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Multicenter database of patients with germ-cell tumors: a Latin American Cooperative Oncology Group Registry (LACOG 0515).

Open AccessPublished:November 11, 2022DOI:https://doi.org/10.1016/j.clgc.2022.11.004

      Highlights

      • Largest cohort of patients with germ-cell tumors treated in Latin America.
      • LACOG 0515 showed OS rates comparable to other contemporary series.
      • No differences in outcomes were observed between public and private centers.

      ABSTRACT

      Purpose

      Germ-cell tumors (GCTs) are the most common malignancy in young men. There is a paucity of data on GCTs in developing countries. LACOG 0515 study aimed to evaluate clinical characteristics and treatment outcomes in patients with GCTs from Brazilian cancer centers.

      Methods

      This is a retrospective cohort study evaluating male patients diagnosed with GCTs from 2000 to 2018 in 13 Brazilian hospitals. We described baseline characteristics, progression-free survival (PFS), and overall survival (OS).

      Results

      A total of 1,232 patients were included, with a median age of 30 years. Histology was seminoma in 47.1% and non-seminoma GCT (NSGCT) in 52.9%. The primary tumor site was testis in 96.5%. At diagnosis, clinical stage I was present in 68.1% and 34.7% and clinical stages IS/II/III in 31.9% and 65.2% of patients with seminoma and NSCGT, respectively. Following orchiectomy, 55.2% of patients with clinical stage I were managed with surveillance. The 5-year disease-free survival rates among patients with stage I were 98.0% in seminoma and 92.3% in NSGCT, with 5-year OS of 99.6% and 97.6%, respectively. Among patients with advanced disease (IS, II and III), the 5-year PFS were 88.7% in seminoma and 68.7% in NSGCT, with 5y-OS of 97.6% and 82.8%, respectively.

      Conclusion

      This is the largest Brazilian cohort of GCTs. Our results show a high rate of adjuvant chemotherapy in patients with clinical stage I. Although our data demonstrate slightly inferior PFS compared with the International Germ Cell Cancer Collaborative Group (IGCCCG) and other contemporary series, the OS rates were similar.

      KEYWORDS

      INTRODUCTION

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      MATERIAL AND METHODS

      Study design and participants

      LACOG 0515 is a retrospective cohort study, which included male patients with histologically proven GCT diagnosed at any stage from 2000 to 2018 in 13 Brazilian hospitals (Supplementary Appendix). Patients with GCT were screened, and those with diagnosis between 2000 to 2018 and with available clinicopathological data (tumor histology) were included in the analysis. The protocol was approved by each Institution's Review Board.

      Procedures

      Eligible patients had their medical records reviewed and data were registered in an electronic platform for clinical data management (OpenClinica). Data items included baseline characteristics (age, ECOG PS, comorbidities, tobacco and drug use, family history of testicular cancer and history of cryptorchidism), primary tumor site, TNM staging (AJCC 7th edition), levels of post orchiectomy serum tumor markers (alpha-fetoprotein – AFP; lactic dehydrogenase – LDH and human chorionic gonadotropin – hCG), IGCCCG risk classification and treatments performed. Primary endpoints were overall survival (OS), defined as the time from diagnosis to death from any cause, disease-free survival (DFS), and PFS. DFS, defined as the time from orchiectomy to recurrence of disease or death, was estimated for patients with CS I. PFS, defined as the time from the first cycle of chemotherapy received to the progression of disease or death, was estimated for patients with advanced disease (CS IS, II or III).

      Statistical analysis

      Statistical analyses were performed with information from 1,232 patients. Quantitative variables were described by median and range, while categorical variables were described by absolute and relative frequencies. OS, PFS, and DFS were estimated and displayed in graphs using Kaplan-Meier method. Median follow-up was estimated using reverse Kaplan-Meier method. The significance level for claim statistical difference between groups was set at 0.05. All analyses were performed using the SAS statistical software (version 9.4; SAS Institute, Inc. Cary, NC). Since the access to treatment may be different in private and public centers, a separate analysis was performed according to the type of healthcare coverage - private versus public.

      RESULTS

      A total of 1,315 patients were identified, of which 39 did not meet the minimum available clinicopathological data, and 44 were diagnosed before the year 2000. Therefore, 83 patients were excluded from the analysis, and a total of 1,232 patients were analyzed. Baseline characteristics are shown in Table 1. Median age was 30 years (range 12-82 years). Histology was seminoma in 47.1% and non-seminoma GCT (NSGCT) in 52.9%. Patients with NSGCT were younger than those with seminoma (median age: 26 years old [range 12-60] versus 34 years old [range 13-82]). Most patients were white (55.5%), had no comorbidities (74.6%), had ECOG PS 0-1 (83.0%), and had no family history of GCT (78.8%). Personal history of cryptorchidism was present in 6.1% of the patients. The primary tumor site was testis in 96.5%, mediastinum in 1.8%, and retroperitoneum in 1.3%. Pathological staging was T1 or T2 in most patients (79.7%). Most patients with seminoma had clinical stage I (68.1%), while clinical stages IS/II/III were more frequent (65.2%) with NSGCT. Tumor characteristics are described in Table 2.
      Table 1Baseline characteristics of included patients
      InformationSeminoma (n=580)NSGCT (n=652)Total (n=1232)
      Median Follow up (95% CI) in months46 (41 - 48)52 (47 - 57)48 (46 – 50)
      Median Age (range) in years34 (13 - 82)26 (12 - 60)30 (12 - 82)
      Institution – n (%)
       Private181 (31.2)163 (25.0)344 (27.9)
       Public399 (68.8)489 (75.0)888 (72.1)
      Race/Ethnicity – n (%)
       White303 (52.2)381 (58.4)684 (55.5)
       Black19 (3.3)16 (2.4)35 (2.8)
       Brown88 (15.2)109 (16.7)197 (16.0)
       Indigenous0 (0.0)1 (0.2)1 (0.1)
       Asian6 (1.0)1 (0.2)7 (0.6)
       Hispanic11 (1.9)3 (0.5)14 (1.1)
       Unknown153 (26.4)141 (21.6)294 (23.9)
      ECOG PS – n (%)
       0407 (70.2)389 (59.7)796 (64.6)
       192 (15.9)135 (20.7)227 (18.4)
       28 (1.4)36 (5.5)44 (3.6)
       33 (0.5)13 (2.0)16 (1.3)
       42 (0.3)5 (0.8)7 (0.6)
       Unknown68 (11.7)74 (11.3)142 (11.5)
      Comorbidities – n (%)
       No411 (70.9)508 (77.9)919 (74.6)
       Yes93 (16.0)73 (11.2)166 (13.5)
       Unknown76 (13.1)71 (10.9)147 (11.9)
      Which comorbidity (n=147) – n (%)
       Hypertension12 (12.9)12 (16.4)24 (14.5)
       Diabetes2 (2.1)2 (2.7)4 (2.4)
       Renal insufficiency1 (1.1)1 (1.4)2 (1.2)
       Heart failure0 (0.0)1 (1.4)1 (0.6)
       Other65 (69.9)50 (68.5)115 (69.3)
       Unknown13 (14.0)7 (9.6)20 (12.0)
      Tobacco use – n (%)
       Yes98 (16.9)111 (17.0)209 (17.0)
       No377 (65.0)422 (64.7)799 (64.8)
       Unknown105 (18.1)119 (18.3)224 (18.2)
      Drug use – n (%)
       No416 (71.7)461 (70.7)877 (71.2)
       Yes18 (3.1)35 (5.4)53 (4.3)
       Unknown146 (25.2)156 (23.9)302 (24.5)
      Which drug (n=53) – n (%)
       Marijuana8 (44.4)20 (57.2)28 (52.8)
       Cocaine7 (38.9)9 (25.7)16 (30.2)
       Other1 (5.6)4 (11.4)5 (9.4)
       Unknown2 (11.1)2 (5.7)4 (7.6)
      Familiar history of GCTs – n (%)
       Yes9 (1.6)17 (2.6)26 (2.1)
       No456 (78.6)527 (80.8)983 (78.8)
       Unknown115 (19.8)108 (16.6)223 (18.1)
      Cryptorchidism – n (%)
       Yes40 (6.9)35 (5.4)75 (6.1)
       No405 (69.8)487 (74.7)892 (72.4)
       Unknown135 (23.3)130 (19.9)265 (21.5)
      n: number of patients.
      Table 2Tumor characteristics by overall histology
      InformationSeminoma (n=580)NSGCT (n=652)Total (n=1232)
      Primary tumor site – n (%)
       Testis559 (96.4)630 (96.6)1189 (96.5)
       Retroperitoneum10 (1.7)6 (0.9)16 (1.3)
       Mediastinum8 (1.4)14 (2.1)22 (1.8)
       Other1 (0.2)1 (0.2)2 (0.2)
       Unknown2 (0.3)1 (0.2)3 (0.2)
      T-stage – n (%)
       Tx40 (6.9)83 (12.7)123 (10.0)
       T1315 (54.3)277 (42.5)592 (48.1)
       T2181 (31.2)208 (31.9)389 (31.6)
       T338 (6.6)72 (11.1)110 (8.9)
       T44 (0.7)10 (1.5)14 (1.1)
       Unknown2 (0.3)2 (0.3)4 (0.3)
      AFP median (IQR)1.94 (1.3 – 3.0)19.9 (2.5 - 350)3 (1.6 - 36)
      HCG median (IQR)1.2 (0.1 – 3.0)4.0 (0.6 - 183)2.36 (0.1 – 18.8)
      LDH median (IQR)360 (266 - 518)416.5 (295 - 818)383.3 (280 -657)
      IGCCCG risk II-III (IS, II e III)
       Good142 (76.7)176 (41.4)318 (52.1)
       Intermediate24 (13.0)96 (22.6)120 (19.7)
       Poor0 (0.0)106 (24.9)106 (17.4)
       Unknown19 (10.3)47 (11.1)66 (10.8)
      Clinical stage at diagnosis – n (%)
       IS10 (1.7)22 (3.4)32 (2.6)
       I395 (68.1)226 (34.7)621 (50.4)
       II112 (19.3)167 (25.6)279 (22.6)
       III63 (10.9)236 (36.2)299 (24.3)
       Unknown0 (0.0)1 (0.1)1 (0.1)
      n: number of patients; IQR: interquartile range.

      Clinical Stage I

      Median follow-up of clinical stage I patients was 47 months (95% CI, 42 to 49 months). Of 621 patients with clinical stage I, 343 (55.2%) patients were managed with surveillance after orchiectomy. A higher proportion of patients with stage I seminoma (N= 173, 43.8%) received adjuvant treatment compared to patients with stage I NSGCT (N=69, 30.5%). The most common adjuvant regimens for seminoma were carboplatin (79.8%) and radiation therapy (18.5%). For NSGCT the most frequent treatments were chemotherapy with bleomycin, etoposide, and cisplatin (BEP, 81.2%), etoposide and cisplatin (EP,7.2%), carboplatin monotherapy (2.9%) and retroperitoneal lymph node dissection (RPLND) (7.2%). The characteristics of GCTs clinical stage I are shown in table 3.
      Table 3Stage I patients characteristics by overall histology
      InformationSeminoma (n=395)NSGCT (n=226)Total (n=621)
      Median Follow up (95% CI) in months43 (40-48)51 (41-61)47 (42-49)
      AFP median (IQR)*2 (1.4 - 3.0)3.6 (2.0 – 41.0)2.3 (1.5 – 3.9)
      HCG median (IQR)*1.2 (0.1 – 3.0)2 (0.1 – 3.3)1.2 (0.1 - 3)
      LDH median (IQR)*327 (241 - 410)326 (227 - 409)327 (238 – 410.5)
      T stage – n (%)
       Tx11 (2.8)12 (5.3)23 (3.7)
       T1247 (62.5)147 (65.0)394 (63.4)
       T2120 (30.4)55 (24.3)175 (28.2)
       T316 (4.1)10 (4.4)26 (4.2)
       T41 (0.2)1 (0.5)2 (0.3)
       Unknown0 (0.0)1 (0.5)1 (0.2)
      Management– n (%)
       Surveillance199 (50.4)144 (63.7)343 (55.2)
       Adjuvant therapy173 (43.8)69 (30.5)242 (39.0)
       Unknown23 (5.8)13 (5.8)36 (5.8)
      Which Adjuvant therapy (n=242) – n (%)
       BEP1 (0.6)56 (81.2)57 (23.6)
       EP2 (1.1)5 (7.2)7 (2.9)
       Carboplatin138 (79.8)2 (2.9)140 (57.8)
       RPLND0 (0.0)5 (7.2)5 (2.1)
       RPLND + BEP0 (0.0)0 (0.0)0 (0.0)
       Radiation therapy32 (18.5)1 (1.5)33 (13.6)
      n: number of patients; IQR: interquartile range.
      The 5-year DFS (5y-DFS) rates among patients with clinical stage I were 98.0% in seminoma and 92.3% in NSGCT (p=0.0014), with 5-year OS (5y-OS) rates of 99.6% and 97.6% (p=0.0224), respectively (Figure 1). 5y-OS in Stage I NSGCTs according to the type of center healthcare coverage was 100% in private versus 97.0% in public centers (p=0.2127) and in stage I seminoma was 100% in private versus 99.4% in public centers (p=0.4895). Kaplan-Meier curves of DFS and OS for stage I GCTs stratified by center healthcare coverage are available in the supplementary appendix (Appendix 1).
      Figure 1:
      Figure 1Kaplan-Meier Curves of overall survival (OS) of stage I GCT, by overall histology

      Clinical Stage IS, II, and III

      Median follow-up of patients with advanced disease (stage IS, II and III) was 49 months (95% CI, 46 to 55 months). The distribution of IGCCCG risk was different between seminoma and non-seminoma. Of advanced seminomas, 85.5% were IGCCCG good risk, whereas 53.4% of NSGCT were IGCCCG intermediate or poor risk.
      Of 482 patients with advanced disease and treatment modalities information available, systemic treatment with chemotherapy was employed in 434 (90.0%) of advanced disease patients. BEP was the most frequent protocol, accounting for 350 patients (80.6%): varying from 66.7% (12) of patients with intermediate-risk seminoma to 88.4% (152) of patients with intermediate- and poor-risk non-seminoma. Other modalities, such as radiation therapy, retroperitoneal lymph node dissection or resection of other sites of disease, were used in less than 10% of patients (Table 4).
      Table 4First-line systemic treatment for advanced disease (Stage IS/II/III patients)
      SeminomaNSGCT
      First line treatment by riskGood (n=142)Intermediate (n=24)Good (n=176)Intermediate + Poor (n=202)
      Chemotherapy (Did the patient receive 1sr line of chemo?)
      Yes109 (76.8)18 (75.0)135 (76.7)172 (85.1)
      No15 (10.5)2 (8.3)25 (14.2)6 (3.0)
      Unknown18 (12.7)4 (18.7)16 (9.1)24 (11.9)
      BEP81 (74.3)12 (66.7)105 (78.4)152 (88.4)
      EP26 (23.8)5 (27.8)27 (20.1)8 (4.6)
      VIP1 (0.9)0 (0.0)2 (1.5)10 (5.8)
      TIP1 (0.9)1 (5.6)0 (0.0)2 (1.2)
      n: number of patients.
      The 5-year PFS (5y-PFS) rates for patients with advanced disease were 88.7% in SGCT and 68.7% in NSGCT (p<0.001) (Figure 2a). 5y-OS rate was 97.6% in advanced seminoma and 82.8% in advanced non-seminoma, (p=0.0002) (Figure 2b). 5y-PFS rates for advanced disease by IGCCC were 84.7% in good risk, 70.3% in intermediate, and 45.5 % in poor risk (p<0.001). 5y-OS rates by IGCCC risk were: 94.3% in good risk, 83.5% in intermediate, and 65.1% in poor risk (p<0.001) (Figure 3).
      Figure 2:
      Figure 2Kaplan-Meier Curves for progression-free survival (2a) and overall survival (2b) of stage IS, II and III GCTs, by overall histology.
      Figure 3:
      Figure 3Kaplan-Meier Curves for progression-free survival (3a) and overall survival (3b) of advanced germ-cell tumor patients (stage IS, II and III), by IGCCCG risk (good, intermediate, poor).
      For advanced GCTs with good and poor risk, there was no statistical difference in 5y-PFS between public and private centers. For intermediate-risk GCTs, 5y-PFS rates were significantly higher in public versus private centers (72.1% vs 61.8%, p=0.0332). No statistical difference was observed in 5y-OS for advanced GCTs in public versus private centers regardless of the risk classification a 5y-OS for good, intermediate, and poor-risk: 100%, 80.4%, and 60.4% in private centers versus 92.7%, 84.1% and 66.2% in public centers. The full analysis according to the type of healthcare coverage – private versus public – is available in the supplementary appendix.

      DISCUSSION

      The present study showed that the baseline and demographic features of Brazilian patients with GCT are similar to the other cohorts described previously. There was, however, a higher proportion of advanced tumors at diagnosis, especially NSGCT

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      Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium.
      ,
      • Beyer J
      • Collette L
      • Sauvé N
      • Daugaard G
      • Feldman DR
      • Tandstad T
      • et al.
      Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium.
      .
      In our Brazilian cohort, which included 482 patients with advanced disease, we found a 5-year PFS of 84.7%, 70.3%, and 45.5% and 5-year OS of 94.3%, 83.5%, and 65.1% for good-, intermediate- and poor-risk, respectively, which is consistent with the literature and similar to a Danish population-based study evaluating overall survival rates in 1,889 patients who had received first-line BEP (bleomycin, etoposide, and cisplatin) regimen. The survival probability in 5 years was 93% for good-risk seminoma, and 94.3%, 83.5%, and 65.1% for good, intermediate- and poor-risk NSGCT. Our OS results are similar to IGCCCG and other contemporary series
      by the Iternational Germ Cell Collaborative Group. International Germ Cell Consensus Classification: A Prognostic Factor Based Staging System for Metastatic Germ Cell Cancers.
      ,
      • Gillessen S
      • Sauvé N
      • Collette L
      • Daugaard G
      • de Wit R
      • Albany C
      • et al.
      Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium.
      ,
      • Albany C
      • Adra N
      • Snavely AC
      • Cary C
      • Masterson TA
      • Foster RS
      • et al.
      Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors.
      . Our cohort also carried a higher proportion of poor-risk disease than the original IGCCCG cohort
      by the Iternational Germ Cell Collaborative Group. International Germ Cell Consensus Classification: A Prognostic Factor Based Staging System for Metastatic Germ Cell Cancers.
      . On the other hand, we had similar proportions of poor prognosis NSGCT to the updated IGCCCG consortium and the Indiana single-institution cohort
      • Gillessen S
      • Sauvé N
      • Collette L
      • Daugaard G
      • de Wit R
      • Albany C
      • et al.
      Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium.
      ,
      • Albany C
      • Adra N
      • Snavely AC
      • Cary C
      • Masterson TA
      • Foster RS
      • et al.
      Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors.
      . A previous single-center Brazilian analysis showed 5-year PFS rates of 83.0%, 70.9% and 35.1% and 5-year OS of 95.3%, 83.6% and 62.2% for good-, intermediate- and poor-risk patients, respectively
      • Vasconcellos VF
      • Bastos DA
      • Pereira AAL
      • Watarai GY
      • Pereira BR
      • de Godoy A
      • et al.
      Clinical Characteristics and Treatment Outcomes of Patients With Advanced Germ Cell Tumor Treated at a Tertiary Cancer Center in Brazil.
      . This single-center analysis had a slightly higher rate of poor-risk patients, compared to ours.
      Regarding PFS rates, our results are slightly inferior compared to PFS rates of contemporary series. The inferior PFS in our cohort may reflect limitations in treatment adherence in first-line setting. A Mexican single-center retrospective analysis showed a significant lack of patients’ adherence to germ-cell tumor treatment, with a loss to medical follow-up of 58% of the included patients
      • Salazar-Mejía CE
      • Zayas-Villanueva O
      • Gutiérrez AG
      • Martinez RJ
      • Wimer-Castillo BO
      • et al.
      GUERRA CEPEDA A
      Clinical characteristics and treatment adherence among men with testicular germ cell tumors: Real-world data from a referral center in Mexico.
      . In Brazil, the lack of adherence to first-line treatments may be due to lower access to specialized oncologic centers after the initial diagnosis
      • da Silva MJS
      • O'Dwyer G
      • Osorio-de-Castro CGS
      Cancer care in Brazil: structure and geographical distribution.
      . Challenges in treatment adherence have been observed in low- and middle-income countries, including Brazil, and they might also have contributed to lower PFS rates. Brazil has more than 2,000 oncology centers. However, only 11% are exclusively dedicated to the public health care system, assisting 75% of the population
      • Nita M
      • Mussolino F
      • Vaz P
      • Riveros B
      • Tolentino A.
      Overview of Oncology Centers Structures in both Public and Private Brasilian Health Care System.
      . Moreover, approximately 40% of the oncology centers are concentrated in state capitals. These barriers may delay the diagnosis and treatment of cancer patients, increasing the rate of advanced disease at diagnosis
      • Chertack N
      • Ghandour RA
      • Singla N
      • Freifeld Y
      • Hutchinson RC
      • Courtney K
      • et al.
      Overcoming sociodemographic factors in the care of patients with testicular cancer at a safety net hospital.
      . Moreover, the low professional adherence to diagnosis and treatment guidelines may lead to a higher rate of relapse
      • Wymer KM
      • Pearce SM
      • Harris KT
      • Pierorazio PM
      • Daneshmand S
      • Eggener SE.
      Adherence to National Comprehensive Cancer Network® Guidelines for Testicular Cancer.
      . This lack of adherence to the guidelines can be a reality in some Brazilian low-volume centers. Patients with GCTs treated in high-volume centers have significantly better outcomes than patients treated in low-volume centers
      • Woldu SL
      • Matulay JT
      • Clinton TN
      • Singla N
      • Krabbe L-M
      • Hutchinson RC
      • et al.
      Impact of hospital case volume on testicular cancer outcomes and practice patterns.
      . Nevertheless, the centers included in our analysis were mostly high-volume centers for the treatment of GCTs, and this may be one explanation for our similar 5y-OS between private and public centers. This similar OS also demonstrates that the treatments in both types of institutions are effective, even for advanced disease. The lower 5y-PFS rates observed in intermediate-risk patients in private centers may be justified by the inclusion of fewer patients from private centers.
      To our knowledge, this is the largest Latin American multicenter retrospective cohort analyzing epidemiology and outcomes of GCT patients. Therefore, our results might direct Brazil and other Latin American countries to better delineate strategies to improve GCT care. Moreover, our cohort comprised different profiles of cancer centers: public and private, located in different regions of the country (capitals and non-capital cities), and therefore might reflect more precisely the epidemiological scenario. However, our study has some limitations that should be addressed. First, as a retrospective study, a selection bias may have occurred. In addition, Brazil has important economic and racial disparities when it comes to healthcare
      • Landmann-Szwarcwald C
      • Macinko J.
      A panorama of health inequalities in Brazil.
      ,
      • Pavão ALB.
      Racial discrimination and health in Brazil: evidence from a population-based survey.
      , and some results might be over or underestimated, limiting extrapolation to a specific country region. In the United States, patients of nonwhite race/ethnicity, low socioeconomic status and underinsurance had less access to testicular cancer care and, consequently, poorer outcomes
      • Macleod LC
      • Cannon SS
      • Ko O
      • Schade GR
      • Wright JL
      • Lin DW
      • et al.
      Disparities in Access and Regionalization of Care in Testicular Cancer.
      . A part of our heterogeneous population may be exposed to the same problems and outcomes.

      CONCLUSIONS

      Our national multicenter retrospective cohort showed a higher proportion of advanced tumors at diagnosis, especially NSGCT, in Brazil. Moreover, a high rate of adjuvant chemotherapy in patients with clinical stage I was demonstrated, which could reflect difficulty of maintaining an adequate patient follow-up. PFS was slightly inferior in our cohort, when compared to IGCCCG and other contemporary series. Nevertheless, OS was very similar to other cohorts. The OS rates suggest that salvage treatments are effective, irrespectively of whether the treatment was performed in a public or private center. Future collaborations with other developing countries around the world may expand the findings and bring opportunities to achieve better outcomes for patients with GCT.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      We thank all the LACOG sites and investigators for collaborating in this research. We thank SAS software to provide a free license to LACOG.

      Funding Sources

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Contributions of the authors

      Concept and design: DAB
      Search and collection of the data: all authors
      Analysis of data and interpretation: all authors
      Statistical analysis: RG
      First draft of the manuscript: DAB and ABLG
      All authors contributed to the content of the report and reviewed further drafts. All authors reviewed and approved the final report before submission. The authors take full responsibility for the scope, direction, and content of the report.
      Additional Contributions: SAS

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