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BJUI Mini Reviews - In this review, the advantages and disadvantages of the different strategies for treating seminomas and nonseminomas, and their associated prognostic factors are discussed , and then future developments are considered.
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![Adjuvant treatment in the management of testis-confined
germ cell tumours after orchidectomy
Teodoro Sava, Francesca Consoli, Antonio Santo and Gian Luigi Cetto
Department of Medical Oncology, University of Verona, Italy
Accepted for publication 27 April 2007
Germ cell tumours are highly curable,
especially when still at the localized stage,
which is the case for most testicular tumours.
Various options are available for organconfined
disease; depending on the
histological review, patients with clinical
stage I seminomas can be offered
radiotherapy, surveillance or chemotherapy,
whereas those with clinical stage I
nonseminomas can be offered retroperitoneal
lymph node dissection, surveillance or
chemotherapy. As it is unlikely that any of
these approaches will have a clear survival
advantage, the most appropriate variables to
be considered are acute and late side-effects,
acceptability and quality of life. In recent
years adjuvant chemotherapy has been
extensively evaluated in patients with
seminoma or nonseminoma. In this review we
discuss the advantages and disadvantages of
the different strategies for treating
seminomas and nonseminomas, and their
associated prognostic factors, and then
consider future developments.
KEYWORDS
testicular tumours, germ cell, chemotherapy,
surveillance
INTRODUCTION
Germ cell testicular tumours (GCTs) are the
most common malignancy among men aged
15–35 years; 7500 new cases were diagnosed
in the USA in 2002 [1]; 60% of all GCTs are
nonseminoma (NSGCTs) and 40% are
seminomas. Currently 85% of patients with
GCT can be cured but it is crucial to improve
the effective therapy for poor-risk patients
and to minimize overtreatment of those with
a good-risk prognosis. It is therefore essential
to be aware of staging and risk assessment,
and to consider possible treatment-induced
side-effects.
As they are so relatively common, GCTs should
be well understood by urologists, oncologists
and other physicians who might have to
manage them. It is clear that the survival
of patients with GCT also depends on the
expertise of the cancer centre at which
they are treated [2]. Not only urologists
and oncologists, but also pathologists,
radiotherapists and radiologists should be
aware of the diagnosis, natural history, risk
factors, clinical staging and management of
testicular cancer. Once the patient has had an
orchidectomy, a pathological diagnosis,
clinical staging and risk assessment need to
be completed before proposing the most
appropriate treatment.
The pathology evaluation includes the
histological classification and the analysis
of prognostic factors [3]. It is fundamental
to distinguish seminomas (which only have
seminomatous elements) from NSGCTs
(which have at least one component from
the other cell types). Of the pure seminoma
tumours, the spermatocytic type must be
excluded; it mainly occurs in elderly men
and it very rarely metastasizes, so it
requires no further treatment. Among the
NSGCTs, the description and relative
proportion of each subtype is important, as
these might affect the prognosis and
management.
Some pathological features play a major
prognostic role, especially in low-stage
diseases, and therefore need to be to be
studied carefully, i.e. the presence of vascular
invasion and the percentage of embryonal
carcinoma in NSGCTs, and the size of the
primary tumour and rete testis invasion in
seminomas. Clinical staging involves a
physical examination, chest radiography,
abdominal CT, and an assay of serum tumour
markers. To establish a diagnosis of clinical
stage I disease, clinical, biochemical or
imaging evidence of disease outside the
testis must be excluded; in particular,
retroperitoneal lymph node metastases
detected on abdominal CT and the persistence
of high levels of tumour markers for longer
than their half-lives should be carefully
excluded.
Subsequently, a testis-confined GCT needs to
be evaluated after analysing its specific
prognostic factors; treatment options will
depend on risk factors, the characteristics
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of healthcare services and the patient’s
preferences. Not all treatments are available
and safe everywhere, and not all approaches
are suitable for all patients. In recent years,
the role of adjuvant chemotherapy has been
extensively investigated for both seminomas
and nonseminomas, and seems to be a valid
option that might reduce some of the sideeffects
or discomfort of the other approaches;
in any case, survival is unaffected by the
treatment option, provided that it is well
conducted.
SEMINOMAS
Nearly 70% of all patients with a diagnosis of
seminoma have cancer confined to the testis
[4]. The prognosis for pure organ-confined
seminoma is excellent and almost all patients
can be cured regardless of the treatment
option selected.
Prognostic factors:
Historically, radiotherapy
(RT) has been the traditional management
technique and, as recurrences are extremely
rare after external-beam RT, it has only
recently become possible to extrapolate
prognostic factors on the basis of
retrospective analyses of the data obtained
from the surveillance programme for
patients with stage I seminoma. Warde
et al.
[5] showed that
≈
20% of patients with
stage I seminoma who were managed with
a surveillance programme relapsed, the only
two identified predictors of relapse being a
primary tumour of
>
4 cm and rete testis
invasion; furthermore, patients with both
risk factors were 3.4 times more likely to
relapse. Recently, Aparicio
et al.
[6] designed
a study to assess the efficacy of a riskadapted
treatment policy. Patients with a
tumour diameter of
<
4 cm and no rete
testis involvement were managed with
surveillance; there were relapses in 6% of
the patients, and they were mainly in the
retroperitoneum. Multivariate analysis
identified two independent poor-risk factors
in this subgroup of patients, i.e. age
<
30 years, and increased
β
hCG levels.
However, as no prospective studies have
validated the role of these prognostic
factors, the treatment options suggested in
the European Germ Cell Cancer Consensus
Group report are not directly related to
them [7].
RT:
Adjuvant RT has been traditionally used
to manage stage I disease because of the
radiosensitivity of seminoma cells, and that
the principal route of diffusion is the
retroperitoneal lymph nodes. However,
although RT to the retroperitoneal lymph
nodes has been the standard technique used
for the last 50 years, the precise treatments
have recently changed considerably. The
para-aortic field is now considered the
standard target and the delivered dose can
be as low as 20 Gy [8]; administered in 10
daily fractions, this dose is as effective as the
previous standard dose of 30 Gy in 15 daily
fractions, and is less toxic. However, some
think that the follow-up (2–3 years) is still
too short to confirm the long-term efficacy
of this approach. The major advantage of RT
is that the 5-year overall survival is nearly
100%, and the overall recurrence rate is 3–
5% [9]. Patients having a relapse (usually in
the mediastinal, supraclavicular or pelvic
nodes) can become disease-free after
chemotherapy but the disadvantage of this is
that
≈
80% have unnecessary treatment and
unnecessary (acute and late) side-effects. A
significant excess of ulcers, cardiac disease
and second malignancies have been related
to RT [10] but recent changes in RT
techniques should reduce such risks in the
near future.
Surveillance:
Patients with a testis-confined
seminoma can be safely managed by
‘watchful waiting’, with only relapsing
patients receiving RT or chemotherapy.
Various studies showed that a surveillance
programme does not compromise overall
survival [5,6,11]. The general relapse rate is
20%, although this decreases to 6–12% if
only low-risk patients are considered (
<
4 cm
tumours with no rete testis invasion), and so
surveillance can avoid unnecessary treatment
for 80–85% of patients. Some authors think
that watchful waiting is appropriate for
all patients with clinical stage I seminomas,
while others restrict it to low-risk patients.
The causes of concern are the long and
unstandardized follow-up, patient
compliance, and the feeling of ‘impending
doom’. This last aspect (a complex pattern of
stress and anxiety related to the fear of
recurrence) should be considered a major
disadvantage in such young patients, and was
aptly christened the ‘sword of Damocles’ by
Loehrer and Bosl [12].
Chemotherapy:
This is chronologically the last
option considered for patients with clinical
stage I seminoma. Germ cells (and particular
seminoma tumours) are uniquely
chemosensitive and platinum-based
chemotherapy results in high cure rates even
for advanced disease. Several authors
evaluated the role of the classical cisplatinum,
etoposide and bleomycin (PEB) regimen,
and other schemes of mono- or
polychemotherapy, and found that although
the results are excellent in terms of relapse
rate and disease-free survival, toxicity is too
high in a population with such a favourable
prognosis. Carboplatin, a less toxic platinumderived
drug, was recently evaluated as a
single drug in the adjuvant setting, and can
now be regarded as the third adjuvant
treatment choice in patients with stage I
seminoma. The conclusions of a randomized
phase III study comparing radiotherapy with a
single-dose (AUC 7) of carboplatin [9] were
that it is safe and effective; the relapse
rate was
≈
4% and the 3-year overall
survival was 100%. The treatment was well
tolerated, the side-effects including mild
thrombocytopenia, and there were fewer
second neoplasms than in the RT arm.
Furthermore, Aparicio
et al.
[6] tested singleagent
carboplatin in patients at high risk of
relapse, in an interesting risk-adaptive
approach study; the patients with at least one
negative prognostic factor (a
>
4 cm tumour
and/or rete testis invasion) were treated with
two courses of adjuvant carboplatin, and the
relapse rate was 3.3%. Although a longer
follow-up is essential to confirm the efficacy
and safety data, adjuvant carboplatin can
already be considered a valid option in this
setting.
DISCUSSION
None of these three treatments has a clear
advantage in efficacy over the others. Some
authors suggest making a choice on the
basis of prognostic factors; adjuvant
treatment for high-risk patients and
surveillance or RT for low-risk patients.
However, this might be only partly correct,
because current knowledge and
understanding of the prognostic factors is
still too limited. Patients with a small
primary tumour of
<
4 cm and with no rete
testis invasion still have a 6% risk of
recurrence, whereas high-risk patients
treated with adjuvant chemotherapy or RT
still have a 3–4% relapse rate. Loehrer and
Bosl [12] criticised the risk-adapted strategy,
particularly the role of two cycles of
carboplatin as adjuvant therapy, because of
the inferiority of carboplatin to cisplatin in
advanced disease, the high rate of relapse,
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that the risk-adaptive model has not been
validated, the shortness of the follow-up,
and the uncertainty of the late consequences
of adjuvant chemotherapy. Oliver
et al.
[13]
replied that adjuvant carboplatin treatment
seemed to be favoured in terms of efficacy
and toxicity and, although a longer followup
is indeed needed, they concluded that
one course of carboplatin can be considered
one of the three standards of care, together
with surveillance and 20 Gy para-aortic RT.
We think that a follow-up programme is
needed regardless of the treatment option,
and this raises the question of why
surveillance is not recommended to all
patients. These young patients should not
be over-treated; 80% are cured with
orchidectomy alone, survival is 100%
irrespective of the selected treatment, but
the side-effects are different. The main
limitations of managing all patients with
surveillance are, of course, patient
compliance, geographical accessibility, the
availability of healthcare services and the
‘sword of Damocles’ syndrome. However, the
trials conducted by Oliver
et al.
and Aparicio
et al.
will need to reach a substantial followup
before adjuvant chemotherapy can be
routinely proposed to all patients in all
hospitals, even though it certainly represents
another option in the treatment of stage I
seminoma.
NONSEMINOMAS
Almost 40% of all patients with NSGCT have a
clinical stage I diagnosis at presentation;
when the disease is confined to the testis, the
cure rate is nearly 99%.
Prognostic factors
Patients with NSGCTs who
are managed by a surveillance programme
have a 25–30% risk of recurrence [14].
Various features have been shown to correlate
with occult retroperitoneal nodal metastases
or a higher risk of recurrence, including
vascular/lymphatic invasion, predominance of
embryonal carcinoma, the absence of yolk sac
elements, the absence of
α
-fetoprotein before
orchidectomy,
<
50% teratoma, and local
extension into the peritesticular structures
[7,15–18], but it is widely accepted that
vascular invasion and predominance of
embryonal carcinoma are the most important
risk factors [7,19]. The relapse rate is 40–50%
in patients with vascular invasion, vs
<
20%
in those without. In general, adjuvant
treatment reduces the relapse rate to
<
5%.
Retroperitoneal lymphadenectomy (RPLND)
provides pathological staging and might be
curative, but only 30% of patients are found
to have positive nodes after RPLND, and so
70% do not actually need this kind of
treatment.
RPLND
is both diagnostic and therapeutic; it
defines the presence or otherwise of
retroperitoneal metastases, and removes
RPLNs as a site of relapse, thus offering the
subsequent advantage of avoiding the
need for imaging surveillance of the
retroperitoneum. It is known that teratoma is
chemoresistant and, when present in the
primary tumour, it can best be treated by
primary RPLND. Some authors criticise the
RPLND approach because even when the
surgeon is highly experienced, 3% of the
patients have a major complication and
chemotherapy is not always avoided. This
is only partly true; to maintain normal
ejaculatory function, it is essential that the
procedure is performed by an expert urologist,
but thanks to Donohue templates, current
nerve-sparing dissection can be considered
safe [20]. This approach remains the standard
in most centres in the USA.
Surveillance:
To minimize direct treatment,
the use of a surveillance strategy has been
extensively evaluated [21,22]. Such a strategy
is possible because
≈
30% of relapsing
patients can be effectively cured with
cisplatin-based chemotherapy. Surveillance
usually consists of monthly determinations of
tumour markers, a chest X-ray and clinical
examination (every 2 months from the second
year on), and CT at least 3 and 12 months
after orchidectomy. The British Medical
Research Council recently conducted a
randomized trial of two vs five CT scans to see
whether this influenced the prognosis,
showing that CT at 3 and 12 months after
orchidectomy were sufficient [22]. Relapses
are characteristically identified on the basis of
tumour markers and/or CT (usually of the
retroperitoneum) and 5-year overall survival
is nearly 98% [23]. Some acknowledged
problems of the surveillance programme are
patient compliance and motivation, because
strict adherence to the clinical staging
procedures (serum markers and CT) is
fundamental. Another important aspect of
the surveillance approach is the expertise of
the centre, and several authors suggested
that a watchful waiting programme is not
appropriate outside a specialist centre [24].
Chemotherapy
: This is the least used
approach for patients with clinical stage I
NSGCT in the USA, but it is being proposed
more often in Europe. Two cycles of PEB are
generally given, and various studies have
evaluated the effect on all patients with
organ-confined and only high-risk NSGCT
[25–29]. After a median follow-up of 5 years a
relapse rate of
<
5% was reported, and the
overall survival is almost 99%. However,
>
40% of the patients are exposed to
unnecessary chemotherapy-related sideeffects,
e.g. nausea, vomiting, haematological
toxicity, neurotoxicity, ototoxicity, and
possible late cardiovascular impairment, and
the late side-effects of cardiovascular disease
and a second malignancy are major causes of
concern.
Several studies of adjuvant chemotherapy
have concentrated on minimizing treatmentrelated
morbidity [30–32]. Dearnaley
et al.
[30] evaluated the replacement of etoposide
by vincristine in the cisplatin/bleomycin
regimen, but found no clear advantage
other than a lower incidence of alopecia.
Gilbert
et al.
[31] used only one cycle of
chemotherapy (etoposide and bleomycin,
with cisplatin or carboplatin) and observed no
change in overall survival. Pectasides
et al.
[32] tested the carboplatin, etoposide and
bleomycin regimen in an attempt to prevent
cisplatin-related side-effects, and concluded
that two carboplatin-based cycles can be as
effective as the cisplatin-containing regimen
in the adjuvant setting of high-risk clinical
stage I NSGCT. A recent large, prospective,
multicentre German trial randomized 382
clinical stage I patients to RPLND or one
course of adjuvant PEB chemotherapy
regardless of prognostic factors [33]. After a
median follow-up of 50 months, there was
low toxicity and a statistically significantly
lower risk of recurrence in the chemotherapy
arm (7.5% vs 1.1%); this result was
interpreted as supporting one course of PEB
over RPLND. However, the number of
retroperitoneal relapses in the RPLND arm
was higher than that previously reported [20],
and certainly a longer follow-up with
frequent abdominal imaging is needed,
because some recurrences were reported even
5 years after PEB treatment. Furthermore, the
study was not designed to analyse high-risk
patients (retrospectively calculated as
representing 43–46% of the study
population) and so no clear indications for
patients with vascular invasion can be
deduced from this trial. However, given the
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uncertainty about the incidence of late events
after chemotherapy, adjuvant chemotherapy
needs careful consideration; according to
some authors, it should only be proposed to
high-risk patients (with vascular invasion
and/or predominance of embryonal
carcinoma) [28,34], but others suggest
proposing it for uncompliant patients,
particularly those attending hospitals with
‘low-volume urological surgery’ in which
RPLND is not routinely used.
DISCUSSION
Nearly all organ-confined NSGCTs can
be cured, regardless of whether the
management technique is RPLND,
surveillance or adjuvant chemotherapy. Link
et al.
[35] recently used computer-based
decision analysis to evaluate the cost factors
influencing the choice of therapy. On the
basis of their model, they concluded that
primary RPLND is never cost-advantageous
over surveillance or primary chemotherapy,
and surgical costs can significantly increase
the overall cost of a surveillance programme;
they also found that adjuvant chemotherapy
might have a cost advantage over
surveillance in the case of high-risk stage I
NSGCTs. We think that this model needs to
be applied to individual centres, because of
the different expertise in each approach in
different parts of the world. Risk-adapted
treatment based on prognostic factors and
the relative risk of progression can be an
approximate guide to choosing the better
option [34] but, unfortunately, prognostic
factors do not identify all patients at high
risk, and it is also the case that low-risk
patients might still develop progressive
disease. On the other hand, and for
appropriately selected patients, surveillance
leads to fewer therapeutic interventions than
does RPLND or adjuvant chemotherapy,
without compromising the probability of
cure. Only a few patients really need direct
RPLND or chemotherapy. Only 10% of
patients undergoing RPLND will benefit from
surgery. However, we are not yet sure if there
is a risk of chemotherapy resistance in
relapsing patients treated with two cycles of
adjuvant PEB; we need a longer follow-up to
answer this question. The follow-up is
needed irrespective of the treatment option;
therefore, might it be logical to propose a
surveillance programme from the beginning?
The new diagnostic approaches that are
currently being investigated expressly for this
type of disease are laparoscopy and positronemission
tomography (PET). Laparoscopic
RPLND is a viable staging tool but its role as a
therapeutic option has not been reliably
determined. In relation to PET, as of 2006, only
one prospective study has been conducted in
an attempt to discriminate patients with no
occult metastatic disease suitable for a
surveillance programme and those requiring
immediate chemotherapy [36]: however, no
clear advantage over CT was documented and
so it remains an investigational tool.
In conclusion, testis-confined GCTTs are
highly curable and there are various
treatment options available. The main aim of
current and future clinical research is to
minimize treatment and its related morbidity
without compromising the high rates of cure.
A more critical analysis of the prognostic
models is needed, especially for patients with
seminoma. In any case, treatment options
should be judged on the basis of the specific
characteristics of the individual centre and
discussed with each patient, whose wishes
must be an integral part of the decisionmaking
process. Patients’ individual
circumstances should be considered; e.g. a
musician would probably have a higher
preference for not having cisplatin-induced
high-tone hearing loss. Similarly, in some
cases the geographical location or work
situation can preclude the selection of a
surveillance programme. Fertility is also an
important issue and should be carefully
considered due to the young age and very
good prognosis of this population.
CONFLICT OF INTEREST
The authors state that there is no conflict of
interest.
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Correspondence: Teodoro Sava, Piazzale L.A.
Scuro 10, 37134 Verona, Italy.
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Abbreviations: (NS)GCT, (nonseminomatous)
germ cell tumour; RT, radiotherapy; PEB,
cisplatinum, etoposide and bleomycin;
RPLND, retroperitoneal lymphadenectomy;
PET, positron-emission tomography](http://urotoday.com/images/stories/bjui_jan2008_cover.gif)