Annals of Oncology 21 (Supplement 5): v147–v154, 2010
doi:10.1093/annonc/mdq177clinical practice guidelines
Testicular non-seminoma: ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up
H.-J. Schmoll1, K. Jordan1, R. Huddart2, M. P. Laguna Pes3, A. Horwich2, K. Fizazi4 & V. Kataja5
On behalf of the ESMO Guidelines Working Group*
1Department of Oncology/Haematology/Haemostaseology, University Hospital Halle, Halle, Germany; 2Department of Academic Radiotherapy, Institute of Cancer
Research, Royal Marsden Hospital, Sutton Hospital, UK; 3Department of Urology, AMC University Hospital, Amsterdam, The Netherlands; 4Department of Medicine,
Institute Gustave Roussy, Villejuif, France; 5Department of Oncology, Kuopio University Hospital, Kuopio and Vaasa Central Hospital, Vaasa, Finland
incidence
The incidence of testicular cancer in Europe is rising with
doubling every 20 years. The current incidence is 6.3/100 000/
year, with the highest rate in Northern European countries
(6.8/100 000/year). The death rate is very low (0.38 cases/
100 000/year). Of testicular tumours, 40% are seminomas
and 60% non-seminomas. Invasive testicular cancer develops
from carcinoma in situ (CIS)/testicular intraepithelial neoplasia
(TIN), often found in the residual nonmalignant testicular
tissue. In a random biopsy, 2%–5% of testicular cancer patients
have CIS in the contralateral testis. This is in accordance with
a 2%–3% rate of synchronous contralateral or metachronous
testicular cancer.
diagnosis
The diagnosis is based on histology of testicular mass
removed by inguinal orchiectomy or by testis-conserving
surgery [IV, B].
Biopsy or, instead, high a-fetoprotein (AFP) and/or human
chorionic gonadotropin (HCG) (without biopsy) in patients
presenting with extragonadal tumour syndrome [IV, B].
In advanced and rapidly progressive disease requiring
urgent chemotherapy, diagnosis may be based on typical
clinical picture and marker elevation alone, without
orchiectomy.
Germ cell tumour may present extragonadally in the
retroperitoneum or mediastinum in a minority of cases.
staging and risk assessment
Full blood count, creatinine, electrolytes and liver enzymes
should be obtained. Tumour markers [AFP, b-HCG and lactate
dehydrogenase (LDH)] are needed for risk assessment
according to UICC/IGCCCG stage and prognostic index.
Markers are determined before orchiectomy and repeated
a minimum of 7 days after orchiectomy (for differentiation
of stage and IGCCCG prognostic group). HCG must be
followed until normalization.
Testicular sonography (7.5 MHz transducer) should be
conducted, also noting the size of the contralateral testis. CT
scan of chest, abdomen and pelvis [III, B]. MRI of the central
nervous system is needed only in advanced stages or with
symptoms. Bone scan should be conducted in the case of
indicators of involvement (e.g. symptoms). PET scanning does
not contribute and routine use is not recommended [I, B].
If fertility is an issue, the following should be conducted:
determination of total testosterone, lutenizing hormone (LH)
and follicle-stimulating hormone (FSH) before operation,
semen analysis and sperm banking (before operation or
chemotherapy).
In the case of a borderline lymph node size in imaging
(normal <1 cm) CT scan should be repeated 6 weeks later
before defining definitive treatment strategy.
If imaging is normal tumour marker decline should be
monitored until normalization in order to discriminate stage I
and disseminated disease.
Early consultation of an oncologist is mandatory. Definition
of stage and risk classification must be done according to the
UICC/American Joint Committee on Cancer (AJCC) and
IGCCCG classification (Table 1).
For histology, the World Health Organization (WHO)
classification must be used and the report must specify the
tumour localization, size, multiplicity, extension of tumour
(e.g. in rete testis or other tissue), pT category (UICC),
histopathological type (WHO) and presence of
syncytiotrophoblasts. In pluriform tumours each individual
component should be described, with percentage presence or
absence of vascular invasion (venous or lymphatic) and
presence of TIN.
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via
L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalrecommendations@esmo.org
Approved by the ESMO Guidelines Working Group: April 2002, last update January
2010. This publication supercedes the previously published version—Ann Oncol 2009;
20 (Suppl 4): iv83–iv88.
Conflict of interest: Professor Schmoll has reported no conflicts of interest; Dr Jordan
has reported that she is a speaker for MSD Germany; Professor Huddart, Dr Laguna
Pes, Professor Horwich, Professor Fizazi and Dr Kataja have reported no conflicts of
interest.
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
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treatment of primary tumour
Orchiectomy is standard of care and partial orchiectomy may
be performed in specific indications [II, B].
Surgery of the primary should be performed before any
further treatment, unless there is life-threatening metastatic
disease and clear clinical diagnosis of germ cell tumour by
marker elevation which requires immediate chemotherapy.
Tumour marker analysis should be performed before surgery
and, if elevated, 7 days after surgery to determine the half-life
kinetics. Tumour markers should be monitored until
Table 1. Staging of non-seminoma according to UICC/AJCC and IGCCCG classification
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normalization. Markers should be taken after surgery, even if
normal.
radical orchiectomy
Radical orchiectomy is performed through an inguinal incision
[II, A]. Any scrotal violation for biopsy or open surgery
should be strongly avoided. Tumour-bearing testis is resected
with the spermatic cord at the level of the internal inguinal ring.
A frozen section is recommended in doubtful cases (of
small tumours) before definitive surgery [II, B], to allow organ-
sparing surgery.
organ-preserving surgery/partial orchiectomy
Radical orchiectomy may be avoided and replaced by organ-
preserving surgery; however, only in highly experienced centres
and, in particular, in cases of synchronous bilateral testicular
tumours, metachronous contralateral (second) testicular
tumour, tumour in a solitary testis and sufficient endocrine
function, and contralateral atrophic testis.
After local resection the spared testicular tissue always
contains TIN, which can be destroyed by adjuvant
radiotherapy. This can and should be delayed in patients who
wish to father children, but for a period as short as possible.
contralateral biopsy for diagnosis of TIN
Some 3%–5% of testicular cancer patients have TIN in the
contralateral testis with the highest risk (‡34%) with testicular
atrophy (volume <12 ml) and age <40 years, and in patients
with extragonadal germ cell tumour prior chemotherapy
(‡33%), but only in 10% post-chemotherapy. If untreated,
invasive testicular tumour develops in 70% of the TIN-positive
testis within 7 years.
The sensitivity and specificity of one random biopsy for the
detection of TIN is very high. Therefore, patients should be
informed about the potential risk of TIN and a contralateral
biopsy should be offered. However, patients themselves should
be given the opportunity to decide whether a biopsy should
be done or only monitoring performed—assuming the same
high level of survival (nearly 100%) whatever strategy is chosen.
If the patient has had chemotherapy a biopsy should not
be taken <2 years from treatment.
treatment of TIN
If TIN has been diagnosed the options include immediate
definitive treatment, surveillance with delayed active treatment
or no treatment. The strategy should be chosen by the patient
depending on the individual needs, in particular if fertility is
an issue. However, fertility potential per se is often very low
in this group of patients. If fertility has to be maintained,
definitive treatment should be delayed and substituted by active
surveillance until conception followed by either active
treatment or further surveillance. If fertility is not relevant,
irradiation with 16–20 Gy (2 Gy fraction, five times per week)
[III] should be performed (the strongest evidence is for 20 Gy).
In patients with TIN and no gonadal tumour (incidental
diagnosis, e.g. by biopsy for infertility or extragonadal germ cell
tumours) orchiectomy is preferred over irradiation, because
of potential damage to the contralateral, non-affected testis by
scattered radiation.
For TIN in patients receiving chemotherapy, chemotherapy
eradicates TIN in two-thirds of patients. Therefore, treatment
for TIN is only indicated if re-biopsy after chemotherapy is
considered; however, not earlier than 2 years after
chemotherapy. Instead of definitive treatment for TIN, it is
strongly suggested to follow up the patient by monitoring
alone, including the possibility of a (re)biopsy.
post-operative treatment
Patients should be treated by oncologists with experience in the
management of testicular cancer. In early stage non-seminoma
there are several treatment options with different treatment
burden and toxicities. The patient must be well informed about
the different treatment modalities, their acute and late
toxicities, and the overall outcome.
If treatment is performed correctly, the cure rate of patients
with non-seminoma in stage I is �99%, in stage IIA/B 98% and
in advanced disease with good prognosis 90%, intermediate
prognosis 80% and poor prognosis 60%.
treatment of non-seminoma stage I
Stage I patients are divided into low risk (20% relapse rate) or
high risk (40%–50% relapse rate) according to the absence
or presence of vascular (lymphatic or venous) invasion. The
prognosis is excellent (98%–100%), whichever management
option is used. The choice should be made on the basis of acute
and late toxicities, overall treatment burden and personal
preferences, including fertility issues associated with family
planning. Sperm banking should be offered if active treatment
is chosen. However, two or even four cycles of PEB are
associated with a high level of residual fertility after recovery
from chemotherapy-associated damage.
The number of cycles of adjuvant chemotherapy is a current
research topic. The option of one cycle of PEB is prospectively
compared with the current standard of two cycles of PEB,
with preliminary data indicating that one cycle of PEB might
be sufficient [IIA].
treatment of low-risk non-seminoma stage I
The standard option for low risk without vascular invasion is
surveillance (Table 2). If surveillance is not applicable
(e.g. no possibility to follow up by markers and imaging),
adjuvant chemotherapy with two cycles of PEB is
recommended.
treatment of high-risk non-seminoma stage I
There are two treatment options: adjuvat chemotherapy (two
cycles of PEB) or surveillance.
risks and benefits. Both options should be discussed, including
detailed information about risks and benefits. The survival
is the same (99%) whichever option is used. In detail:
� surveillance. Relapse rate �40%–50%; therefore
chemotherapy (three cycles of PEB) eventually required for
only 50% of the patients.
� adjuvant chemotherapy. Relapse rate �3%–4%, but
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chemotherapy (two cycles of PEB) used for 100% of the
patients.
role of RPLND in stage I low-/high-risk patients
For very restricted cases, only if surveillance or adjuvant
chemotherapy is declined by the patient due to very specific
or personal reasons, a nerve-sparing RPLND may be
considered. This treatment has the highest treatment burden
with the lowest efficacy and should be performed by
specialized surgeons only, in order to minimize
complications including loss of ejaculation. The risk of
relapse is reduced but not eliminated since the risk to develop
lung metastases remains.
treatment of non-seminoma stage IIA/B
These stages belong to the IGCCCG good prognosis category.
stage IIA, marker negative
There are two equivalent strategies.
strategy 1. Only follow-up every 6 weeks until either regression/
normalization or progression with treatment accordingly
(Table 3).
strategy 2. Active treatment with either biopsy or nerve-sparing
RPLND.
Both options have the same overall result. Further
management depends on the results of the follow-up or
RPLND (Table 4).
stage IIA, marker positive, or stage IIB, marker
positive or negative
The standard treatment is chemotherapy with PEB for three
cycles (Table 3). PE for four cycles may be used if there are
arguments against the use of bleomycin.
In the case of complete response no further treatment is
necessary. In the case of residual tumour (>1 cm lymph node
diameter) resection of this residual lesion should be performed,
followed by routine follow-up (independent of the result of
the resection).
treatment of advanced non-seminoma
stage [stage Is, IIb, IIc, III]
The treatment options for advanced non-seminoma with good,
intermediate and poor prognosis are given in Table 4. This
table also gives the individual steps for further management
depending on the result of the primary chemotherapy,
including secondary surgery after chemotherapy and salvage
treatment.
Patients with good prognosis receive three cycles of PEB. PEB
can be given as classical 5- or 3-day protocol [I, B]. If there
are arguments against the use of bleomycin, e.g. factors
predisposing for bleomycin-induced acute or cumulative
pneumonitis/fibrosis, PEB can be substituted by PE · 4 cycles.
In intermediate and poor prognosis patients PEB for four
cycles is standard, given as 5-day schedule. Since four cycles are
given, the 3-day schedule should not be applied [I, B]. PEB can
be substituted in the case of factors against the use of bleomycin
by PEI for four cycles.
Chemotherapy cycles must be repeated every 3 weeks,
independent of leukocyte count but with platelet
recovery >100 000 count (at day 22); only in this case and
in the case of infection at day 22 should the next cycle be
delayed until recovery.
Supportive management with prophylactic use of G-CSF or
antibiotics and modern anti-emetic therapy (5HT3 receptor
antagonist + steroid 6 NK-1 receptor antagonist) are
recommended.
High-dose chemotherapy has proved not to be of benefit
in three randomized trials.
management after primary
chemotherapy
If restaging 4 weeks after the last treatment cycle reveals
elevated markers and/or residual tumour, the next steps depend
on the individual situation of the patient.
In principal, any residual tumour must be resected if there
is no marker increase within the first weeks after termination
of chemotherapy.
In the case of a marker plateau, the resection should be
delayed since there is a good chance that this represents
a ‘pseudomarker plateau’ resulting from necrotic tumour tissue
Table 2. Treatment algorithm for non-seminoma stage I
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which is still resolving and liberating tumour markers into
the blood. These patients should be followed up in short
intervals until markers have been normalized or the final
decision with respect to the resection can be made.
In the case of multiple metastases in several organs or
brain or liver, resection is probably not appropriate and the
indications and extent of resection should be discussed with
experts and treated at specialized centres.
Further management depends on the result of the primary
treatment and secondary surgery. In the case of complete
response or R0 resection with scar tissue only or differentiated
teratoma or viable tumour <10% of the resected specimen,
follow-up is recommended, whereas in the case of >10% viable
tumour, consolidation chemotherapy with, for example, two
cycles of VIP should be considered and seems to be
appropriate[III].
In the case of incomplete resection of viable tumour and/or
residual tumour, salvage chemotherapy should be applied, as
well as in the case of relapse from complete remission (CR) or
progression after marker normalization in the case of
unresectable residual lesions.
monitoring during and after treatment
Tumour markers must be determined before every cycle. Four
weeks after the last cycle, determination of tumour markers
as well as imaging (chest X-ray, CT scan or MRI of the initial
sites) should be conducted.
A PET scan is regarded as experimental (should not be
performed outside of clinical trials).
salvage chemotherapy
Relapse after a longer (>3 months) period following initial
favourable response does not always represent a platinum-
resistant situation. Cisplatin is part of salvage treatment
protocols, preferably together with further agents that have not
been used in the first-line treatment. After second-line and,
in some cases, also after third-line treatment, chemosensitivity
may still be present.
Standard first-line salvage chemotherapy is standard-dose
VIP, TIP or VeIP. There is no proven benefit of high-dose
chemotherapy either in first- or second-line salvage treatment
in any patient subgroup.
In refractory patients, e.g. those who never reach a marker-
negative complete response after first-line treatment or have
no favourable response after salvage treatment, no standard
treatment can be recommended. Gemcitabine/paclitaxel may
be considered as an option. High-dose chemotherapy in this
setting is experimental and should only be performed in clinical
trials. Surgery should be part of the strategy, particularly in
those patients with localized or late relapse, and with poor
response to chemotherapy. Patients should be included
in clinical trials and referred to expert centres whenever
possible.
Table 3. Treatment algorithm for non-seminoma stage II A/B
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late relapse
If technically feasible, radical surgical resection of all lesions
should be performed, irrespective of the level of tumour
markers, particularly in poor responders to chemotherapy. If
the lesions are not completely resectable, at least a biopsy
should be obtained for histological assessment. Salvage
chemotherapy should be initiated.
Late relapses (when chemotherapy has been used as part of
the management) respond less well to new chemotherapy
(often yolk sac tumour, AFP-positive, slow-growing teratoma).
If the patient responds to salvage chemotherapy, secondary
surgery should be conducted whenever possible.
late toxicity
There is a 3% risk of developing contralateral testis tumour
during the first 15 years