity
of irradiation, and to identify the pattern of recurrences after treatment in order
to optimise radiotherapy portal definition. Subsequent to the commencement of our
study, several small pilot series showed recurrence rates and an overall survival
(OS) comparable to the results obtained with conventional hockey-stick treatment (Read
and Johnston, 1993; Niewald et al, 1995; Kiricuta et al, 1996; Logue et al, 1998;
Sultanem et al, 1998). Finally, in 1999, a large randomised MRC trial was published
demonstrating that confinement of the treatment portals to the para-aortic region
did not adversely affect the overall relapse rate compared to hockey-stick portals
(Fossa et al, 1999). This trial therefore established para-aortic radiotherapy as
the new standard of irradiation for stage I seminoma. In 2001, yet another randomised
MRC trial (TE18/19) demonstrated that reduction of the para-aortic radiation dose
to 20 Gy was safe without an increase in relapse rates as compared to 30 Gy (Jones
et al, 2001).
Interim results of the per protocol population of our trial have been reported previously
(Bamberg et al, 1999) lending further evidence to the role of para-aortic radiotherapy
as the new standard of radiotherapy in stage I seminoma. We now present an intention-to-treat
analysis of the entire study population after a median time to follow-up of 61 months.
PATIENTS AND METHODS
Patient selection and staging process
Patients with pure testicular seminoma in clinical stage I disease according to the
Royal Marsden classification system were eligible for the trial (no evidence of metastases).
High inguinal ablation of the tumorous testicle was required in every patient. The
staging procedure comprised a computed tomography (CT) of abdomen and pelvis, a chest
CT or chest X-ray, and analysis of tumour markers alpha-fetoprotein (AFP) and human
chorionic gonadotropin (β-HCG) prior and subsequent to ablation of the testis. During
the first year of the study, only patients with negative presurgical levels of β-HCG
were admitted. During the second and third year of the trial, patients with elevated
β-HCG levels of up to 200 IU l−1 were admitted as well, once there was evidence that
initial β–HCG elevation did not adversely affect the prognosis of the patients (Mirimanoff
et al, 1993). Exclusion criteria were a positive AFP level prior to orchiectomy, a
history of prior abdominal/pelvic radiotherapy or chemotherapy, withdrawal of informed
consent, concurrent severe diseases, or treatment with cobalt-60 machines. All patients
were asked for informed consent according to the Declaration of Helsinki.
Margins of the treatment portals were defined according to the following criteria.
The upper field border was set to the cranial rim of the 11th thoracic vertebra, and
the lower field margin was defined by the inferior border of the fourth lumbar vertebra.
Lateral field margins were defined by the ends of the lateral vertebral processes,
resulting in a width of the fields between 9 and 11 cm. Radiation portals were assigned
using treatment simulators in all patients.
Radiotherapy was applied through ventro-dorsal opposing fields with 4–20 MV photons
of linear accelerators. Both opposing fields were treated daily for five times a week
with a fraction of 2.0 Gy day−1 as specified in the ICRU 29 report for opposing fields.
A total dose of 26 Gy was applied in 17 days. If treatment interruptions of more than
3 days occurred, the total dose was increased to 30 Gy.
Protocol violations were classified as major violations (MAV) if they had either a
potentially adverse effect on the therapeutic efficacy of radiotherapy, or if they
were apt to increase treatment-related side effects (no chest imaging or no CT abdomen/pelvis
for staging, no AFP or elevated AFP prior to ablation, incorrect stage assignment,
dose prescription of less than 25 Gy or more than 34 Gy). Protocol violations were
classified as minor violations (MIV) if no negative effect on treatment outcome or
toxicity of irradiation was assumed.
Follow-up examinations were performed every 3 months for the first 2 years after radiotherapy
and every 6 months thereafter. Clinical examination, analysis of AFP and β-HCG, chest
X-ray, and assessment of late toxicities were required at each visit. Computed tomography
scans of abdomen and pelvis were taken twice a year for the first 2 years, and annually
thereafter. Abdominal ultrasound was performed in turn with abdomino-pelvic CT scans
(twice a year during the first 2 years, once a year after the second year).
The primary end point of the study was relapse-free survival at 5 years. Since a potent
salvage chemotherapy is available for relapsing patients, disease-specific survival
(DSS) was chosen as a secondary end point with an expected survival of at least 95%
at 5 years. Furthermore, acute and late gastrointestinal and cutaneous toxicities
(see below) were defined as secondary end points.
Monitoring of side effects
Acute and late side effects of treatment (gastrointestinal and cutaneous/soft tissue
effects) were recorded during radiotherapy and at each follow-up visit using the EORTC/RTOG
Data monitoring and data processing
The pathohistologic, diagnostic, therapeutic, and follow-up data were recorded on
specially prepared forms and entered into a computerised database at the coordinating
centre (Tübingen University) using the study monitoring system of the Institute for
Medical Information Processing (IMI, Tübingen University). After closing of the database
for this analysis (31 December 2001), all data were transferred to the IMI for further
The trial was designed as an observational study over a period of 3 years. With an
expected population of 600 at 3 years, a one-sided 95% confidence interval for a single
proportion using the large sample normal approximation will extend 1.3% from an expected
proportion of 3.7%. Thus, a 3.7% crude relapse rate for the entire study population
with a one-sided 95% confidence limit extending to 5% would ensure that a rate of
5% – considered to be the highest acceptable relapse rate – would not be surpassed.
Failure from treatment was continuously monitored over the treatment period and early
termination of the study was planned once the critical relapse rate was observed during
the treatment period.
Continuous variables were described by use of statistical characteristics (means,
standard deviations). Discrete variables are described as counts and percentages.
Kaplan–Meier estimates and their 95% confidence intervals were computed for disease-free
survival (DFS), OS, and DSS at 5 and 8 years after the end of radiotherapy. For statistical
analysis, the database was converted into SAS files and the SAS system (SAS 6.11 for
Windows) was used.
Between April 1991 and March 1994, 721 patients were enrolled for the study by 48
institutions (see Appendix A). There was no follow-up information available in 43
patients. These patients were excluded from the analysis as were another three patients
once informed consent had been withdrawn. Median time to follow-up of the remaining
study population of 675 patients was 61 months (range 0.6–121 months). Median age
of the patients was 34 years (range 16–73). A right-sided tumour was observed in 51.9%
of the patients, 47.7% had a left-sided tumour, and three patients (0.4%) presented
with bilateral seminoma. The distribution by tumour histology and T stage is shown
in Table 1
Distribution of primary tumours by histology and T stage according to 1987 TNM classification
Patients n (%)
No further subclassification
Patients n (%)
. In all, 82 patients (12.2%) presented with an elevated β-HCG prior to ablation testis.
A total of 485 patients (71.9%) were staged and treated strictly per protocol (PP),
while 115 (17%) and 75 patients (11.1%) had major or minor protocol violations, respectively.
Median radiation dose for PP, MAV, and MIV was 26 Gy (range 25–34 Gy).
Tumour control and survival
In all, 26 patients have relapsed from treatment (18 PP, four MAV, and four MIV).
Of 26 recurrences, 22 were located in infradiaphragmatic lymph nodes. There was one
mediastinal and one supraclavicular relapse. Three patients developed distant metastases.
A total of 24 patients were salvaged by chemotherapy or irradiation (Table 2
Recurrence from testicular cancer after adjuvant radiotherapy
Primary tumour location
Time to relapse
Location of recurrent disease
Histology of relapse
Treatment for relapse
Liver, lung, iliac left
4 × PEI+IF-RT left iliac 36 Gy
Th 8–10 with intraspinal tumour growth
IF-RT 40.5 Gy+2 × PEB
C4–6 and cervical lymph nodes
4 × PEB+IF-RT 30 Gy
Vesicular seminalis righta
4 × carboplatin, on local relapse in vesicula seminalis: pelvic RT to 26 Gy and prostatic
boost to 30 Gy
Seminoma and lymphoma
Mantle-field RT 30 Gy
6 × PEB
3 × PEB+surgery
Left kidney hilum
Left iliac+left kidney hilum
4 × PEB, 2 × PEI, surgery for residual lymphoma
Right upper iliac commune, bifurcation
Surgery+3 × PEB
Low para-aortic iliac left
Surgery+3 × PEB
Left kidney hilum and iliac commune left
4 × PEB
Surgery+IF-RT 26 Gy
IF-RT 30 Gy
Iliac right, bifurcation
4 × PEB
3 × PEI
3 × PEB
Surgery+3 × PEV
Surgery (inguinal left)+RT bilateral iliac/inguinal and left scrotal: 42 Gy
34 months after PD: para-aortic/iliac and mediastinal; CR after 4 × CEB
High iliac right and para-aortic right
Refused salvage treatment
Right kidney hilum
2 × PEB
Iliac commune left/external iliac
Surgery+chemotherapy, schedule unknown
Surgery+IF-RT 36 Gy
40 months after PD: inguinal left; CR after surgery+2 × PEB
4 × PEB+1 × PEI
3 × PEB
Left kidney hilum, para-aortic
4 × PEI
ND=not done; CR=complete remission; PEB= cisplatin, etoposide, bleomycin; PEI= cisplatin,
etoposide, ifosfamide; PEV=cisplatin, etoposide, vincristin; CEB=carboplatin, etoposide,
bleomycin; IF-RT=involved-field radiotherapy; RT=radiotherapy; PD=primary diagnosis.
Patient suffered from second tumour (meningioma).
Recurrence combined with cc-cb-lymphoma.
, Figure 1
Locations of infradiaphragmatic recurrences. The numbers refer to Table 2.
). There was no ‘in-field’ relapse except for one patient who on review of the initial
CT scans was found to have stage IIB seminoma. This patient progressed rapidly after
radiotherapy, was submitted to lymphadenectomy, and died from cerebral embolism after
surgery. A second patient suffering from retroperitoneal recurrence refused salvage
chemotherapy and died of progressive disease. This patient was part of the PP population.
In addition, there were four nonseminoma-related deaths. On relapse, 11 patients (1.63%)
had tumour involving the ipsilateral pelvis. However, isolated ipsilateral recurrence
was rare with only four patients affected (0.59%). Median time to relapse was 14 months
(range 0–86 months). Disease-free survival for PP, MAV, and MIV were 96.1% (95% CI:
94.2–97.9%), 95.8% (95% CI: 91.7–99.9%), and 94.1% (95% CI: 88.3–99.7%) at 5 years,
and 94.9% (95% CI: 92.0–97.8%), 95.8% (95% CI: 91.7–99.9%), and 94.1% (95% CI: 88.3–99.7%)
at 8 years, respectively. Disease-free survival and DSS for the entire population
were 95.8 (95% CI: 94.2–97.4%) and 99.6% (95% CI: 99.2–100%) at 5 years, and 94.9%
(95% CI: 92.5–97.3%) and 99.6% (95% CI: 99.2–100%) at 8 years, respectively (Figure
Kaplan–Meier curve for the entire study population. Pts=patients; DFS=disease-free
survival, OS=overall survival.
). There was no statistically significant difference between the three study populations
for DFS or DSS (log rank P=0.71). Overall survival at 5 and 8 years was 99.1% (95%
CI: 98.4–99.9%) and 98.6% (95% CI: 97.3–99.9%), respectively.
Acute and late toxicity
Maximum acute toxicity of radiotherapy was dominated by nausea grade I, which was
observed in 46.1% of all patients (Table 3
Maximum acute toxicity of radiotherapy assessed for skin, nausea, and diarrhoea
). Grade 2 and 3 nausea was documented in 6.7 and 4.0% of the patients, respectively.
Skin toxicity was mild with grade 1, 2, and 3 side effects in 5.0, 0.3, and 0%, respectively.
Likewise, diarrhoea was infrequent with grade 1, 2, and 3 toxicity in 9.6, 1.0, and
1.0% of the patients. There were no grade 4 side effects. Furthermore, there were
no statistically significant differences in acute toxicity between the PP, MAV, or
On follow-up, four patients (0.6%) exhibited slight hyperpigmentation in the former
treatment field (grade 1), and one patient (0.2%) developed telangiectasia (grade
2). A mild subcutaneous fibrosis EORTC (grade 1) was documented in one patient (0.2%).
In all, 10 patients (1.5%) reported occasional diarrhoea (grade 1) and one patient
(0.2%) had occasional diarrhoea with slight cramps (grade 2). No grade 3 or 4 late
toxicity has been observed.
Secondary tumours were observed in 17 patients (2.5%). Among these, there were seven
contralateral testicular cancers and one contralateral carcinoma in situ. Nontesticular
tumours comprised centroblastic–centrocytic lymphoma, acute leukaemia, meningioma,
glioblastoma, head-and-neck cancer, gastrointestinal cancers, and nasal basalioma.
Four patients died due to uncontrolled secondary malignancies.
Adjuvant radiotherapy has been the standard treatment for stage I seminoma for decades.
However, optimal management of the patients is still a matter of controversy (Milosevic
et al, 1999; Classen et al, 2001). In spite of high cure rates achieved with adjuvant
radiotherapy, efforts have been made to introduce alternative treatment strategies
that would potentially reduce major side effects of irradiation. Among these, impairment
of fertility by scattered radiation to the contralateral testis (Jacobsen et al, 1997),
gastrointestinal morbidity (Fossa et al, 1989), and the risk of radiation-induced
malignancies (Travis et al, 1997) are of major concern. In order to avoid these side
effects, a policy of ‘watch and wait’ has been evaluated at some centres (Maase et
al, 1993; Warde et al, 1997) applying treatment only to those patients suffering from
relapse. Other study groups have investigated the role of single-agent carboplatin
as adjuvant treatment (Oliver et al, 1994; Dieckmann et al, 2000).
Yet another strategy to limit side effects of adjuvant treatment is to minimise the
target volume of radiotherapy by confining the treatment portals to the para-aortic
lymph nodes, which have previously been shown to be the site of primary lymphatic
drainage of the testicles (Busch et al, 1965). Our trial reported here is the largest
prospective study evaluating the role of limited para-aortic radiotherapy in stage
I seminoma in a nonrandomised setting. The low relapse rate observed in our study
compares favourably to results of previously published pilot series using this treatment
schedule (Willich et al, 1986; Niewald et al, 1995; Kiricuta et al, 1996; Logue et
al, 1998; Sultanem et al, 1998). While these reports were limited by mostly retrospective
analysis of the patients and small study populations, our trial now provides profound
evidence for the feasibility and safety of limited para-aortic radiotherapy in stage
I seminoma in a sufficiently large number of patients.
There was no follow-up information available in 43 patients who were consequently
excluded from the analysis. Owing to the small proportion of patients excluded, it
is unlikely that this would have had a relevant influence on the calculation of survival
parameters and the principle conclusion of our trial that para-aortic radiotherapy
yields excellent results with respect to tumour control.
The rate of ipsilateral iliac relapses observed in our patients was low (1.63%). This
rate is well in the range of 0–2.2% observed by other authors for limited para-aortic
treatment (Kiricuta et al, 1996; Logue et al, 1998; Sultanem et al, 1998). It can,
however, be speculated that inclusion of ipsilateral iliac lymph nodes into the target
volume might have prevented relapse from seminoma in some of our patients. Yet, at
the same time, routine treatment of the pelvis would have been of no value in more
than 98% of the patients merely contributing to treatment-related toxicity instead.
This finding of only a very small benefit from pelvic irradiation is supported by
a randomised MRC trial directly comparing para-aortic treatment to conventional hockey-stick
radiotherapy (Fossa et al, 1999). The trial reported a significant but very small
increase in pelvic recurrences of 1.8% when omitting iliac treatment.
Any increase in the pelvic recurrence rate after para-aortic treatment has to be weighted
against the overall DFS in these patients. When comparing the relapse rate of 5.1%
observed in our trial (including one patient with initial stage IIB seminoma) to reported
recurrence rates of 2–6% for conventional ‘hockey-stick’ irradiation (Zagars and Babaian,
1987; Vallis et al, 1995; Bauman et al, 1998), there seems to be no obvious compromise
in overall tumour control by omitting pelvic radiotherapy. Finally, with a disease-specific
mortality of less than 1%, survival was not compromised in our study. These findings
are again supported by the previously mentioned MRC trial, which could reliably exclude
an increase in the overall relapse rate of more than 4.6% and a decrease in survival
of more than 1.7% for patients treated with limited para-aortic radiotherapy (Fossa
et al, 1999).
Our study is limited by the nonrandomised trial design, and conclusions drawn from
this study might be considered to be less compelling. However, it has recently been
demonstrated that well-designed observational trials do not systematically overestimate
the magnitude of treatment effects as compared to randomised studies (Benson and Hartz,
2000; Concato et al, 2000). Therefore, with a large number of homogeneously managed
patients, our study provides sound evidence that omission of pelvic treatment is safe
without a clinically relevant increase in the overall relapse rate.
Protocol violations observed in 28% of our patients are of major concern, since nonadherence
to protocol requirements might impact on treatment outcome. However, neither DFS nor
acute toxicity was significantly influenced by conservatively defined major or minor
protocol violations, respectively. This finding indicates that protocol violations
documented in our trial do in fact not confound our results. They rather reflect some
heterogeneity in treatment quality, which may be expected in any trial with a large
number of participating centres.
With four patients recurring with involvement of the ipsilateral kidney hilum and
another three patients failing near the lower field border at high iliac commune lymph
nodes, moderate extension of the portals to cover these areas might have prevented
relapse from seminoma in some of our patients. In fact, field alignment in the recent
MRC trials (Fossa et al, 1999; Jones et al, 2001) included the kidney hilum ipsilateral
to the primary tumour and covered one more lumbar vertebra including L5. This moderate
extension of the portals is not expected to increase significantly toxicity of radiotherapy
but rather bears the potential to further lower locoregional relapse rates of irradiation.
Based on the result from our trial, we recommend to extend standard field margins
to cover the fifth lumbar vertebra and to include the ipsilateral kidney hilum.
Computed tomography scans of abdomen and pelvis for follow-up were mandatory in our
trial. However, the majority of patients with infradiaphragmatic recurrence had relapse
that involved the pelvis. Therefore, the need for abdominal CT scans is questionable
since the detection rate of isolated abdominal recurrences was in fact very low.
The radiation dose of 26 Gy applied in our trial, although somewhat lower than 30–35 Gy
recommended by other European authors (Fossa et al, 1989, 1999; Kiricuta et al, 1996),
is sufficient for control of microscopic seminoma, since no true in-field recurrence
was observed. Furthermore, there is now convincing evidence that a further dose reduction
to 20 Gy is safe without compromise in tumour control as has recently been demonstrated
by MRC trials TE18/19 (Jones et al, 2001).
We observed a strikingly low incidence of acute toxicity. In addition, no major late
toxicity like duodenal ulcers, or gastrointestinal discomfort, which have been observed
by others (Fossa et al, 1989), was noted in our patients. Fossa et al (1999) reported
a considerably higher rate of acute grade 2 and 3 side effects of 14 and 11% nausea,
respectively. The radiation dose used in their trial was 30 Gy as compared to 26 Gy
in our study. A further dose reduction to 20 Gy can therefore be expected to translate
into an even more favourable profile of toxicity (Jones et al, 2001) thus beneficially
impacting on the quality of life of the patients. Furthermore, the shortened treatment
schedule will possibly reduce the days off work. These benefits of the reduced treatment
dose may ultimately lower the socioeconomic costs caused by stage I seminoma. Finally,
reducing the radiation dose to 20 Gy may also be beneficial with respect to the risk
of radiation-induced secondary malignancies. These are a serious concern in seminoma
patients, and a significant risk of radiation-induced tumours has previously been
demonstrated (Travis et al, 1997). A total of 17 patients in our series suffered from
secondary tumours, and nine of these were nontesticular events. Considering this low
rate of nontestis tumour events, there is no obvious excess of secondary malignancies,
but longer follow-up is warranted for a more reliable assessment of the risk of secondary
cancers in this cohort of seminoma patients as the reported latency is some 10–15
years (Travis et al, 1997).
To overcome potential disadvantages of adjuvant radiotherapy, single-agent carboplatin
chemotherapy has gained increasing interest in recent years. Several small pilot studies
demonstrated low relapse rates in the range of 3–5% using 1–2 courses of carboplatin
(Oliver and Ong, 1996; Krege et al, 1997; Dieckmann et al, 2000). The potential advantage
of this treatment option may be the reduced treatment time, treatment of micrometastasis
outside the strictly defined portals of radiotherapy, reduction in the risk of secondary
malignancies, and improvements in treatment-related toxicities. However, equivalence
of adjuvant radiotherapy and carboplatin chemotherapy in terms of relapse rates has
yet to be demonstrated, and two randomised trials are currently conducted by the MRC
and the German Testicular Cancer Study Group (GTCSG) to clarify this question. Yet
another potential alternative to adjuvant radiotherapy is the surveillance strategy.
The intention of this approach is to reserve active treatment to those patients relapsing
after primary orchidectomy and to spare the majority of patients any potentially toxic
adjuvant treatment. Several study groups could demonstrate that the DSS of the patients
managed by surveillance is not compromised as compared to radiotherapy. The rate of
relapse is in the range of 14–19%, and the DSS approaches 100% (Horwich et al, 1992;
Maase et al, 1993; Oliver et al, 1994; Warde et al, 1997). In a pooled analysis of
the three largest surveillance protocols, the tumour size (>4 cm) and tumour invasion
of the rete testis were identified as independent prognostic factors for relapse (Warde
et al, 2002). These risk factors may help to identify patients with a high or low
risk of relapse and may be beneficial for information of the patient in the process
of decision-making in adjuvant treatment. However, a risk-adapted surveillance strategy
using these factors has up to date not prospectively been evaluated.
In conclusion, our trial provides further evidence in a large study population with
long-term follow-up that limited para-aortic irradiation in stage I testicular seminoma
is safe and feasible yielding excellent cure rates at a very low rate of treatment-related
toxicity. In comparison to published data on conventional hockey-stick treatment,
the rate of recurrences is not increased. Those patients suffering from relapse can
be cured by systemic treatment or radiotherapy. Judging from our trial and the previously
reported randomised study (Fossa et al, 1999), we consider limited para-aortic treatment
for stage I seminoma as the new standard of radiotherapy (Krege et al, 2001) against
which other potential alternatives like surveillance or adjuvant carboplatin chemotherapy
have to be compared. We recommend standard field margins extending from Th11 to the
fifth lumbar vertebra and including the ipsilateral kidney hilum.