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Evaluation of High-Dose Chemotherapy and
Autologous Stem Cell Transplant in Salvage
Treatment of Extragonadal Germ Cell Tumours
Alper TOPAL
Gülhane Askerî Tıp Akademisi
Ismail ERTURK
Gülhane Askerî Tıp Akademisi
Caglar KOSEOGLU
Gülhane Askerî Tıp Akademisi
Aysegul DUMLUDAG
Gülhane Askerî Tıp Akademisi
Ömer Faruk KUZU
Gülhane Askerî Tıp Akademisi
Berkan KARADURMUS
Gülhane Askerî Tıp Akademisi
Esmanur KAPLAN TUZUN
Gülhane Askerî Tıp Akademisi
Huseyin ATACAN
Gülhane Askerî Tıp Akademisi
Nurlan MAMMADZADA
Gülhane Askerî Tıp Akademisi
Gizem YILDIRIM
Gülhane Askerî Tıp Akademisi
Ramazan ACAR
Gülhane Askerî Tıp Akademisi
Nuri KARADURMUS
Gülhane Askerî Tıp Akademisi
Article
Keywords: high-dose chemotherapy, extragonadal germ cell tumours, autologous stem cell
transplantation, salvage therapy
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Abstract
Background
We aimed to evaluate the survival analysis, response rates and factors affecting response to high-dose
chemotherapy (HDCT) and autologous stem cell transplantation (OSCT) in patients with
relapsed/refractory extragonadal germ cell tumours.
Methods
The study included patients diagnosed with extragonadal germ cell tumors who underwent HDCT +
ASCT between November 2016 and January 2023 at Gülhane Training and Research Hospital. Clinical
characteristics and follow-up data were retrospectively analyzed from patient records and the hospital
electronic system. Patients under 18 years of age and those without medical records were excluded.
Patient characteristics, post-HDCT progression-free survival (PFS), overall survival (OS) data, factors
affecting survival, and treatment-related mortality (TRM) were examined. The relationship between
clinical factors and OS/PFS was analyzed.
Results
Twenty-ve patients were included. After HDCT + ASCT, complete response (CR) was observed in 6
patients (24%), partial response (PR) in 15 patients (60%) and progressive disease (PD) in 4 patients
(16%). TRM was observed in 1 (4%) patient. Median follow-up was 25.4 months. Median PFS and OS
after HDCT + ASCT were calculated to be 4.9 months and 12.2 months, respectively.
Conclusions
Salvage HDCT + ASCT is an option in the treatment of extragonadal germ cell tumours, offering the
potential for prolonged survival and cure.
1. Introduction
Testicular cancer is the most common solid malignancy in men aged 15-35 years, 95% of which are
germ cell tumours (GCTs)1,2. Male GCTs generally originate in the testis. However, 2% to 5% are of
extragonadal origin3. The location of EGCTs varies according to age. In adults, they tend to occur in the
midline of the anterior mediastinum, retroperitoneal region, suprasellar and pineal regions4. Like gonadal
germ cell tumours, EGGCTs occur in histological types similar to GCTs. These include seminomatous
(germinoma/dysgerminoma) and nonseminomatous germ cell tumours, including endodermal sinus
tumour, yolk sac tumour, embryonal carcinoma, choriocarcinoma and mature or immature teratoma5.
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Testicular and EGCTs also share similar serological features, such as secretion of the tumour markers
alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (β-HCG)6.
Although EGGCT have similar histological, serological and cytogenetic features to gonadal GCT, their
clinic, behaviour and biology are different. EGGCTs have worse chemosensitivity and prognosis than
gonadal tumours, especially nonseminomatous tumours7,8. Primary mediastinal and retroperitoneal
seminomatous EGCTs have an equivalent prognosis to their primary gonadal counterparts. However,
nonseminomatous EGGCTs have a worse prognosis than seminomatous EGGCTs.6.
Treatment of EGGCT is similar to that of gonadal GCT. After histological classication into seminoma
and non-seminoma, chemotherapy (CT) is administered according to risk classication. Surgical
resection may also be performed in patients with residual tumour after treatment. Ecacy and survival
increase with multimodal treatment options9,10. There is no standard salvage treatment for
recurrent/refractory EGGCT patients. High-dose chemotherapy (HDCT) with autologous stem cell
transplantation (ASCT) is an effective option for EGGCT patients and is used as salvage treatment11,12.
In our study, we aimed to show the real world data of our single-centre experience regarding the ecacy
of salvage HDCT+ASCT in patients with relapsed/refractory EGGCT.
2. Materials & Methods
2.1 Study & Patient Selection:This study was a retrospective cross-sectional study. The study population
consisted of male patients aged 18 years and older with recurrent/refractory EGGCT, who underwent
HDCT and ASCT at the Bone Marrow Transplant Unit of Gülhane Training and Research Hospital between
November 2016 and January 2023. Patients who had received at least one line of platinum-containing
chemotherapy and subsequently relapsed were selected for HDCT and ASCT. Patients younger than 18
years, female patients, and patients without medical records were excluded. Clinical characteristics and
follow-up data, including age, histology, metastatic site, number of lines of treatment prior to HDCT,
serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) levels prior to HDCT,
International Prognostic Factor Study Group (IPFSG) classication, and International Germ Cell Cancer
Collaborative Group (IGCCCG) classication, Incidence of febrile neutropenia, objective response rate
(ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-
related mortality (TRM), complete response (CR) status and factors affecting CR were analysed.
2.2 High-Dose Chemotherapy Regimen, ASCT and Endpoints: For CD34+ stem cell collection, 10 mcg/kg
granulocyte colony stimulating factor (GCSF) was given subcutaneously for 5 days. Stem cells were then
collected. All patients received carboplatin and etoposide (CE) as HDCT regimen. Carboplatin (600
mg/m2) and etoposide (600 mg/m2) were administered on days 1, 2 and 3. Stem cell reinfusion was
performed after 2 days of rest. All patients received oral levooxacin 500 mg, oral uconazole 400 mg
and oral acyclovir 400 mg for infection prophylaxis. In addition, prophylactic antiemetics and oral care
products were also included in the treatment regimen. Complete blood counts were performed daily until
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the patient achieved engraftment. Platelet engraftment was dened as a platelet count of at least
20,000/mm3 for three consecutive days, while neutrophil engraftment was dened as a neutrophil count
of at least 2000/ mm3. Platelet and erythrocyte suspensions were transfused to maintain levels of
20,000 platelets per mm3 and 8g erythrocytes per dL, respectively.
Platinum-refractory disease was dened as tumor progression within 3 months of the last cisplatin-
based chemotherapy. The primary endpoint was overall survival (OS) following high-dose chemotherapy
(HDCT). Progression-free survival (PFS) is dened as the time from transplantation to the occurrence of
disease progression, while overall survival (OS) is dened as the time from transplantation to death or
last follow-up. TRM was dened as death within 1 month of ASCT. Radiological response was evaluated
by positron emission tomography/computed tomography (PET-CT) three months after treatment.
Radiological evaluation was assessed by a trained radiologist according to RECIST 1.1 criteria. Complete
remission (CR) is dened as the absence of radiologically active residual lesions and negative blood
biomarkers. Partial response (PR) is dened as a 50% reduction in the sum of the product of the longest
diameters of measurable lesions or a greater than 90% reduction in elevated serum markers. SD was
dened as no objective tumour regression evidenced by no decrease in the sum of the longest diameters
of any measurable lesion and no objective increase in tumour burden evidenced by no increase in the
product of the longest diameters of any measurable lesion. PD was dened as an increase of more than
25% in the product of the longest diameters of any measurable lesion, the appearance of new lesions or
an increase in serum markers. ORR was calculated as the proportion of all patients achieving complete
response (CR) and partial response (PR), while DCR was calculated as the proportion of all patients
achieving CR, PR and stable disease (SD). Patients who achieved CR after transplantation were followed
up without treatment. Patients with PR and marker positive SD were treated with oral etoposide, while
those with progressive disease (PD) were treated with GemPOX (Gemcitabine/Paclitaxel/Oxaliplatin)
regimen (gure1).
2.3 Statistical Analysis: Statistical analyses were performed using SPSS version 22.0 software. The
continuous independent variables were analyzed using the Mann–Whitney U and Student t test.
Normally distributed continuous variables were expressed as mean ± standard deviation, while non-
normally distributed variables were expressed as median. Kaplan-Meier survival function analyses and
log-rank tests were used to calculate cumulative survival and treatment correlations. The categorical
data were analyzed for signicance using Pearson's chi-squared and Fisher's exact tests. A p-value less
than 0.05 was considered statistically signicant. Bonferroni correction was applied to variables that
were signicant in the univariate analysis.
2.4 Ethical Approval: The retrospective study was approved by the local ethics committee (approval
number (2024/216). All procedures were performed in accordance with the ethical standards of the
Good Clinical Practice Guidelines of the Turkish Medical and Medical Device Institution and the
Declaration of Helsinki.
3. Results
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The study included 25 male patients. The mean age at diagnosis was 28 years (21-48). 52% (13 patients)
were of retroperitoneal origin, 44% (11 patients) of mediastinal origin and 4% (1 patient) of brain origin.
The most common histology was mixed germ cell tumour with a rate of 52% (13 patients). According to
the IPFSG classication, 12 patients (48%) were in the very high risk group and 15 patients (60%) were in
the low risk category according to the IGCCCG classication. The most common sites of metastasis
were retroperitoneal lymph nodes (68%) and lung (48%). 72% of patients (18 patients) had platinum-
sensitive disease. Almost all patients (24 patients, 96%) received 1 line of therapy prior to TIP. There were
2 patients (8%) with elevated AFP and 4 patients (16%) with elevated beta-HCG before transplantation
(clinicopathological features are shown in Tables 1 and 2).
Grade 4 neutropenia, thrombocytopenia and febrile neutropenia were observed in all patients. Treatment-
related mortality (TRM) was 4% (1 patient) and the patient died of septic shock due to prolonged
neutropenia. Post-transplant response evaluation showed complete response (CR) in 7 patients (28%),
partial response (PR) in 9 patients (36%), stable disease (SD) in 1 patient (4%) and progressive disease
(PD) in 8 patients (32%). The objective response rate was 64% and the disease control rate (DCR) was
68%. Median follow-up was 25.4 months, median progression-free survival (PFS) was 4.9 months (95%
CI: 2.19-7.66) and median overall survival (OS) was 12.2 months (95% CI: 6.51-17.99). The one year CR
rate was 28% and 72% (5 patients) of patients who achieved CR showed disease progression within one
year. Two patients are still being followed with CR. During follow-up, 76% (19 patients) of patients who
received HDCT+ASCT died.
According to the results of the univariate analysis, the presence of retroperitoneal lymph node
metastasis (p=0.002), AFP elevation before HDCT (p<0.001), tumour response after HDCT (p=0.02),
presence of CR (p=0.003), objective response rate (ORR) (p=0.003) and DCR (p=0.004) were found to be
factors inuencing PFS. Although tumour location was not found to be signicant for PFS, PFS was
numerically better for tumours of retroperitoneal origin (9.8 months, 95% CI: 1.90-17.67). Although there
was no statistical signicance in histological subtype, PFS was better in those with mixed germ cell
histology (10.6 months, 95% CI: 2.12-19.09).
In univariate analyses for OS, histological subtype (p<0.001), presence of retroperitoneal lymph node
metastasis (p=0.002), absence of liver metastasis (p=0.02), IPFSG classication (p=0.001), IGCCCG
classication (p=0. 002), platinum sensitivity (p=0.004), beta-HCG (p<0.0001) and AFP elevation before
HDCT (p=0.003), tumour response after HDCT (p<0.0001), presence of CR (p=0.009), ORR (p<0.0001)
and DCR (p<0.0001) were identied as factors inuencing OS (Table 3).
Tumour location was found to be signicant for OS. Signicance was found between retroperitoneum
and mediastinum in favour of retroperitoneum (p=0.008). The OS signicance of histological subtype
was due to the difference between yolk sac and choriocarcinoma (p=0.004, in favour of yolk sac) and
mixed germ cell tumour and choriocarcinoma (p<0.001, in favour of mixed). The OS signicance of
IPFSG classication was driven by the difference between intermediate and high risk (p=0.015, in favour
of intermediate) and intermediate and very high risk (p=0.001, in favour of intermediate) (Figure 2). The
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OS signicance of IGCCCG classication was due to the difference between good and poor (p=0.007, in
favour of good) and intermediate and poor risk (p=0.01, in favour of intermediate) (Figure 2). The OS
signicance of tumour response after HDCT was due to the difference between CR and PD (p=0.001, in
favour of CR) and PR and PD (p=0.008, in favour of PR) (gure 2: Kaplan-Meier estimates of overall
survival).
The median OS of patients with CR was 23.9 months (non-CR: 10.6 months), which was statistically
signicant (p=0.009). When the factors affecting CR were analysed, no factor predicting CR was found
(table 4). While 6 of 8 patients with PD after HDCT+ASCT received GemPOx (2 patients could not receive
chemotherapy due to low performance status), all 10 patients with PR+SD response received oral
etoposide.
4. Discussion
In this study, mediastinal EGGCT, IGCCCG low risk, IPFSG high/very high risk, platinum-refractory disease,
high AFP and beta hCG levels, presence of liver metastases and non-CR status after HDCT+ASCT were
associated with poor OS.
Many salvage chemotherapy series for patients with metastatic germ cell tumours include patients with
extragonadal primary tumours.13-15. However, patients with EGGCT are usually a small subpopulation
and have rarely been studied separately. Our study is one of the rare studies that evaluated this
population separately.
In our study, 52% of our patients had retroperitoneal, 44% mediastinal and 4% brain origin. There are 2
separate studies by Bokemeyer et al. In the rst study, mediastinal and retroperitoneal seminomas were
shown to have a similar prognosis (5-year OS 88% in both groups). In the other study, non-seminomatous
mediastinal GCTs were shown to have a worse prognosis than retroperitoneal GCTs (5-year OS 42% and
65% respectively). Conrming this, Beyer et al showed that non-seminomatous histology and mediastinal
origin were associated with shorter failure-free survival (FFS) in a series of 110 patients.6,16. In our
study, the comparison between seminoma and non-seminoma could not be made because 1 patient was
diagnosed with seminoma. When we looked at histological subtype, we found that patients diagnosed
with choriocarcinoma and mediastinal origin had a shorter OS.
The classication of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal
role in the management of metastatic germ cell tumors. In a 23-year analysis of 9728 patients with
metastatic non-seminomatous GCT, IGCCCG classication was shown to be prognostic. In this analysis,
the presence of non-pulmonary visceral metastasis (NPVM) was found to be a poor prognostic factor.
The presence of NPVM makes the patient directly poor risk17.In our study, the OS of patients with liver
metastases was signicantly shorter. In the update of this study published in 2021, 5-year PFS increased
from 82% to 89% and 5-year OS from 86% to 95% in patients with good prognosis and from 67% to 79%
and 72% to 88% in patients with intermediate prognosis. Lactate dehydrogenase (LDH) was an additional
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adverse prognostic factor. While 3-year PFS was 80% and 3-year OS was 92% in patients with good
prognosis and LDH levels above 2.5 times the upper limit of normal, these rates were 92% and 97% in the
group with low LDH levels18.In our study, the presence of retroperitoneal lymph node metastasis was
positively signicant for both PFS and OS. This was thought to be due to the fact that the majority of
patients with retroperitoneal lymph node metastasis (76%) were of retroperitoneal origin. IPFSG
classication is also important in determining prognosis like IGCCCG. IPFSG and IGCCCG classications
were shown to be prognostic in the series of Connolly et al19. In a series of 173 patients by Einhorn et al,
patients with good IGCCCG class had signicantly longer survival20. Similarly, IPFSG and IGCCCG
classications showed statistical signicance for OS in our study. According to IPFSG classication, 48%
of our patients were in the very high risk group, while 60% of our patients were in the poor risk group
according to IGCCCG classication. From this, it can be inferred that a large proportion of our patient
population would have a poor prognosis. As a matter of fact, this was the case. Within 3 months after
HDCT, 3 patients died and 5 patients progressed. All of these patients were in the poor risk group.
Platinum sensitivity is important for GCTs. Platinum sensitivity is known to be associated with better
survival. Studies have shown that patients with platinum-sensitive disease have longer survival20-22. Our
study also supports this. Although not reaching signicance for PFS, patients with platinum-sensitive
disease had signicantly longer survival.
AFP and Beta HCG are important for GCTs both in diagnosis, follow-up and prognosis23. In a series of
110 patients (48 patients extragonadal) who underwent HDCT+ASCT, Beyer et al. showed that high AFP
and Beta-HCG levels were associated with non-response to HDCT15. Rodney et al analysed mediastinal
GCTs in a series of 635 patients and found that Beta-HCG≥1000IU/L was associated with poor
prognosis. In our study, AFP and Beta-HCG≥1000IU/L were associated with worse OS. At the same time,
PFS was signicantly shorter in patients with AFP≥1000IU/L.24.
In a series of 31 patients with EGGCT by Hainsworth et al, 12 patients relapsed after primary
chemotherapy. Although the salvage regimens used were not mentioned, long-term DFS was achieved in
only one patient (3%)25. Josefsen et al. reported the results of salvage therapy in 55 patients with
recurrent germ cell tumours, 12 of whom had extragonadal primary tumours. The disease-free survival
rate for the total group was 27% at 5 years. Long-term disease-free survival was achieved in three of the
12 extragonadal patients (25%)26.
Motzer et al. reported an overall survival rate of 20% after a median follow-up of 37 months following
salvage chemotherapy. Of these 94 patients, 14 (15%) had extragonadal primary tumours and none of
these patients were alive 2 years after salvage treatment. In this study, primary site was not a signicant
predictor of response to salvage chemotherapy, but there was a trend towards lower CR rates in patients
with extragonadal primaries. However, non-seminomatous EGGCTs have been shown to be associated
with a poor prognosis. High levels of beta-HCG and lactate dehydrogenase and the number of
metastases have also been associated with an unfavourable prognosis.13.
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Loehrer et al. reported one of the largest series to date using conventional dose chemotherapy (CDCT)
as rst-line salvage therapy. This study was designed to evaluate the ecacy of vinblastine, ifosfamide
and cisplatin (VeIP) as second-line treatment. Of 100 patients with progressive disseminated gonadal
GCT, 30 were disease-free, while none of the 32 patients with extragonadal non-seminomatous tumours
included in the study were cured.27.
Saxman et al. reported a large series on the results of salvage chemotherapy in patients with EGGCT. Of
the 73 patients analysed, all had EGGCT with non-seminomatous histology. In contrast to the results of
salvage chemotherapy in patients with testicular germ cell tumours, only 7% of their patients achieved
long-term disease-free survival. Eight patients received HDCT as rst-line salvage treatment and 28
patients received it as third-line treatment. None of these 28 patients achieved long-term disease-free
survival. Primary mediastinal location suggested as negative prognostic factor28.Similarly, mediastinal
origin was associated with poor prognosis in our study.
In the study by Pico et al, conventional dose chemotherapy (CDCT) and HDCT were compared in patients
with relapsed/refractory GCT. There were 31 patients diagnosed with EGGCT in the general population.
The 2-year OS of mediastinal GCTs was 22%, while that of retroperitoneal GCTs was 51%.14. In the 2nd
stage HDCT+ASCT study by De Giorgi et al. in 59 patients with EGGCT, the 1- and 2-year survival of
patients with mediastinal EGGCT was 46% and 23%, respectively. The 1- and 2-year survival rates for
patients with retroperitoneal EGGCT were 76% and 48%, respectively. The CR rate was 43% in patients
with retroperitoneal EGGCT and 23% in patients with mediastinal EGGCT12. In the series of 40 patients
by Randolph et al. 9 patients had extragonadal origin. 8 patients had mediastinal origin and CR could not
be obtained in any of them. Median survival was 2 months29.In another study, the median OS of 10
EGGCT patients who underwent HDCT+ASCT was 15 months.30.In our study, median PFS was 4.9
months and median OS was 12.2 months. 1 and 2-year survival of patients with mediastinal EGGCT was
45% and 0%, while 1 and 2-year survival of patients with retroperitoneal EGGCT was 66% and 57%. CR
rate was found to be 30% in patients with retroperitoneal origin and 22% in patients with mediastinal
origin.
In a series of 6 patients with mediastinal non-seminomatous GCT by Kumano et al, PR was achieved in 5
patients and SD in 1 patient after HDCT+ASCT (17). In the study by Siegert et al, CR was obtained in 5
patients (31%) and PR in 5 patients (31%) with EGCCT31. In our study, 7 patients achieved CR (33%). Of
the 7 patients who achieved CR, 2 patients are still being followed as disease-free with CR. Recurrence
was observed in the other 5 patients.
In most of the studies mentioned above, patients underwent 2 or more cycles of HDCT. Patients who
underwent two cycles of transplantation have been shown to have signicantly better survival12,20,29.
Our country’s healthcare system allows 1 transplantation. Therefore, we use the TIP (rarely VIP) regimen
as induction chemotherapy and HDCT as consolidation chemotherapy. TIP is therefore an important part
of our HDCT + ASCT process.
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The mortality risk of HDCT+ASCT is considerably higher compared to conventional chemotherapies. The
highest reported rate is 25%.32. In a retrospective study by Kilari et al. of 2395 male germ cell tumour
patients who underwent HDCT, the largest series to date, TRM was reported in the range of 4-8%33. In
the study of Connolly et al. including 111 GCT patients, TRM was reported as 4.5%19. In our study,
similar results were obtained despite the small sample size (4%).
In summary, although EGGCTs show similar histological features with gonadal GCTs, their clinical
behaviour is more aggressive and survival is shorter than gonadal GCTs5,15. Therefore, EGGCTs should
be considered as a separate entity. New strategies are needed for patients with EGGCTs. Salvage
chemotherapy and HDCT+ASCT do not provide long-term survival in patients with incomplete response,
and complete response rates are low compared to gonadal GCTs31,34. Especially patients with
mediastinal primary tumours and non-seminomatous patients have worse survival5,6. Considering that
HDCT was shown to be superior to conventional dose chemotherapy in the study by Beyer et al, it can be
considered that HDCT is the best option for EGGCTs for the time being15.
Limitations:
Our study has several limitations. Firstly, it is a retrospective study. Secondly, our study is a single-centre
experience with a relatively small number of patients, which may have affected the results of some
analyses
5. Conclusion
Despite the small sample size, our study is one of the largest case series evaluating the outcomes of
salvage HDCT in EGGCT. Our data support the use of HDCT and ASCT as salvage therapy in patients with
relapsed/refractory EGGCT. Although CR rates are low, it provides evidence that cure can be achieved in
patients with CR. In a rare disease such as EGGCT, HDCT and ASCT treatment may be an appropriate
treatment regimen that can be used as salvage therapy in second-line and beyond, providing real-world
data.
Declarations
Author Contributions: Con-ceptualization, A.T. and N.K.; methodology, A.T and I.E..; software, A.D.;
validation, O.F.K., A.D. and C.K.; formal analysis, B.K.; investigation, E.K.T.; resources, H.A.; data curation,
A.T., N.M. and G.Y.; writing—original draft preparation, A.T. and N.K.; writing—review and editing, A.T. and
R.A.; visualization, A.T.; supervision, A.T. and I.E.; project administration, A.T. and N.K. All authors have
read and agreed to the published version of the manuscript.
Funding: This research did not receive any specic grant from funding agencies in the public,
commercial, or not-for-prot sectors.
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Institutional Review Board Statement: The retrospective study was approved by the local ethics
committee (approval number (2024/216). Allprocedures were performed in accordance with the ethical
standards of the Good Clinical Practice Guidelines of the Turkish Medical and Medical Device Institution
and the Declaration of Helsinki.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: The data that support the ndings of this study are not openly available due
to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data
are located in controlled access data storage at Gulhane Research & Training Hospital. Example from:
https://doi.org/10.1186/s12910-022-00758-z
Conicts of Interest: The authors declare no conicts of interest.
References
1. Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024.
CA: A Cancer Journal for Clinicians
74, 12–49 (2024). https://doi.org:https://doi.org/10.3322/caac.21820
2. Akdag, G.
et al.
Outcomes of surveillance versus adjuvant treatment for patients with stage-I
seminoma: a single-center experience. World journal of urology 41, 2201–2207 (2023).
https://doi.org:10.1007/s00345-023-04482-0
3. Hartmann, J. T.
et al.
Prognostic variables for response and outcome in patients with extragonadal
germ-cell tumors. Annals of oncology: ocial journal of the European Society for Medical Oncology
13, 1017–1028 (2002). https://doi.org:10.1093/annonc/mdf176
4. Rivera, C.
et al.
Prognostic factors in patients with primary mediastinal germ cell tumors, a surgical
multicenter retrospective study. Interactive cardiovascular and thoracic surgery 11, 585–589 (2010).
https://doi.org:10.1510/icvts.2010.238717
5. Schmoll, H. J. Extragonadal germ cell tumors. Annals of oncology: ocial journal of the European
Society for Medical Oncology 13 Suppl 4, 265–272 (2002). https://doi.org:10.1093/annonc/mdf669
. Bokemeyer, C.
et al.
Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results
from an international analysis. Journal of clinical oncology: ocial journal of the American Society
of Clinical Oncology 20, 1864–1873 (2002). https://doi.org:10.1200/jco.2002.07.062
7. Fizazi, K.
et al.
[Primary mediastinal non-seminomatous germ-cell tumors: from clinics to biology].
Bulletin du cancer 84, 313–327 (1997).
. Toner, G. C., Geller, N. L., Lin, S. Y. & Bosl, G. J. Extragonadal and poor risk nonseminomatous germ
cell tumors. Survival and prognostic features. Cancer 67, 2049–2057 (1991).
https://doi.org:10.1002/1097-0142(19910415)67:8<2049::aid-cncr2820670807>3.0.co;2-h
9. Beyer, J.
et al.
Maintaining success, reducing treatment burden, focusing on survivorship: highlights
from the third European consensus conference on diagnosis and treatment of germ-cell cancer.
Page 12/16
Annals of oncology: ocial journal of the European Society for Medical Oncology
24, 878–888
(2013). https://doi.org:10.1093/annonc/mds579
10. Patrikidou, A.
et al.
European Association of Urology Guidelines on Testicular Cancer: 2023 Update.
European urology
84, 289–301 (2023). https://doi.org:10.1016/j.eururo.2023.04.010
11. Albany, C. & Einhorn, L. H. Extragonadal germ cell tumors: clinical presentation and management.
Current opinion in oncology 25, 261–265 (2013). https://doi.org:10.1097/CCO.0b013e32835f085d
12. De Giorgi, U.
et al.
Second-line high-dose chemotherapy in patients with mediastinal and
retroperitoneal primary non-seminomatous germ cell tumors: the EBMT experience. Annals of
oncology: ocial journal of the European Society for Medical Oncology 16, 146–151 (2005).
https://doi.org:10.1093/annonc/mdi017
13. Motzer, R. J.
et al.
Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-
Kettering Cancer Center experience (1979–1989). Cancer 67, 1305–1310 (1991).
https://doi.org:10.1002/1097-0142(19910301)67:5<1305::aid-cncr2820670506>3.0.co;2-j
14. Pico, J. L.
et al.
A randomised trial of high-dose chemotherapy in the salvage treatment of patients
failing rst-line platinum chemotherapy for advanced germ cell tumours. Annals of oncology: ocial
journal of the European Society for Medical Oncology 16, 1152–1159 (2005).
https://doi.org:10.1093/annonc/mdi228
15. Beyer, J.
et al.
High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate
analysis of prognostic variables. Journal of clinical oncology: ocial journal of the American Society
of Clinical Oncology 14, 2638–2645 (1996). https://doi.org:10.1200/jco.1996.14.10.2638
1. Bokemeyer, C.
et al.
Extragonadal seminoma: an international multicenter analysis of prognostic
factors and long term treatment outcome. Cancer 91, 1394–1401 (2001).
17. International Germ Cell Consensus Classication: a prognostic factor-based staging system for
metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. Journal of clinical
oncology: ocial journal of the American Society of Clinical Oncology 15, 594–603 (1997).
https://doi.org:10.1200/jco.1997.15.2.594
1. Beyer, J.
et al.
Survival and New Prognosticators in Metastatic Seminoma: Results From the
IGCCCG-Update Consortium. Journal of clinical oncology: ocial journal of the American Society of
Clinical Oncology 39, 1553–1562 (2021). https://doi.org:10.1200/jco.20.03292
19. Connolly, E. A.
et al.
High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-
volume specialized centres. BJU international 130 Suppl 1, 5–16 (2022).
https://doi.org:10.1111/bju.15648
20. Einhorn, L. H.
et al.
High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors.
New England Journal of Medicine 357, 340–348 (2007).
21. Yildiran Keskin, G. S.
et al.
High-Dose Chemotherapy and Autologous Stem Cell Transplantation for
Salvage Therapy of Relapsed/Refractory Germ Cell Tumors: A Single-Center Experience. Oncology
research and treatment 47, 262–272 (2024). https://doi.org:10.1159/000538660
Page 13/16
22. McHugh, D. J. & Feldman, D. R. Conventional-Dose versus High-Dose Chemotherapy for Relapsed
Germ Cell Tumors.
Advances in urology
2018, 7272541 (2018).
https://doi.org:10.1155/2018/7272541
23. Gilligan, T. D.
et al.
American Society of Clinical Oncology Clinical Practice Guideline on uses of
serum tumor markers in adult males with germ cell tumors. Journal of clinical oncology: ocial
journal of the American Society of Clinical Oncology 28, 3388–3404 (2010).
https://doi.org:10.1200/jco.2009.26.4481
24. Rodney, A. J.
et al.
Survival outcomes for men with mediastinal germ-cell tumors: the University of
Texas M. D. Anderson Cancer Center experience. Urologic oncology 30, 879–885 (2012).
https://doi.org:10.1016/j.urolonc.2010.08.005
25. Hainsworth, J. D., Einhorn, L. H., Williams, S. D., Stewart, M. & Greco, F. A. Advanced extragonadal
germ-cell tumors. Successful treatment with combination chemotherapy. Annals of internal
medicine 97, 7–11 (1982). https://doi.org:10.7326/0003-4819-97-1-7
2. Josefsen, D., Ous, S., Høie, J., Stenwig, A. E. & Fosså, S. D. Salvage treatment in male patients with
germ cell tumours. British journal of cancer 67, 568–572 (1993).
https://doi.org:10.1038/bjc.1993.104
27. Loehrer, P. J., Sr., Gonin, R., Nichols, C. R., Weathers, T. & Einhorn, L. H. Vinblastine plus ifosfamide
plus cisplatin as initial salvage therapy in recurrent germ cell tumor. Journal of clinical oncology:
ocial journal of the American Society of Clinical Oncology 16, 2500–2504 (1998).
https://doi.org:10.1200/jco.1998.16.7.2500
2. Saxman, S. B., Nichols, C. R. & Einhorn, L. H. Salvage chemotherapy in patients with extragonadal
nonseminomatous germ cell tumors: the Indiana University experience. Journal of clinical oncology:
ocial journal of the American Society of Clinical Oncology 12, 1390–1393 (1994).
https://doi.org:10.1200/jco.1994.12.7.1390
29. Broun, E. R.
et al.
Long-term outcome of patients with relapsed and refractory germ cell tumors
treated with high-dose chemotherapy and autologous bone marrow rescue. Annals of internal
medicine 117, 124–128 (1992). https://doi.org:10.7326/0003-4819-117-2-124
30. Hartmann, J. T.
et al.
Second-line chemotherapy in patients with relapsed extragonadal
nonseminomatous germ cell tumors: results of an international multicenter analysis. Journal of
clinical oncology: ocial journal of the American Society of Clinical Oncology 19, 1641–1648
(2001). https://doi.org:10.1200/jco.2001.19.6.1641
31. Siegert, W.
et al.
High-dose treatment with carboplatin, etoposide, and ifosfamide followed by
autologous stem-cell transplantation in relapsed or refractory germ cell cancer: a phase I/II study.
The German Testicular Cancer Cooperative Study Group. Journal of clinical oncology 12, 1223–1231
(1994).
32. Broun, E. R., Nichols, C. R., Einhorn, L. H. & Tricot, G. J. Salvage therapy with high-dose chemotherapy
and autologous bone marrow support in the treatment of primary nonseminomatous mediastinal
Page 14/16
germ cell tumors. Cancer 68, 1513–1515 (1991). https://doi.org:10.1002/1097-
0142(19911001)68:7<1513::aid-cncr2820680708>3.0.co;2-8
33. Kilari, D.
et al.
Autologous Hematopoietic Stem Cell Transplantation for Male Germ Cell Tumors:
Improved Outcomes Over 3 Decades. Biology of blood and marrow transplantation: journal of the
American Society for Blood and Marrow Transplantation 25, 1099–1106 (2019).
https://doi.org:10.1016/j.bbmt.2019.02.015
34. Lotz, J. P.
et al.
High dose chemotherapy with ifosfamide, carboplatin, and etoposide combined with
autologous bone marrow transplantation for the treatment of poor-prognosis germ cell tumors and
metastatic trophoblastic disease in adults. Cancer 75, 874–885 (1995).
https://doi.org:10.1002/1097-0142(19950201)75:3<874::aid-cncr2820750320>3.0.co;2-q
Tables
Table 1 to 4 are available in the Supplementary Files section.
Figures
Figure 1
Treatment evaluation after HDCT
Page 15/16
Figure 2
Kaplan–Meier estimates of overall survival
Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download.
