International Germ Cell Cancer Collaborative Group Research Articles

Association between glutathione S-transferases M1 expression and treatment outcome in germ cell tumor patients.

Cisplatin-based chemotherapy is the mainstay in the treatment of germ cell tumors (GCTs). Glutathione S-transferases (GSTs) are polymorphic enzymes that catalyze the glutathione conjugation of alkylating agents, platinum compounds, and free radicals formed by chemotherapy and are thus implicated in developing treatment resistance. This study aimed to assess the expression level of GST mu 1 (GSTM1) and its association with treatment outcomes in patients with GCT. This translational study included tumor specimens from 207 patients with newly diagnosed GCTs, as well as cisplatin-sensitive GCT cell line xenografts and their resistant variants for all histological variants of GCTs. GSTM1 expression was detected by reverse transcription-quantitative PCR and immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method. GSTM1 expression was correlated with patient/tumor characteristics and treatment outcomes. The highest GSTM1 expression was observed in seminoma, followed by choriocarcinoma, embryonal carcinoma, and yolk sac tumor, while the lowest was observed in teratoma (p<0.0001). There was no association between GSTM1 expression in tumor tissue and patient/tumor characteristics. The low GSTM1 expression was associated with significantly better relapse-free survival compared with high GSTM1 (HR=0.50, 95% CI 0.23-1.09, p=0.03) but not overall survival (HR=0.61, 95% CI 0.24-1.54, p=0.22). Multivariate analysis showed that the prognostic value of GSTM1 was independent of the International Germ Cell Cancer Collaborative Group (IGCCCG) score. These data revealed the prognostic value of GSTM1 in GCTs, with a high GSTM1 expression associated with worse outcomes, suggesting that GSTM1 could be responsible, in part, for treatment resistance in GCTs.

Brain metastases in testicular cancer: A single-institution experience in Guatemala.

e17019 Background: Brain metastases secondary to germ cell tumors develop in 2 to 3% of patients, in addition to implying a poor prognosis, its incidence in advanced stages increases to 10-15%. The European Urology Association guidelines recommend performing imaging studies using MRI or brain contrasted tomography to rule out metastases in patients with multiple lung metastases, or high beta subunit of human Chorionic Gonadotropin (β-HCG) values, or those in the poor-prognosis International Germ Cell Cancer Collaborative Group (IGCCCG) risk group. Methods: Retrospective descriptive study in patients with brain metastasis for testicular cancer at the Liga Nacional Contra el Cáncer – INCAN Guatemala, from 2018 to 2022. From medical records, we obtained: demographic, clinico-pathological and treatment data. Median was calculated for age, while frequencies and percentages were computed for the categorical variables. Results: Of the 238 patients diagnosed with testicular cancer, 22% (52) presented a β-HCG above 5,000 IU/L, of which 27% (14) developed brain metastases with a mean age of 28 years. Corresponding to 6% of the total cases studied. Among histological subtypes the most common was choriocarcinoma (43%), follow by mixed germ cell cancer (36%), embrionary carcinoma (14%) and classic seminoma (7%). All of the patients belonged to prognostic group S2. Most patients reported first symptom was headache (42%), followed by seizures (21%), cognitive dysfunction (15%), motor dysfunction (10%) and others (12%). Management of these patients included: orchidectomy in all of them, 57% (8) of patients died, of them 50% (4) of patients died before any other therapy. The rest of them, received chemotherapy and none received radiotherapy or surgery for the brain metastases. Conclusions: The presence of brain metastases in testicular cancer increases the mortality produced by the disease as previously reported in other regions of the world, reason why the early suspicion of it, should prompt the evaluation with a brain MRI or computed tomography.

Prognostic factors and survival in men with testicular germ cell tumors (GCT).

e17018 Background: The International Germ Cell Cancer Collaborative Group (IGCCCG) has recently discovered new factors for GCT in 2021. We have estimated previously known and new prognostic factors in patients with nonseminomatous germ cell tumors (NSGCT) and seminoma treated at N.N. Petrov NMRC of Oncology. Methods: From 2011 to 2021, the study included 273 adult patients receiving standard cisplatin-based chemotherapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival was estimated using the Kaplan-Meier and Cox methods. Results: 5-year OS rates were 94%, 85% and 70% in the good, intermediate, and poor prognosis groups, respectively for NSGCT and 95% and 86% in good and intermediate prognosis groups for seminoma (p&lt;0.05). 5-year PFS rates were 74%, 51%, and 41% for NSGCT and 76% and 62% for seminoma of the above-mentioned prognostic groups, respectively (p&lt;0,05). Presence of pulmonary metastases (mts) (HR 0.177; 95% CI: 0.051-0.612; p=0.006), non-pulmonary visceral mts (HR 4.636; 95% CI: 1.710-12.570; p= 0.003), elevated LDH of ≥ 2.5 limit of normal (≥ 2.5 × ULN) (HR 4.107; 95% CI: 1.614-10.451; p= 0.003), treatment in high-experienced clinic (HR 0.37; 95% CI: 0.147-0.919; p=0.0032), and non-compliance with guidelines (HR 3.731; 95% CI: 1.456-9.564; p= 0.006) was significantly associated with OS in NSGCT. The presence of pulmonary mts (HR 0.15; 95% CI: 0.024-0.877; p=0.035) and elevated LDH ≥ 2.5 × ULN (HR 0.109; 95% CI: 0.015-0.775; p=0.027) were the only factors associated with poor OS in seminoma. The presence of pulmonary mts (HR 0.446; 95% CI: 0.247-0,804; p=0.007), non-pulmonary visceral mts (HR 2.668; 95% CI: 1.390-5,120; p=0.003) and treatment in high-experienced clinic (HR 1.852; 95% CI: 1.059-3.238; p=0.031), were significantly associated with inferior PFS in NSGCT. Pulmonary mts were the only significant (HR 0.301; 95% CI: 0.100-0.910; p=0.033) factor in the multivariate OS analysis for all testicular GCT. The absence of non-pulmonary visceral mts (HR 0.522: 95% CI: 0.265-0.963; p=0.019) and compliance with guidelines (HR 0.565; 95% CI: 0.309-0.910; p=0.038) were significant factors in the multivariate PFS model for all patients with testicular GCT. Conclusions: The original IGCCCG classification remains the reference for treatment decisions for testicular GCT in daily practice. Non-compliance with guidelines and treatment in high-experienced clinic could become additional poor prognostic factors.

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Salvage Therapy of Relapsed/Refractory Germ Cell Tumors: A Single-Center Experience

Introduction: The optimal management of relapsed/refractory germ cell tumors remains unsettled. In this study, we aimed to evaluate the efficacy of high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) as salvage therapy in patients who progressed after at least one line of cisplatin-based chemotherapy. Methods: We retrospectively reported the results of 133 patients who underwent HDCT and ASCT as salvage therapy from 2016 to 2021. Patients received 3 cycles of paclitaxel, ifosfomide and cisplatin (TIP) regimen as induction and 1 cycle of carboplatin 700 mg/m2 on days 1–3 plus etoposide 750 mg/m2 on days 1–3, followed by ASCT. Demographic and clinicopathological features of patients, the International Germ Cell Cancer Collaborative Group (IGCCCG) risk group at diagnosis, serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) levels before HDCT, treatment-related complications and survival outcomes were recorded. Results: The median age of the patients was 31 (range 18–62). The median follow-up was 31.1 months (95% CI, 28.9–33.3 months). During the median follow-up period, 74 of the 133 patients were still alive, and 63 of these were in complete remission. The median progression-free survival (PFS) was 25.8 months (95% CI, 8.1–43.4 months). The 2-year PFS rate was 50.3% and the 2-year overall survival (OS) rate was 60.8%. Variables that remained statistically significant in multivariable analysis and were associated with poor prognosis were mediastinal primary tumor location, presence of brain metastases, and higher AFP and HCG levels at baseline. Conclusion: One course of HDCT and ASCT after induction with TIP is an effective and feasible treatment option for salvage treatment of relapsed/refractory germ cell tumors, with cure rates of up to 60%.

Impact of teratoma on survival probabilities of patients with metastatic non-seminomatous germ cell cancer: Results from the IGCCCG Update Consortium

AimsTo resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT). Patients and methodsUsing the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method. ResultsAmong 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001). ConclusionTeratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups.

A population-based validation of the IGCCCG Update Consortium for survival in metastatic non-seminoma testis cancer.

In 2021, the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium reported improved overall survival (OS) rates in a modern cohort of metastatic non-seminoma testis cancer patients within each of the IGCCCG prognosis groups (96% in good vs. 89% in intermediate vs. 67% in poor), compared to the previous IGCCCG publication (92% in good vs. 80% in intermediate vs. 48% in poor). We hypothesized that a similar survival improvement may apply to a contemporary North-American population-based cohort of non-seminoma testis cancer patients. The Surveillance, Epidemiology, and End Results (SEER) database (2010-2018) was used. Kaplan-Meier plots and multivariable Cox regression models tested the effect of IGCCCG prognosis groups on overall mortality (OM). Of 1672 surgically treated metastatic non-seminoma patients, 778 (47%) exhibited good vs. 251 (15%) intermediate vs. 643 (38%) poor prognosis. In the overall cohort, five-year OS rate was 94% for good prognosis vs. 87% for intermediate prognosis vs. 65% for poor prognosis. In multivariable Cox regression models predicting OM, intermediate (Hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.4-3.9, P<0.001) and poor prognosis group (HR 6.6, 95% CI 1.0-1.0, P<0.001) were independent predictors of higher OM, relative to good prognosis group. The survival improvement reported by the IGCCCG Update Consortium is also operational in non-seminoma testis cancer patients within the most contemporary SEER database. This observation indicates that the survival improvement is not only applicable to centres of excellence, but also applies to other institutions at large.

Treatment efficacy implications of incorrect utilization of tumor marker levels and risk group assignment according to the International Germ Cell Consensus Classification (IGCCCG).

505 Background: Patients withmetastatic germ cell tumors of the testis (GCTs) are risk-stratified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification system for further therapy decision. This risk classification is based on metastatic load as well as tumor marker levels of AFP, HCG and LDH assessed pre-chemotherapy after orchiectomy treatment. An incorrect classification is possible when pre-orchiectomy marker levels are used, possibly resulting in over- or undertreatment of patients. Therefore, the aim was to investigate the potential frequency and clinical relevance of incorrect risk stratification using pre-orchiectomy tumor marker levels. Methods: Patients with metastasized nonseminomatous GCT (NSGCT)were included in a multicenter registry analysis which was conducted by investigators of the German Testicular Cancer Study Group (GTCSG). Based on the marker levels at different timepoints, IGCCCG risk groups were calculated. The agreement was tested using Cohen’s kappa. Results: A total of698 of 1983 (35%) patients were diagnosed with metastatic NSGCTs, and 546 (78%) had sufficient data for 232 follow-up data points. By using pre-orchiectomy tumor marker levels, 111 patients (20%) would have been incorrectly classified. Seventy-five patients (14%) were classified into a higher risk category, and 36 patients (6%) were classified into a lower risk category. Cohen’s kappa was 0.69 (p &lt; 0.001), showing a strong agreement between the use of both marker timepoints. The treatment of misclassified patients would have resulted in an overtreatment of 75 patients or undertreatment of 36 patients. Conclusions: The use of pre-orchiectomy tumor marker levels may lead to an incorrect risk classification and might subsequently lead to under- or overtreatment of patients. Part of these data were published in: Majewski et al. Cancer Med. 2023.

Clinico-epidemiological Profile and Outcome of Testicular Germ Cell Tumors: A Retrospective Study from a Tertiary Cancer Centre of North-East India

Introduction: Testicular Germ Cell Tumor (GCT) is a disease of young adults and is also highly curable. But in India, most of the patients present in an advanced stage and succumb to the disease as compared to the Western nations where patients present at an earlier stage and are mostly cured. Also, there is a scarcity of literature on testicular GCT from the Indian subcontinent. We present our experience from the Tata Memorial Centre of North-east India. Methods: This retrospective study was conducted at Tata Memorial Centre - BBCI, Guwahati for the period of 5 years from January 2018 to December 2022. The study focused on epidemiology, clinical presentation, and treatment outcomes. Results: Seventy-two cases of testicular GCTs were studied (28 cases were seminoma, and 44 were non-seminoma). Most common presenting stage was stage I in seminoma (53.6%), and stage III (77.2%) in non-seminoma. As per the International Germ Cell Cancer Collaborative Group (IGCCCG) classification, 25%, 35%, and 40% of patients were good-risk, intermediate-risk, and poor-risk in non-seminoma. In patients with seminoma, 54% and 46% were in good and intermediate-risk, respectively. Seventy-two percent and 21% had achieved a radiologic complete response (CR) and partial response (PR) with conventional chemotherapy in patients with seminoma. Radiologic CR and PR rates were 20% and 61% among non-seminoma patients. The median recurrence-free survival (RFS) was 43 months. RFS was better in seminoma versus non-seminoma, stage I versus stage III, and good-risk versus high-risk group. Conclusion: Most of our patients presented with an advanced stage of the disease and a high nodal burden. In patients with non-seminoma GCT, the best response to conventional chemotherapy was a partial response. The use of an alternative chemotherapy regimen to improve outcomes for such patients can be further explored.

Delivered relative dose intensity in adolescent and young adult germ cell tumours in England: Assessment of data quality and consistency from clinical trials compared to national cancer registration data.

Adolescent and young adults (AYA) with germ cell tumours (GCT) have poorer survival rates than children and many older adults with the same cancers. There are several likely contributing factors to this, including the treatment received. The prognostic benefit of intended dose intensity is well documented in GCT from trials comparing regimens. However, evidence specific to AYA is limited by poor recruitment of AYA to trials and dose delivery outside trials not being well examined. We examined the utility of cancer registration data and a clinical trials dataset to investigate the delivery of relative dose intensity (RDI) in routine National Health Service practice in England, compared to within international clinical trials. Linked data from the Cancer Outcomes and Services Dataset (COSD) and the Systemic Anti-Cancer Therapy (SACT) dataset, and data from four international clinical trials were analysed. Survival over time was described using Kaplan-Meier estimation; overall, by age category, International Germ-Cell Cancer Collaborative Group (IGCCCG) classification, stage, tumour subtype, primary site, ethnicity and deprivation. Cox regression models were used to determine the fully adjusted effect of RDI on mortality risk. The quality of both datasets was critically evaluated and clinically enhanced. RDI was found to be well maintained in all datasets with higher RDIs associated with improved survival outcomes. Real-world data demonstrated several strengths, including population coverage and inclusion of sociodemographic variables and comorbidity. It is limited in GCT however, by the poor completion of data items enabling risk classification of patients and a higher proportion of missing data.

Patterns of Relapse in Australian Patients With Clinical Stage 1 Testicular Cancer: Utility of the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Surveillance Recommendations.

International guidelines advocate for active surveillance as the preferred treatment strategy for patients with stage 1 testicular cancer after orchidectomy although a personalized discussion is required. We conducted an analysis of individuals registered in iTestis, Australia's testicular cancer registry, to describe the patterns of relapse and outcomes of patients treated in Australia where the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Surveillance Recommendations are widely adopted. A total of 650 individuals diagnosed between 2000 and 2020 were included, 63% (411 of 650) seminoma and 37% (239 of 650) nonseminoma. The median age was 34 years (range 14-74). 26% (106 of 411) with seminoma and 15% (36 of 239) nonseminoma received adjuvant chemotherapy. After a median follow-up of 43 months (range 0-267) postorchidectomy, relapse occurred in 10% (43 of 411) of seminoma and 18% (43 of 239) of nonseminoma. The two-year relapse-free survival was 92% (95% CI, 89 to 95) and 82% (95% CI, 78 to 87) in seminoma and nonseminoma, respectively. All relapses (86 of 86) were detected at a routine surveillance visit; 98% (85 of 86) were asymptomatic and detected solely through imaging (62 of 86, 72%), tumor markers (6 of 86, 7%), or a combination (17 of 86, 20%). The most common relapse site was isolated retroperitoneal lymphadenopathy (53 of 86, 62%). No nonpulmonary visceral metastases occurred. At relapse, 98% (84 of 86) had International Germ Cell Cancer Collaborative Group (IGCCCG) good prognosis; 2 of 86 intermediate prognosis (both nonseminoma). No deaths occurred. In our cohort of stage 1 testicular cancer, where national surveillance recommendations have been widely adopted, recurrences were detected at routine surveillance visits and, almost exclusively, asymptomatic with IGCCCG good-prognosis disease. This provides reassurance that active surveillance is safe.

MP50-06 SURVIVAL OF TESTICULAR PURE TERATOMA VS. MIXED GERM CELL TUMOR PATIENTS ACROSS ALL STAGES

MP50-06 SURVIVAL OF TESTICULAR PURE TERATOMA VS. MIXED GERM CELL TUMOR PATIENTS ACROSS ALL STAGES

EDEN (Etude Désescalade sEmiNome): Prospective therapeutic de-escalation and miRNA-M371 biomarker evaluation phase II study for stage IIa/IIb &lt; 3 cm seminomas.

TPS434 Background: At diagnosis, 10 to 15% of testicular pure seminomas have a stage II defined by the presence of retroperitoneal lymph node metastases. The optimal choice of treatment modalities are associated with excellent efficacy but also acute and late toxicities. De-escalating treatment for seminoma patients with stage IIb, IIc and III and good prognosis according to IGCCCG (International Germ Cell Cancer Collaborative Group) based on negative FDG-PET (Fluorodeoxyglucose Positron Emission Tomography) after 2 cycles of EP (etoposide, cisplatine) chemotherapy seems feasible and safe according to SEMITEP cohort 2 results (Loriot Y, and al GETUG SEMITEP Trial: Eur Urol. 2022 Aug;82(2):172-179). Serum levels of microRNA (miR)-371a-3p (miRNA-M371) have been significantly associated with clinical stage and response to treatment in testicular germ cell tumors, with sensitivity and specificity higher than those of classic markers. The aim of the study NCT05529251 is to propose a new therapeutic approach for the stages IIa/IIb. Methods: This phase II, multicenter, prospective, randomized, non-comparative, de-escalation study will include patient with primary testicular seminomatous germ cell tumor with stage IIa/IIb &lt; 3 cm in largest diameter seminoma, histologically proved after orchiectomy and good prognosis according to IGCCCG and LDH (Lactate DesHydogenase) &lt; 2.5 x Upper Limit of Normal (ULN). They must have progressive disease and no prior treatment with radiotherapy or chemotherapy. In case of negative week-3 (after 1 EP cycle) PET-scan, patients will be randomized according to 2 arms ARM A: Boost of radiotherapy 20 to 30 Gray (Gy); ARM B Carboplatin AUC7 chemotherapy. In case of positive week-3 PET-scan: 3 courses of EP chemotherapy (ARM C). Primary outcome will include progression-free rate at 36 months. Secondary Outcome Measures will be serum level of miRNA M371, correlation with response to treatments and PET scan results, overall survival (OS), quality of life and tolerance to treatment. Blood samples (miRNA-M371) will be collected at screening, at the time of randomization before second cycle of chemotherapy or radiotherapy, at the end of treatment and at relapse. Enrollment has started in October 2022. A total of 90 patients will be included in the interventional study, leading to approximately 60 patients with negative FDG-PET randomized. Clinical trial information: NCT05529251 .

Predicting outcomes in female germ cell tumors using a modified International Germ Cell Cancer Collaborative Group classification system to guide management

ObjectiveWe previously developed preoperative and pre-chemotherapy modified versions of the male International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic model and assessed it in female patients with germ cell tumors (GCTs). We sought to validate these modified IGCCCG (mIGCCCG) models in a new cohort. MethodsWe queried institutional databases for female patients with GCTs treated at Memorial Sloan Kettering Cancer Center from 1/1/1990–6/1/2020. The mIGCCCG model classifies patients with non-dysgerminomas as good, intermediate, or poor risk based on tumor markers using male IGCCCG cutoffs and absence/presence of non-pulmonary/peritoneal visceral metastasis. In dysgerminomas, good- and intermediate-risk groups are defined by absence/presence of non-pulmonary/peritoneal visceral metastasis. Progression-free survival (PFS) and overall survival (OS) were estimated for each group in the validation and combined original and validation cohorts. Associations between individual clinical factors and outcomes were evaluated. ResultsAmong 183 female patients with GCTs, clinical characteristics and outcomes were similar between the original (n = 93) and validation (n = 90) cohorts. In multivariable models, higher stage, older age, and non-dysgerminoma histology predicted worse PFS and OS (p < 0.05). Among 162 patients who received chemotherapy, preoperative and pre-chemotherapy mIGCCCG models were significantly associated with PFS and OS (p < 0.001 for all groups). With the preoperative model, 3-year PFS rates were 94%, 76%, and 50% in the good-, intermediate-, and poor-risk patients, respectively; OS rates were 96%, 86%, and 52%, respectively. Even within stage groups, mIGCCCG risk classifications were associated with clinical outcomes. ConclusionsA female-specific mIGCCCG risk model effectively stratifies patients and should be incorporated into clinical trials.

Predicting outcomes in female germ cell patients using a modified International Germ Cell Cancer Collaborative Group classification system to guide management (100)

<b>Objectives:</b> The International Germ-Cell Cancer Collaborative Group (IGCCCG) classification guides testicular germ-cell tumor (GCT) management, but there is no validated risk-based model for female patients (pts). We devised modified IGCCCG (mIGCCCG) classifications for female GCT pts undergoing chemotherapy, validated it in a separate cohort, and investigated clinical-pathologic factors associated with survival outcomes. <b>Methods:</b> An mIGCCCG risk classification was created in a test cohort of female GCT pts treated at a single center (1990-2012). In non-dysgerminomas, good, intermediate and poor-risk groups were stratified by tumor markers or metastatic site (AFP<1,000 ng/mL, HCG <5,000 mIU/mL or LDH<1.5x upper limit of normal (ULN); AFP 1,000-10,000 ng/mL, HCG 5,000-50,000 mIU/mL or LDH 1.5-10xULN; AFP>10,000 ng/mL, HCG>50,000 mIU/mL or LDH>10xULN OR non-pulmonary visceral [excluding peritoneal] metastases, respectively). In dysgerminomas, good and intermediate-risk groups were segregated by non-visceral metastases. The mIGCCCG risk model was validated in an independent cohort treated at the same institution (1986-2020). Progression-free survival (PFS) and overall survival (OS) were estimated among all pts using the Kaplan-Meier method. Differences by clinical-demographic factors were assessed with the log-rank test and Cox proportional-hazards models. <b>Results:</b> Median age, race, stage, histology, and chemotherapy regimen were similar between the original (<i>n</i>=93) and validation (<i>n</i>=94) cohorts. As in the original cohort, both preoperative and pre-chemotherapy mIGCCCG models were significantly associated with outcome in the validation and combined cohorts (Figure 1). Using pre-chemotherapy tumor markers, estimated 3-year OS rates for good, intermediate, and poor-risk pts were 89%, 92%, and 45%, respectively, in the original cohort, whereas 100%, 80%, and 50% in the validation cohort and 94%, 88%, and 51% in the combined cohort (all p-values <0.001). Using preoperative tumor markers, estimated 3-year OS rates for good, intermediate, and poor-risk pts were 92%, 86%, and 46%, respectively, in the original cohort, whereas 100%, 86%, and 60% in the validation cohort, and 96%, 86% and 54% in the combined cohort (all p-values <0.01). On multivariable regression analyses, worse PFS outcomes were associated with the higher stage (HR: 4.3, 95% CI: 1.5-12.0, p=0.006), non-dysgerminoma histology (HR: 3.4, 95% CI: 1.8-6.4, p<0.001), and older age (HR: 1.17 per 5-year increase, 95% CI: 1.03-1.32, p=0.01). Worse OS was also associated with the higher stage (HR: 3.7, 95% CI: 1.6-8.7, p=0.003), non-dysgerminoma histology (HR: 4.8, 95% CI: 1.1-20.0, p=0.04), and older age (HR: 1.28 per 5-year increase, 95% CI: 1.09-1.50, p=0.002). <b>Conclusions:</b> A female-specific mIGCCCG risk score identifies good-risk pts with better outcomes who may benefit from less intensive chemotherapy than intermediate- and poor-risk pts requiring more intensive chemotherapy and surveillance.Fig. 1

Management of stage II seminoma: a contemporary UK perspective.

Background and AimsTesticular Germ Cell Tumours (TGCTs) are the commonest young adult male cancer, with excellent survival outcomes even with metastatic disease. Chemotherapy, radiotherapy, and surgery are international guideline-dictated standard of care (SOC) treatments for International Germ Cell Cancer Collaborative Group (IGCCCG) “good risk” TGCT, but are associated with significant toxicities. Therapy de-escalation aims to reduce treatment morbidity whilst preserving cure rates, and has been adopted by some centres for stage IIA/B seminoma. Here, we report on the contemporary UK treatment landscape for stage IIA/B seminoma.MethodsA questionnaire-based survey of NHS England-designated specialist cancer centres hosting supra-regional specialist multi-disciplinary team (sMDT) services (n = 13) as well those within NHS Scotland, NHS Wales and Health and Social Care Northern Ireland. Respondents were asked to order preferences of SOC and therapy de-escalation treatments for stage IIA/B seminoma.ResultsWe identified significant geographical heterogeneity in treatment preferences. Whilst up to a third of centres have adopted a treatment de-escalation regimen, the majority deliver combination chemotherapy or radiotherapy.ConclusionA wider recognition of UK treatment heterogeneity and consideration of therapy de-escalation strategies at supra-regional sMDTs will increase stage IIA/B seminoma treatment options as part of clinical trials with oncological and quality of life endpoints.

Safety of Minimizing Intensity of Follow-up on Active Surveillance for Clinical Stage I Testicular Germ Cell Tumors

BackgroundWe have recommended active surveillance as the preferred management option for clinical stage I (CSI) testicular germ cell tumors (GCTs) since 1980. Over time, the recommended intensity of surveillance has decreased; however, the impact on relapse detection has not been investigated. ObjectiveTo examine relapse rate, time to relapse, extent of disease, and burden of treatment at relapse across decreasing surveillance intensity over time. Design, setting, and participantsCSI GCT patients under active surveillance from 1981 to 2021 were included in this study. Outcome measurements and statistical analysisThrough four major iterations in both nonseminomatous (NSGCT) and seminoma surveillance schedules, visit frequency, blood testing, and imaging have been decreased successively. Low-dose, noncontrast computed tomography (CT) scans were adopted in 2011. Categorical variables and time to relapse were compared using chi-square and Fisher’s exact or Kruskal-Wallis test, respectively. Results and limitationsA total of 1583 consecutive patients (942 with seminoma and 641 with NSGCT) were included. In seminoma, chest x-rays were reduced from 13 to one and CT scans were reduced from 20 to ten. Relapse rate, time to relapse, N or M category, and International Germ Cell Cancer Collaborative Group (IGCCCG) classification did not change. In NSGCT, chest x-rays were reduced from 27 to zero and CT scans were reduced from 11 to five. Relapse rate (from 46.2% to 21.2%, p = 0.002) and the median time to relapse (from 6.54 to 4.47 mo, p = 0.025) decreased. No difference in relapsed disease burden was identified by N, M, and S category or IGCCCG classification. Treatment burden at relapse and GCT cancer deaths remained similar for seminoma and NSGCT. Limitations include the retrospective design and large time period covered. ConclusionsDespite considerable reductions in surveillance intensity, we did not observe an increase in disease extent, treatment burden, or GCT cancer deaths upon relapse. These results support that our current lower-intensity active surveillance schedules are safe for managing CSI GCT. Patient summaryOur current reduced-intensity surveillance schedules for clinical stage I germ cell tumors appear to be safe.

High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres.

To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019. We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors. The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT. This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.

Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium.

PURPOSEThe classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990.MATERIALS AND METHODSData on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set.RESULTSCompared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update).CONCLUSIONThe IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.

Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium.

PURPOSEThe classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium.MATERIALS AND METHODSData on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients.RESULTSCompared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH.CONCLUSIONPFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.

Outcome of testicular non-seminomatous germ cell tumours: report from a tertiary cancer centre in eastern India.

Non-seminomatous germ cell tumour (NSGCT) is a rare but highly curable malignancy. The literature on the management and outcomes of NSGCT is scarce from India. Here, we report the demography and treatment outcomes of NSGCT treated at our centre. This is a retrospective analysis of testicular and retroperitoneal NSGCT patients treated from March 2011 to December 2019. Patients were staged appropriately with imaging, pre- and post-operative tumour marker. Patients received stage adjusted adjuvant treatment after high inguinal orchiectomy. Patients with advanced disease were risk stratified as per International Germ Cell Cancer Collaborative Group (IGCCCG) classification. A total of 100 patients were treated with a median age of 28 years (Range: 18–51). Primary site was testis in 92 and retroperitoneum in 8 patients. Testicular violation was present in 17 (18%) patients. The stage of the disease was I in 32, II in 19 and III in 49 patients, respectively. IGCCCG risk groups were good in 29 (46%), intermediate in 13 (21%) and poor in 21 (33%) patients. Eleven patients (24%) underwent retroperitoneal lymph node dissection amongst 45 with post-chemotherapy residual disease. After a median follow-up of 26.6 months (range: 2.2–100.7), 3-year event-free survival and overall survival (OS) were 70.7% ± 5.6% and 78.2% ± 5.4%, respectively. S3 tumour marker (p = 0.01) and non-pulmonary visceral metastasis (p < 0.001) emerged as independent poor prognostic factors for OS in multivariate analysis. To conclude, testicular NSGCT has very high cure rate. Two-third patients present with advanced disease and one-third of them had poor risk disease. S3 tumour marker and non-pulmonary visceral metastasis are poor risk factors for OS.