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Germ Cell Tumours
cisplatin-refractory patients with non-seminomatous germ cell tumours. KIT positive staining for VEGF. The percentage of VEGF-positive cells
was expressed in 11 of 23 tumours, especially in teratoma with malignant correlated significantly with the microvessel count in germ cell tumours.
transformation and tissue samples from late relapses. A phase II study of The authors have shown that VEGF expression is associated with
imatinib has been performed at Indiana University in six refractory germ cell lymphovascular and venous involvement and the presence of metastases.
tumour patients who expressed KIT. No response has been observed.
70
Only two reports have been published on administration.
77,78
The first
Pedersini et al. have reported a complete response to imatinib treatment in patient had cisplatin-refractory disease and received high-dose
a patient with cisplatin-refractory seminoma who remained free of disease chemotherapy (ifosfamide carboplatin and etoposide [ICE] regimen) in
24 months after the initiation of treatment.
71
association with bevacizumab 7.5mg/kg on days one and 22.
63
The
patient achieved a partial response with more than 99% decrease of
Epidermal Growth Factor Receptor serum marker levels. Progression-free survival was five months. The
Epidermal growth factor receptor (EGFR) is a 170kDa transmembrane second patient had inoperable growing teratoma and received
glycoprotein, a member of the type I receptor tyrosine kinase family. The bevacizumab 10mg/kg/day biweekly.
78
The size of the tumour was stable
protein is overexpressed in tumours of the neck, head, cervix and for six months after beginning the treatment. Abdominal pain
esophageous. EGFR expression has been analysed by histoimmunochemistry disaappeared. On treatment discontinuation, tumour size increased.
(HIC) in a large series of 182 germ cell tissue samples.
72
EGFR staining was
observed in 79% of teratomas with epithelial component, 29% of Studies of new drugs combined with VEGF-targeted agents are ongoing.
embryonal carcinomas and all syncytiotrophoblastic cells. No EGFR staining Indiana University has developed a protocol combining oxaliplatin and
was observed in yolk sac tumours, seminomas and intratubular neoplasias. bevacizumab in patients with refractory or relapsed germ cell tumours. Two
A smaller series published by Moroni et al.
73
has reported the same pattern ongoing phase II trials are currently investigating the effect of sunitinib in
of EGFR staining according to histology. In relapsed patients, positive EGFR patients with refractory or relapsed germ cell tumours. It is difficult to
staining was observed in the majority of late relapses (more often yolk sac evaluate new targeted drugs in this disease because chemotherapy is still
tumours) and in half of the patients with malignant transformation of the standard treatment. Trials comparing standard chemotherapy with or
teratoma.
69
No clinical study with an EGFR-targeted agent has been without targeted drugs are needed. Nevertheless, the number of patients
published in germ cell tumours. Indiana University has just completed a concerned is too small to initiate phase III trials. On the other hand, even if
trial with gefitinib; results are pending. a large amount of biological information is becoming available,
38
there is
insufficient biological background to identify specific targets. In our opinion
HER-2/neu Protein it would be interesting to select specific clinical settings (e.g. growing
HER-2/neu is overexpressed in 25–30% of breast cancers and is teratoma for the study of differentiation mechanisms, refractory
associated with poor prognosis. The expression of the HER-2/neu protein undifferentiated tumours for drug resistance and stem cell biology) and try
and the amplification of the gene have been analysed in tissue samples targeted drugs while studying variations of molecular characteristics before
of primary and refractory germ cell tumours. Ninety-six samples have and after therapy. To date, germ cell tumours have not really been the
been analysed using HIC for HER-2/neu protein expression and object of such translational studies.
fluorescence in situ hybridisation (FISH) for HER-2/neu gene
amplification.
74
HER-2/neu protein was overexpressed in 22 of 96 Conclusion
samples of germ cell tumours, none of 22 primary testis tumours, eight Over the past 20 years, the BEP regimen has remained the standard of
of 25 active residual masses after chemotherapy, seven of 29 late care for patients with germ cell tumours, with either three cycles of BEP
relapses and seven of 20 primary mediastinal tumours. HER-2/neu gene or four cycles of EP in good-prognosis patients, or four cycles of BEP in
amplification was observed in only four samples: three of 29 late relapses those with intermediate or poor prognosis. No randomised trial has
and one of 20 primary mediastinal germ cell tumours. The authors of the shown a superiority of other associations or HDCT over BEP for first-line
study concluded that the lack of correlation between HIC and FISH is not treatment. More than 80% of patients are cured with a combination of
in favour of the development of clinical trials with trastuzumab. chemotherapy and the resection of residual masses. Nevertheless, the
Kollmannsberger et al. reported a response to trastuzumab treatment in prognosis of poor-risk patients is poor and trials with combinations of
a patient with cisplatin-refractory disease.
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new drugs such as paclitaxel and oxaliplatin with BEP in first-line
treatment are ongoing. In relapse, the situation differs because only 25%
Anti-angiogenic Therapy of patients are cured with the VeIP regimen. The results of first-line
Vascular endothelial growth factor (VEGF), thymidine phosphorylase salvage treatments with the TIP regimen in patients with good risk of
expression and vessel density have been evaluated using HIC in 80 germ relapse are encouraging. New drugs are being developed for salvage
cell tumours: 33 pure seminomas (25 stage I and eight metastatic) and treatment in cisplatin-sensitive, refractory or absolute refractory disease.
47 non-seminomatous germ cell tumours (20 stage I and 27 The most active chemotherapy drugs as single agents are gemcitabine,
metastatic).
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VEGF protein was more often expressed in germ cell tissue oxaliplatin and paclitaxel. Targeted drugs are being evaluated in relapsed
than normal tissue, with 41% of germ cell tumour samples exhibiting or refractory germ cell tumours. ■
1. Williams SD, Stablein DM, Einhorn LH, et al., Immediate 3. Fléchon A, Biron P, Droz JP, High-dose chemotherapy with paclitaxel shows antitumor activity in patients with previously
adjuvant chemotherapy versus observation with treatment at hematopoietic stem-cell support in germ-cell tumor patient treated germ cell tumors, J Clin Oncol, 1994;12(11):2277–83.
relapse in pathological stage II testicular cancer, N Engl J Med, treatment, Int J Cancer, 1999;83(6):844–7. 6. Bokemeyer C, Beyer J, Metzner B, et al., Phase II study of
1987;317(23):1433–8. 4. Beyer J, Kramar A, Mandanas R, et al., High-dose paclitaxel in patients with relapsed or cisplatin-refractory
2. Loehrer PJ Sr, Gonin R, Nichols CR, et al., Vinblastine plus chemotherapy as salvage treatment in germ cell tumors, J Clin testicular cancer, Ann Oncol, 1996;7(1):31–4.
ifosfamide plus cisplatin as initial salvage therapy In recurrent Oncol, 1996;14(10):2638–45. 7. Sandler AB, Cristou A, Fox S, et al., A phase II trial of
germ cell tumor, J Clin Oncol, 1998;16(7):2500–2504. 5. Motzer RJ, Bajorin DF, Schwartz LH, et al., Phase II trial of paclitaxel in refractory germ cell tumors, Cancer, 1998;82(7):
90 EUROPEAN ONCOLOGY
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