Evaluation of High-Dose Chemotherapy and Autologous Stem Cell Transplant in Salvage Treatment of Extragonadal Germ Cell Tumours

doi:10.21203/rs.3.rs-4701515/v1

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Evaluation of High-Dose Chemotherapy and Autologous Stem Cell Transplant in Salvage Treatment of Extragonadal Germ Cell Tumours

https://doi.org/10.21203/rs.3.rs-4701515/v1

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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-five 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.

Biological sciences/Cancer

Biological sciences/Stem cells

Health sciences/Oncology

Health sciences/Urology

high-dose chemotherapy

extragonadal germ cell tumours

autologous stem cell transplantation

salvage therapy

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 origin ³. 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 regions ⁴. 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 teratoma ⁵. 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 tumours ^7,8. 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 classification into seminoma and non-seminoma, chemotherapy (CT) is administered according to risk classification. Surgical resection may also be performed in patients with residual tumour after treatment. Efficacy and survival increase with multimodal treatment options ^9,10. 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 treatment ^11,12.

In our study, we aimed to show the real world data of our single-centre experience regarding the efficacy of salvage HDCT+ASCT in patients with relapsed/refractory EGGCT.

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) classification, and International Germ Cell Cancer Collaborative Group (IGCCCG) classification, 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 levofloxacin 500 mg, oral fluconazole 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 the patient achieved engraftment. Platelet engraftment was defined as a platelet count of at least 20,000/mm3 for three consecutive days, while neutrophil engraftment was defined 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 defined 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 defined as the time from transplantation to the occurrence of disease progression, while overall survival (OS) is defined as the time from transplantation to death or last follow-up. TRM was defined 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 defined as the absence of radiologically active residual lesions and negative blood biomarkers. Partial response (PR) is defined 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 defined 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 defined 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 (figure1).

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 significance using Pearson's chi-squared and Fisher's exact tests. A p-value less than 0.05 was considered statistically significant. Bonferroni correction was applied to variables that were significant 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.

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 classification, 12 patients (48%) were in the very high risk group and 15 patients (60%) were in the low risk category according to the IGCCCG classification. 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 influencing PFS. Although tumour location was not found to be significant 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 significance 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 classification (p=0.001), IGCCCG classification (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 identified as factors influencing OS (Table 3).

Tumour location was found to be significant for OS. Significance was found between retroperitoneum and mediastinum in favour of retroperitoneum (p=0.008). The OS significance 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 significance of IPFSG classification 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 OS significance of IGCCCG classification 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 significance 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) (figure 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 significant (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.

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 first 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). Confirming 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 classification 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 classification 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 risk ¹⁷. In our study, the OS of patients with liver metastases was significantly 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 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 levels ¹⁸. In our study, the presence of retroperitoneal lymph node metastasis was positively significant 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 classification is also important in determining prognosis like IGCCCG. IPFSG and IGCCCG classifications were shown to be prognostic in the series of Connolly et al ¹⁹. In a series of 173 patients by Einhorn et al, patients with good IGCCCG class had significantly longer survival ²⁰. Similarly, IPFSG and IGCCCG classifications showed statistical significance for OS in our study. According to IPFSG classification, 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 classification. 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 survival ^20-22. Our study also supports this. Although not reaching significance for PFS, patients with platinum-sensitive disease had significantly longer survival.

AFP and Beta HCG are important for GCTs both in diagnosis, follow-up and prognosis ²³. 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 HDCT ¹⁵. 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 significantly 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 significant 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.

Loehrer et al. reported one of the largest series to date using conventional dose chemotherapy (CDCT) as first-line salvage therapy. This study was designed to evaluate the efficacy 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 first-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 factor ²⁸. 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 EGGCT ¹². 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 months ²⁹. 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 EGCCT ³¹. 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 significantly better survival ^12,20,29. 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.

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 GCTs ^5,15. 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 GCTs ^31,34. Especially patients with mediastinal primary tumours and non-seminomatous patients have worse survival ^5,6. 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 being ¹⁵.

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

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.

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 specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Institutional Review Board Statement: 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.

Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement: The data that support the findings 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

Conflicts of Interest: The authors declare no conflicts of interest.

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Table 1 to 4 are available in the Supplementary Files section.

No competing interests reported.

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Evaluation of High-Dose Chemotherapy and Autologous Stem Cell Transplant in Salvage Treatment of Extragonadal Germ Cell Tumours

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