Testicular germ cell cancer is the most common malignancy in men aged between 15 and
35 years (Hartmann et al, 1999, Bosl and Motzer, 1997). An important subset of germ
cell tumours (GCT), approximately 5–7%, is of extragonadal origin (Collins and Pugh,
1964). In adults, these tumours most commonly arise in the midline of the body, particularly
in the retroperitoneum and the mediastinum. Conventional cisplatin-based chemotherapy
has demonstrated activity in patients with extragonadal GCT, and long-term survival
rates approach those of patients with advanced-stage metastatic gonadal GCT (Nichols
et al, 1990b, Hidalgo et al, 1997). Primary nonseminomatous tumours of the mediastinum
have a poor outcome with conventional chemotherapy and the presence of a mediastinal
location defines the patient as ‘poor prognosis’ according to the IGCCCG classification
irrespective of additional metastatic sites or elevated tumour marker concentrations
(Ulbright et al, 1984; Toner et al, 1991; Bukowski et al, 1993; Childs et al, 1993;
Harding et al, 1993; Saxman et al, 1994; Hidalgo et al, 1997; International Germ Cell
Consensus Classification, 1997; Ganjoo et al, 2000). High-dose chemotherapy with autologous
peripheral blood stem cell transplantation (HD-CT) is used as a therapeutic option
with acceptable toxicity in patients with relapsed GCT, and has also been investigated
as first-line therapy in patients fulfilling ‘intermediate’ or ‘poor prognosis’ criteria
according to the IGCCCG classification (Motzer et al, 1993,1997; Bokemeyer et al,
1998). A retrospective matched-pair analysis demonstrated that first-line HD-CT is
associated with a potential survival benefit of approximately 15% at 2 years in ‘poor
prognosis’ patients compared to standard-dose cisplatin-based chemotherapy (Bokemeyer
et al, 1999). This report summarises our experience with HD-CT in patients with mediastinal
nonseminomatous GCT. Those patients were included into a German multicentre trial
using HD-VIP regimen as first-line treatment in patients fulfilling either ‘advanced
disease’ criteria according to the Indiana classification or IGCCCG ‘poor prognosis’
criteria since its introduction in 1995 (Birch et al, 1986; International Germ Cell
Consensus Classification, 1997).
PATIENTS AND METHODS
From January 1993 to July 1998, 28 patients with primary mediastinal nonseminomatous
GCT were treated with sequential first-line HD-VIP chemotherapy followed by autologous
peripheral blood stem cell transplantation within a German prospective, multicentre
trial. Eligibility criteria included nonseminomatous histology, any primary site,
‘advanced disease’ according to the Indiana University Criteria (Birch et al, 1986)
or ‘poor prognosis’ according to the IGCCCG (International Germ Cell Consensus Classification,
1997), adequate kidney function (creatinine clearance >60 ml min−1) and liver function
(bilirubin <1.5-fold upper normal limit, liver enzymes <three-fold upper normal limit),
no prior chemotherapy as well as informed consent. The local ethical committee had
approved the study. Treatment consisted of one cycle of standard-dose VIP-chemotherapy
(cisplatin 20 mg m−2, etoposide 75 mg m−2, ifosfamide 1200 mg m−2, daily for 5 days)
plus granulocyte-colony stimulating factor (G-CSF) 5 μg kg−1 starting at day 7 followed
by peripheral blood stem cell collection and subsequently three sequential cycles
of HD-VIP chemotherapy. Another HD-VIP cycle was allowed in case of declining but
not completely normalised tumour marker concentrations. The dosages of the high-dose
cycles were escalated over six different patient cohorts. No intraindividual dose
escalation was performed. Data on the treatment protocol have been reported elsewhere
(Bokemeyer et al, 1998). The dosages applied ranged from 200 to 350 mg m−2 for etoposide,
1.6–2.4 gm−2 ifosfamide and cisplatin 20 (levels 4–6) to 30 mg m−2 (levels 1–3) daily
for five consecutive days every 3 week. All patients received autologous peripheral
blood stem cell transplantation (at least 1 × 106 CD 34+ cells kg−1 body weight) at
day 7 after every 5-day HD-VIP application as well as 5 μg kg−1 body weight G-CSF
(filgrastim) support subcutaneously starting 24 h after completion of chemotherapy
(for details see Figure 1
Figure 1
Design of sequential HD-VIP with PBSCT. SD=standard dose; HD=high dose; G-CSF=granulocyte-colony-stimulating
factor; PBSC(T)=autologous peripheral blood stem cell (transplantation). *Five patients
received a 4th HD-VIP cycle because of declining, but not completely normalised, tumour
maker concentrations.
). All patients have been analysed on an intention-to-treat principle. An extragonadal
mediastinal GCT by definition required the absence of testicular abnormalities on
physical examination and ultrasonography. In case of testicular abnormalities, biopsy
was performed to exclude invasive testicular germ cell cancer. Testicular intraepithelial
neoplasia or a scar found at biopsy was not a cause for exclusion from study. Resection
of residual tumour masses after chemotherapy was planned, if technically feasible,
for all patients with marker negative partial remission (PR) or in patients with still
decreasing but not completely normalised markers and partial radiological responses.
Resected specimens were categorised according to the following criteria: necrosis
referred to findings of necrotic debris only in the resected specimen. Differentiated
teratoma referred to the finding of mature teratoma in the absence of either malignant
transformation or GCT such as embryonal carcinoma, yolk sac carcinoma, choriocarcinoma
or seminoma. Any of the latter histological findings were considered as vital tumour
as well as teratoma with malignant transformation. In case of a complete resection
of all residual masses, patients were categorised depending on the histological results
as no evidence of disease (NED) (either vital tumour, differentiated teratoma or necrosis).
However, in four patients who had attained serologic complete remission (CR) but had
persistent minor radiographic abnormalities, individual investigators have chosen
to observe such patients without surgery because of nonresectability. Those patients
were formally coded as PR in the follow-up status if their residual abnormalities
remained stable or decreased on imaging studies over a 1-year period.
A CR was defined as the complete disappearance of all clinical, radiological and biochemical
evidence of disease after chemotherapy. Marker negative partial remission (PRm-) was
assumed in patients with any decrease in the sum of the products of diameters of measurable
lesions and normalisation of tumour markers. Progressive disease (PD) was defined
as either residual lesions increasing in size or occurrence of new lesions and/or
elevation of tumour markers at repeated controls.
Statistical analysis
Statistical analysis was performed using SPSS (SPSS for Windows 10.0. software SPPS
Inc., Chicago, IL, USA). For all living patients, the status as of January 2002 was
obtained. The overall survival (OS) calculation used death due to any reason as the
end point. Various patients' characteristics such as, categorial variables, extent
of disease at diagnosis, evidence of bone, lung, liver, brain, lymph node involvement,
age grouping or tumour marker grouping (according to the IGCCCG classification) were
investigated as potential prognostic factors by univariate analysis. For the survival
time, the proportion of survivors was estimated by the Kaplan–Meier method (Kaplan
and Meier, 1958), and the log-rank test was used for comparison. For ordered categorial
variables, the log-rank test for trends was used. All factors with a P-value <0.05
were considered as significant. All reported P-values were two-sided.
The survival data of patients with high-dose chemotherapy have been compared with
the cohort of patients receiving cisplatin-based conventional dose chemotherapy available
from the International Extragonadal Germ Cell Tumour Study Group, which comprised
individual treatment data on 635 patients with extragonadal GCT from 11 European and
US cancer centres (Bokemeyer et al, 2002; Hartmann et al, 2002). A small proportion
of patients with conventional dose chemotherapy received double-dose cisplatin, which
had no impact on efficacy in a randomised, prospective intergroup study (Nichols et
al, 1991).
RESULTS
Patients' characteristics
Twenty-eight patients with primary mediastinal nonseminomatous GCT were treated within
the HD-VIP protocol from 1993 to 1998. The median age was 32 years (range, 20–50).
A detailed list of the patients' characteristics is given in Table 1
Table 1
Characteristics of 28 patients with nonseminomatous mediastinal GCT
Characteristics
No. of pts
%
Median age – years (range)
32 (20–50)
–
Histology
Nonseminomatous GCTa
28b
100
Teratocarcinoma
4
14
Endodermal sinus tumour
8
29
Choriocarcinoma
8
29
Embryonal Cell
1
4
Serologic diagnosis onlyc
1
4
other GCT histology
6
21
Elevated serum tumour markers
α-fetoprotein
17
61
Median (range) in ng ml−1
912 (1 to 31.114)
Human chorionic gonadotropin
10
36
Median (range) in mIU ml−1
34 (0.9 to 300.000)
Lactate dehydrogenase
12
43
Median (range) in IU l−1
360 (113 to 2.682)
Extent of disease
Localised mediastinal mass
10
32
Additional lung/pleural involvement
7
25
Visceral metastases
11
39
Sites of metastases
Bone
5
18
Lung
17
61
Liver
7
25
CNS
3
11
LN
3
11
Other
5
18
Previous chemotherapy
–
–
a
GCT=germ cell tumour;
b
A total of 12 of 28 patients have been included in Bokemeyer et al (1998);
c
Patient had a mediastinal mass without histologic diagnosis of the tumour and elevation
of tumour marker concentrations β-HCG and/or AFP indicating a mediastinal nonseminomatous
GCT.
. Due to the presence of the primary mediastinal GCT, all patients were classified
as ‘poor prognosis’ testicular germ cell cancer according to the IGCCCG classification.
Even without considering the primary tumour site, 18 patients (64%) fulfilled ‘poor
prognosis’ criteria either because of the additional presence of visceral metastases
or ‘poor marker’ status. Serum concentrations of the tumour markers α-fetoprotein,
β-human chorionic gonadotropin and lactate dehydrogenase were elevated in 61, 36 and
43% of the 28 patients, respectively. Ten patients had localized disease confined
to the mediastinum (36%), seven (25%) had additional thoracic involvement and 11 patients
(39%) had evidence of visceral disease.
Treatment side effects
A total of 89 high-dose cycles with a median number of 3 (range, 3–4) per patient
were given to the 28 patients with mediastinal primary tumours resulting in a median
duration of WHO grade IV granulo- and thrombocytopenia of 6 and 4 days. Median time
to haematologic recovery from the start of treatment was at days 15 and 16, respectively.
WHO grade III/IV mucositis/enteritis occurred in nine (32%) patients. Nine (32%) patients
developed grade III/IV fever/infection. No toxic death occurred. Chemotherapy-related
neurotoxicity grade I/II was observed in five (18%) patients.
Response to treatment
Median follow-up duration was 43 months (range, 7–113) for all patients and 52 months
(range, 22–113) for surviving patients. Follow-up data and response evaluation are
summarised in Table 2
Table 2
Response to treatment and current follow-up status
No. of pts
%
Response to treatmenta
CR/NEDnecrosis
11 (4b/7)
39 (14/25)
NEDvital tumour
7c
25
NEDteratoma
1
4
PRm−
4
14
PD
5
18
Follow-up status
NED
17d
61
Continuously NED
16
57
PR (>1 year)
1
4
DoD
8
29
Dead due to haematologic disorder
2e
7
Estimated OS
%
CI95%
At 2 years
68
51–85
At 5 years
64
46–82
Estimated PFS
At 2 years
64
47–82
At 5 years
56
37–75
a
Evaluation of response based on CT scans and determination of serum tumour marker
concentrations.
b
Including one patient with consolidation CNS radiation for CNS metastases.
c
One patient with non-germ cell tumour elements.
d
One patient after resection of mature teratoma at relapse.
e
One patient with simultaneous relapse of GCT (after achievement of PRm−) and development
of haematologic disorder (myelodysplasia with abnormal megakaryocyctes).
CR=complete remission after chemotherapy alone; NEDvital tumour/teratoma/necrosis=no
evidence of disease after complete resection of vital tumour or differentiated teratoma;
PR=partial remission; PD=Progressive disease; DoD=dead of disease; CI=confidence interval;
OS=overall survival; PFS=progression-free survival; pts=patients.
. Nineteen of 28 patients (68%) obtained a disease-free status after treatment. Of
the 19 patients with no evidence of disease after treatment, 16 are continuously in
CR and in addition, one of four patients with PRm- after HD-VIP is currently alive.
Two patients have relapsed from CR with recurrent GCT (n=1) and teratoma (n=1). Relapses
occurred after 32 and 43 months after treatment. The patient who had developed teratoma
remained alive and disease free 37 months after mediastinal resection and atypical
right upper lobectomy. Three of four patients relapsed after achievement of a marker
normalised PR at 2, 5 and 10 months after completion of chemotherapy. Two patients
developed haematologic disorders, one an acute myelogenous leukaemia and the other
a myelodysplasia with abnormal megakaryocytes, 12 and 18 months after initial therapy.
Both died shortly after the occurrence of the haematologic disorder. Patients, who
did not attain a CR to HD-VIP, received different second-line chemotherapy regimens
including VeIP (Loehrer et al, 1998) Loehrer et al, 2001 not cited in ref. List, TIP
(Rick et al, 2001), continuation of standard VIP and oral etoposide; however, none
of the patients responded to salvage treatment. Neither the median progression-free
survival (PFS) nor the median OS has been reached. The estimated 2- and 5-year PFS
rates are 64% (95 % CI, 47–82%) and 56% (95% CI, 37–75%), and the estimated OS rates
are 68% (95% CI, 51–85%) at 2 years and 64% (95% CI, 46–82%) at 5 years.
Univariate analysis on prognostic factors for survival
Results are summarised in Table 3
Table 3
Univariate analysis of patients' and treatment characteristics for their influence
on OS in nonseminomatous mediastinal GCT
Characteristics
No. of pts (%)
Calculated 5-year OS rate (%)
P
Calculated 5-year PFS rate (%)
P
Extent of disease
Mediastinum only
10 (32)
90
90
Lung/pleural
7 (25)
57
29
Visceral disease
11 (36)
45
0.08
45
0.02
Bone metastases
No
23 (82)
64
59
Yes
5 (18)
60
0.87
60
0.93
Lung metastases
No
11 (39)
89
89
Yes
17 (61)
53
0.23
41
0.03
CNS metastases
No
25 (89)
58
54
Yes
3 (11)
100
0.22
100
0.18
Liver metastases
No
21 (75)
80
75
Yes
7 (25)
14
<0.01
14
<0.01
Lymph nodes
1
No
25 (89)
66
63
Yes
3 (11)
33
0.12
33
0.38
Age
20–25
6 (21)
0
0
26–30
7 (25)
86
86
31–35
7 (25)
57
43
36–40
5 (18)
80
80
>40
3 (11)
100
0.02
67
0.27
Tumour marker status2
AFP
Good/intermediate
18 (64)
67
56
Poor
7 (25)
57
0.65
57
0.87
β-HCG
Good/intermediate
20 (71)
65
60
Poor
5 (18)
60
0.86
40
0.37
LDH
Good/intermediate
24 (86)
67
58
Poor
1 (4)
0
0.14
0
0.29
1
Additional regional lymph node involvement outside of the midline.
2
According to International germ cell consensus classification, 1997.
β-HCG=beta human chorionic gonadotropin; LDH=lactate dehydrogenase; LN=lymph nodes;
OS=overall survival; PFS=progression-free survival; pts=patients.
. A significant inferior PFS was found for patients who had a disease extending beyond
the mediastinum with evidence of liver or pulmonary metastases. Disease confined to
the mediastinum indicated a superior outcome. The presence of liver metastases was
identified to worsen OS. Elevation of tumour marker concentrations and categorisation
into ‘good/intermediate’– vs ‘poor’ – marker according to the IGCCCG did not influence
either PFS or OS.
Comparison to standard-dose cisplatin-containing treatment programmes
Two hundred fifty three patients with mediastinal GCT, who had received cisplatin-based
conventional chemotherapy between 1979 and 1996, were available from the database
of the International Extragonadal Germ Cell Tumour Study Group comprising 635 patients
with extragonadal GCT from 11 cancer centres in the US and Europe (Bokemeyer et al,
2002; Hartmann et al, 2002). The results of patients with nonseminomatous mediastinal
GCT undergoing standard-dose regimen were compared with our experience in patients
with dose-intensive chemotherapy according to the HD-VIP protocol (Table 4
Table 4
Comparison of trials in patients with primary mediastinal nonseminomatous GST including
conventional cisplatin-based regimen and high-dose chemotherapy
Conventional dose
a
HD-VIP
Variable
No. of pts
%
No. of pts
%
Patients
253
28
CR/PRm- (assessable)
157 (244)
45
17 (28)
61
Status
NED
114
45
17
61
AwD
11
4
1
4
Dead
121
48
10
36
Lost to follow-up
9
4
–
–
Median 5-year PFS rate (%)
42
56
Median 5-year OS rate (%)
46
64
Median PFS (months)
15
Not reached
Median OS (months)
40
Not reached
HD=high dose; CR=complete remission; PRm-=marker normalized partial remission; NED=no
evidence of disease; AwD=alive with disease; PFS=progression-free survival; OS=overall
survival; pts=patients.
a
Data about patients receiving standard cisplatin chemotherapy are derived from the
database of the International Extragonadal Germ Cell Tumour Study Group (in part described
in Bokemeyer et al, 2002, Hartmann et al, 2002).
, Figures 2A,B
Figure 2
Overall survival (A) and PFS (B) for patients with primary mediastinal nonseminoma
treated on programmes that included either high-dose chemotherapy (HD-VIP) or conventional
dose cisplatin-based combination chemotherapy (date about patients receiving standard
cisplatin chemotherapy are derived from the database of the International Extragonadal
Germ Cell Tumour Study Group (in part described in Bokemeyer et al, 2002; Hartmann
et al, 2002). mos= months
). There was a higher 5-year OS rate with dose-intensive therapy compared to standard-dose
cisplatin protocols of 64% vs 46% as well as 57% vs 42% for PFS rates at 5 years.
The corresponding hazard ratios for PFS and OS in patients receiving HD-VIP compared
to standard cisplatin chemotherapy were 0.67 (95% CI, 0.42 – 1.17) and 0.59 (95% CI,
0.38 – 1.01), respectively.
DISCUSSION
Although the principles of management of patients with mediastinal nonseminomatous
GCT parallel those of metastatic nonseminomatous testicular GCT, patients with mediastinal
primaries clearly have a worse prognosis compared to patients with gonadal GCT. Accordingly,
the presence of a mediastinal primary tumour in patients with nonseminomatous GCT
was identified as a major adverse prognostic factor by the IGCCCG. Such patients appear
to represent a clinically and biologically distinct disease entity (Nichols et al,
1985,1987,1990a; Hartmann et al, 2000b,2001a,2001b), associated with lower complete
response rates to chemotherapy, high rates of relapse and more frequent failures to
salvage chemotherapy (Saxman et al, 1994, Loehrer et al, 1998; Hartmann et al, 2001a).
Historically, the incorporation of cisplatin into chemotherapy regimens has yielded
survival rates of approximately 30–40% in retrospective analyses (Garnick et al, 1983;
Logothetis et al, 1985; Delgado et al, 1993; Dulmet et al, 1993; Toner et al, 1991;
International germ cell consensus classification, 1997). Two prospective series based
on 31 and 41 patients reported a long-term survival rate of >50% following conventional
cisplatin-based chemotherapy plus secondary surgery (Nichols et al, 1990b, Bukowski
et al, 1993). The database of the International Extragonadal Germ Cell Tumour Study
Group contains 287 patients with primary mediastinal tumour location and nonseminomatous
histology from 11 Cancer Centres (Bokemeyer et al, 2002; Hartmann et al, 2002). Of
these patients, 253 have been treated with conventional cisplatin-based chemotherapy.
The 2- and 5-year OS rates of those patients were 55 and 46%, and 47 and 42% for PFS.
The analysis of the International Extragonadal Germ Cell Tumour Study Group demonstrated
that patients with primary mediastinal GCT have a heterogeneous prognosis depending
on patients' characteristics (Hartmann et al, 2002). Patients having localised mediastinal
disease without elevation of HCG at initial diagnosis and who were of young age, revealed
a favourable survival (OS 83% at 2 years) compared to patients presenting with adverse
prognostic variables such as presence of visceral metastases or of lung metastases
(OS 34 or 42% at 2 years). One conclusion from this investigation is that patients
with localised disease confined to the mediastinum have an acceptable prognosis when
treated by a multidisciplinary approach with aggressive surgery of the residual mediastinal
tumour mass.
However, more than half of the patients with mediastinal nonseminomatous GCT failed
to achieve a durable response to conventional cisplatin-based chemotherapy. The success
of carboplatin/etoposide- (CE) or carboplatin/etoposide/cyclophosphamide- (CEC) containing
high-dose chemotherapy with autologous peripheral blood stem cell transplantation
(HD-CT) in the treatment of patients with relapsed disease led to its investigation
as initial first-line treatment in patients fulfilling ‘poor prognosis’ criteria.
With this approach as initial treatment, the time to blood count recovery is shorter,
toxicity is reduced, and further dose intensification is feasible compared with its
use in heavily pretreated patients (Motzer et al, 1996). Two consecutive trials conducted
by investigators at the MSKCC suggested a therapeutic benefit for HD-CT when used
as first-line treatment for ‘poor prognosis’ patients (Motzer et al, 1993,1997). The
long-term survival rates for all ‘poor prognosis’ patients have been 54 and 67% after
HD-CT with the CE- or CEC-regimen. These trials included single patients with primary
mediastinal nonseminomatous GCT; however, no detailed data on response and outcome
for this subgroup of patients due to the small numbers were reported.
The use of initial dose intensification in patients with nonseminomatous mediastinal
GCT appears reasonable because the results with salvage treatment, even including
HD-CT, have been rather disappointing. It appears that more than 90% of patients with
relapsed mediastinal nonseminoma fail to obtain a durable, complete remission in the
salvage setting (Josefsen et al, 1993; Saxman et al, 1994; Loehrer et al, 1998; Hartmann
et al, 2001a).
The current series on the use of intensive first-line HD-VIP for patients with primary
mediastinal nonseminoma indicates the feasibility of this approach, and a 15–20% absolute
survival improvement for these patients receiving sequential HD-VIP as initial treatment
compared to the use of conventional induction chemotherapy might be achievable. Calculation
of the hazard ratios portended a 33% and 41%-risk reduction in recurrence and death
probability for patients treated with HD-VIP compared to standard cisplatin chemotherapy.
However, this is based on a small sample size in the high-dose chemotherapy group.
The comparison of high-dose and standard-dose chemotherapy was not performed as a
prospective randomised trial, and therefore patient selection and stage migration
might be an issue since both groups of patients had been treated in a different time
period.
Prognostic factors for patients receiving HD-VIP in the univariate analysis have been
similar to those in the International Extragonadal Germ Cell Tumour Study Group database
– localised mediastinal disease vs visceral disease, for example, liver, bone, CNS
metastases and lung/pleural involvement. The OS rates at 2 years achieved in this
investigation compared to the expected rates according to the prognostic index of
the International Extragonadal Germ Cell Tumour Study Group for mediastinal nonseminomas
have been 100 vs 65% for patients with localised disease, 57 vs 42% for disease confined
to the thorax (patients with lung or pleural metastases) and 45 vs 34% for patients
with presence of visceral metastases (Hartmann et al, 2002), suggesting that the results
observed in this investigation of dose-intensified HD-VIP chemotherapy might not be
achieved due to a selection of patients possessing more favourable prognostic characteristics.
The only way to truly ascertain the difference between standard- and high-dose chemotherapy
is to perform a randomised trial. An ongoing phase III trial has been initiated in
the US to define the role of HD-CT including high-dose carboplatin instead of cisplatin
in ‘intermediate’ and ‘poor prognosis’ patients. This trial also includes patients
with primary mediastinal nonseminoma. However, because of the rarity of mediastinal
location within the group of poor prognosis patients, this trial will only include
approximately 12–18 patients with primary mediastinal GCT in each arm that will not
allow a sufficient subgroup analysis.
Overall, the survival rates in patients with mediastinal GCT have been improved over
the years – particularly due to aggressive postchemotherapy surgery of residual mediastinal
masses – now approaching the rate which is achieved in patients with ‘poor prognosis’
metastatic disease according to the IGCCCG classification (International Germ Cell
Consensus Classification, 1997). More than half of the patients in the current series
have undergone a multidisciplinary treatment approach including aggressive postchemotherapy
surgery and the use of consolidation radiation of the brain in one patient. As in
patients with metastatic gonadal GCT, radical surgical resection of residual masses
after first-line chemotherapy is indicated, whenever technically possible either as
a one-stage or as a sequential procedure (Kay et al, 1987; Wright et al, 1990; Nichols
et al, 1990b; Hartmann et al, 1997; Ganjoo et al, 2000; Vuky et al, 2001). In this
series, all 10 patients with disease confined to the mediastinum regardless of other
prognostic factors that are relevant for metastastic gonadal GCT, for example, tumour
marker status, are disease-free. One of these patients died due to a haematologic
disorder without evidence of GCT relapse.
As described before, there is approximately a 6% risk to develop a haematologic disorder
in patients with primary mediastinal nonseminoma, which represents a biological phenomenon
not related to chemotherapy (Nichols et al, 1985,1990a; Hartmann et al, 2000b). The
haematologic malignancies have a very aggressive clinical course with patients either
dying before treatment, not responding to antileukaemic therapy, or achieving remissions
of very short duration. In the current investigation, two patients died due to haematologic
disorders 12 and 18 months after completion of GCT treatment.
Investigational approaches in progress explore whether the outcome of patients with
mediastinal primary GCT can be further improved with the use of first-line sequential
HD-CT or with the addition of further active drugs to the HD-VIP regimen (Hartmann
et al, 2001c). In order to improve the prognosis of patients with mediastial GCT,
it appears mandatory to include these patients into controlled clinical trials at
experienced centres.