Review
10.1517/13543784.17.4.511 © 2008 Informa UK Ltd ISSN 1354-3784 511
Targeted therapies for patients
with germ cell tumors
Martin H Fenner † , Gernot Beutel & Viktor Grünwald
Hannover Medical School, Department of Hematology, Hemostaseology,
Oncology and Stem Cell Transplantation, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
Background : Patients with advanced germ cell tumors can be cured with
cisplatin-based chemotherapy but the outcome remains unsatisfactory for
patients with relapsed disease. Targeted therapies have changed the
standard of care for many advanced solid tumors. Objective : To identify
clinically available drugs that have the potential as targeted therapies
in germ cell tumors. Methods : A literature search was carried out for
expression and mutation status of receptor tyrosine kinases in germ cell
tumors, also a literature and clinical trial database search for completed
and ongoing clinical trials with targeted therapies in germ cell tumors.
Results/conclusions : c-KIT is mutated in some seminomas and bilateral germ
cell tumors. Several case reports and small clinical trials with trastuzumab,
thalidomide and imatinib were identified and clinical trials with sunitinib
and bevacizumab are ongoing. We expect an increased use of targeted
therapies in advanced germ cell tumors in the next few years.
Keywords: angiogenesis , bevacizumab , c-KIT , germ cell tumor , sunitinib , targeted therapy ,
testicular cancer
Expert Opin. Investig. Drugs (2008) 17(4):511-522
1. Introduction
Although both surgery and radiotherapy are important treatment modalities for
patients with advanced germ cell tumors (GCTs), these patients are usually
treated with chemotherapy. The treatment goal is very different from that for
almost all other solid tumors because the introduction of cisplatin in 1974 made
advanced GCTs a curable disease. In the landmark study by Einhorn and
Donohue [1] , 74% of patients with disseminated GCTs achieved a complete
remission with cisplatin, vinblastine and bleomycin (PVB) chemotherapy.
Vinblastine was replaced by etoposide 10 years later [2] because of higher response
rates and fewer side effects in the bleomycin, etoposide and cisplatin (BEP) treat-
ment arm. Further changes in the BEP protocol (e.g., by using ifosfamide instead
of bleomycin [3] ) have not increased response rates or reduced toxicities. Depending
on the presence of the prognostic criteria defined by the International Germ Cell
Cancer Consensus Group (IGCCCG) [4] , 50 – 90% of patients with metastatic
disease will be cured. High-dose chemotherapy with autologous stem cell support
is effective and well-tolerated in patients with poor prognosis according to the
IGCCCG criteria [5] . A recently completed US intergroup randomized Phase III
trial failed to show the superiority of this approach over conventional chemo-
therapy in patients with poor prognosis [6] but was underpowered to detect a
20% difference in durable complete responses at one year (the primary end point)
in the two treatment arms. There was also no difference in the secondary end
points of time to treatment failure and overall survival. A European randomized
Phase III trial comparing high-dose chemotherapy with conventional BEP
chemotherapy in patients with poor prognosis [7] was closed in June 2007 because
of poor recruitment. The BEP protocol therefore remains the standard treatment
1. Introduction
2. Molecular biology of
germ cell tumors
3. Clinical experience with
targeted therapies for
solid tumors
4. Clinical trials with targeted
therapies in germ cell tumors
5. Expert opinion

Targeted therapies for patients with germ cell tumors
512 Expert Opin. Investig. Drugs (2008) 17(4)
regimen for metastatic disease in all IGCCCG prognostic
groups [8,9] . Patients with late relapse (i.e., relapse more than
two years after successful treatment [10] ) and patients with
teratoma with malignant transformation (i.e., transformation
into other histologies such as sarcoma [11] ) represent a
special challenge, as these patients often do not achieve
long-lasting remissions with chemotherapy.
In case of relapse after cisplatin-based chemotherapy, up
to 50% of patients can still be cured by high-dose
chemotherapy [12,13] . Sequential high-dose chemotherapy
with carboplatin and etoposide results in fewer treatment-
related deaths compared to a single course of high-dose
chemotherapy with an additional alkylating agent [14] , and is
the most frequently used protocol. Patients with good prog-
nostic features (first relapse, seminoma, complete remission
for at least six months after first-line chemotherapy) will
have similar long-term remission rates using conventional
chemotherapy with either etoposide, ifosfamide and cisplatin
(VIP) or paclitaxel, ifosfamide and cisplatin (TIP) [15] . The
one randomized Phase III trial in this patient population
compared four cycles of VIP or VeIP (vinblastine, ifosfamide
and cisplatin) with three such cycles followed by one cycle
of high-dose chemotherapy. The trial failed to show a
benefit for high-dose chemotherapy [16] . Prognostic factors
such as those mentioned above are probably as important as
the treatment regimen for the outcome of these patients.
Patients who relapse after high-dose chemotherapy can
only be offered palliative chemotherapy and only selected
patients will achieve long-term remissions. Patients often
have an impaired bone marrow reserve, renal function
abnormalities and polyneuropathy because of several
previous cisplatin-based chemotherapies. Many chemothera-
peutic drugs have been evaluated in this patient population,
and many of them, including bendamustine, epirubicin,
topotecan and irinotecan, have no single-agent activity [17] .
Gemcitabine, oxaliplatin or paclitaxel alone or in two or
three drug combinations are the most active drugs. The
combination of all three drugs induced 51% objective
responses in this heavily pretreated patient population [18] .
Paclitaxel, but not the other two drugs, has also been used
earlier in the treatment of the disease, including an ongoing
study for the first-line treatment of patients with IGCCCG
intermediate-prognosis metastatic disease [19] .
Targeted therapy has radically changed the treatment of
many advanced solid tumors, including renal-cell
carcinoma [20-22] . Whereas GCTs have been a model for
successfully treating advanced solid tumors with chemotherapy,
GCTs have lagged behind other solid tumors in the application
of targeted therapies. Targeted therapies are probably as
active in GCTs as in other solid tumors. Only the relatively
small number of patients not successfully treated with
cisplatin-based chemotherapies has slowed the development of
targeted therapies in these patients. This review will discuss
the available preclinical and clinical data for targeted therapies
in GCTs and the potential future treatment strategies.
2. Molecular biology of germ cell tumors
GCTs are derived form the germ cell lineage and can be
divided into three subgroups. These subgroups differ in
clinical presentation and in their pathogenesis and
molecular changes:
1. Teratomas and yolk sac tumors in children
2. Seminomas and non-seminomatous GCTs in young adults
3. Spermatocytic seminomas in older men [23] .
Teratomas and yolk sac tumors can develop in boys
and girls in gonadal and extragonadal sites. Teratomas are
usually benign, whereas yolk sac tumors are treated with
chemotherapy. Spermatocytic seminomas are derived from
more mature germ cells, are characterized by gains in
chromosome 9 and almost never metastasize [24] . Seminomas
and non-seminomatous germ cell tumors (NSGCTs) are
derived from pluripotent primordial germ cells (PGCs)
and are by far the most common GCTs, representing about
95% of all tumors [25] . The remainder of the discussion will
therefore focus on these tumors.
2.1 Genetic and epigenetic changes
A gain in the short arm of chromosome 12 is the only
consistent cytogenetic abnormality in GCTs [26] . These
changes can be found in approximately 80% of NSGCTs
and 50% of seminomas. These tumors have either an
isochromosome 12 (i(12p)) or an over-representation of
genetic material located on chromosome 12p. On i(12p),
the region most frequently amplified is 12p11.2-p12.1,
containing the SOX5 , JAW1 and K-RAS genes [27] . K-RAS
mutations are rare in GCTs. The largest study, by Olie et al. ,
detected three K-RAS mutations (all in exon 12) in
40 seminoma samples and one K-RAS mutation (exon 12)
in 60 NSGCT samples [28] . In samples from 44 patients
with cisplatin-refractory tumors (22 primary tumors and
33 surgical specimens from metastatic sites) not a single
K-RAS mutation was detected [29] . Another candidate gene
on chromosome 12p is the CCND2 gene, mapped to 12p13.
CCND2 and its product, cyclin D2, control the cell cycle
at the G1/S checkpoint through the recruitment of the
catalytic partners Cdk4 and Cdk6. Cyclin D2 is over-
expressed in about 70% of GCTs but no genomic alterations
can be detected by Southern blot [30] .
NANOG is an embryonic transcription factor that is
also located in the amplified region on chromosome 12p.
Santagata et al. studied the expression of NANOG in tumor
samples from GCT patients and found an expression in
20/20 seminomas, 18/18 embryonal carcinomas, 0/19
teratomas, 0/6 yolk sac tumors and 0/5 choriocarcinomas [31] .
NANOG is a useful marker for the diagnostic workup of
metastatic seminomas and embryonal carcinomas but its
role in the pathogenesis of GCTs is not yet defined.
Microsatellite instability, decreased protein expression of the
mismatch repair genes hMLH1 and hMSH2 , or hMLH1