International Germ Cell Consensus Classification Group Research Articles

Comprehensive Assessment of Selected Immune Cell Subpopulations Changes in Chemotherapy-Naïve Germ Cell Tumor Patients.

The pattern of immune cell distribution in testicular germ cell tumors (GCT) significantly differs from the immune environment in normal testicular tissues. The present study aimed to evaluate the role of different leukocyte subpopulation in GCTs. A cohort of 84 chemotherapy-naïve GCT patients was analyzed. Immunophenotyping of peripheral blood leukocyte subpopulations was carried out by flow cytometry. In addition, the data assessing the immunophenotypes and the baseline clinicopathological characteristics of the included subjects were statistically evaluated. Their prognostic value for the assessment of progression-free survival (PFS) and overall survival (OS) was estimated. The percentage of different innate/adaptive immune cell subpopulations was significantly associated with poor risk-related clinical features, including the number of metastatic sites, presence of retroperitoneal, mediastinal, lung, brain and non-pulmonary visceral metastases as well as with the S-stage and International Germ Cell Consensus Classification Group (IGCCCG) risk groups. In univariate analysis, the percentages of neutrophils, eosinophils, dendritic cells type 2, lymphocytes and T cytotoxic cells were significantly associated with PFS, while the neutrophil, non-classical monocyte and lymphocyte percentage were associated with OS. However, all these outcome correlations were not independent of IGCCCG in multivariate analysis. The data indicated a link among different innate/adaptive peripheral immune cell subpopulations in GCT patients. In addition, the association between these subpopulations and tumor characteristics was also investigated. The findings of the present study may contribute to a deeper understanding of the interactions between cancer and innate/adaptive immune response in GCT patients.

Clinical Characteristics and Treatment Outcomes of Patients With Advanced Germ Cell Tumor Treated at a Tertiary Cancer Center in Brazil.

PURPOSEReported treatment outcomes for patients with advanced germ cell tumors (aGCT) are based mainly on series from developed nations. Data from low- and middle-income countries are underrepresented.MATERIAL AND METHODSFrom 2000 to 2015, a retrospective analysis identified 300 patients with aGCT treated at our institution. Kaplan-Meier methods were used for analysis of progression-free survival (PFS) and overall survival (OS) according to the International Germ Cell Consensus Classification Group (IGCCCG).RESULTSPatients’ median age was 28 years. According to the IGCCCG, 57% had good-, 18.3% intermediate-, and 24.7% poor-risk disease. Median α-fetoprotein levels were 2.9, 243, and 3,998 ng/mL, and those of human chorionic gonadotropin were 0.4, 113, and 301.5 mUI/mL in IGCCCG good-, intermediate-, and poor-risk groups, respectively. At a median 46 months of follow-up, 93 PFS events and 45 deaths had occurred and estimated 5-year PFS and OS were 69% and 85%, respectively, including 83% and 95.3% in good-risk, 70.9% and 83.6% in intermediate-risk, and 35.1% and 62.2% in poor-risk patients, respectively. In multivariable analysis, Eastern Cooperative Oncology Group performance status ≥ 2 was a significant independent prognostic factor with a hazard ratio of 2.58 (95% CI, 1.55 to 4.29; P < .001) and 6.20 (95% CI, 2.97 to 12.92; P < .001) for PFS and OS, respectively.CONCLUSIONBrazilian patients with aGCT in this cohort had similar outcomes as patients in the IGCCCG database. In comparison with contemporary series, patients with intermediate- and poor-risk aGCT had slightly inferior PFS and OS, possibly due to a high percentage of patients with poor performance status and less use of high-dose chemotherapy.

Clinical characteristics and treatment outcomes of patients (pts) with advanced germ cell tumor (aGCT) treated at a tertiary cancer center in Brazil.

568 Background: Reported treatment outcomes for pts with aGCT are largely based on series from developed countries. Data from less developed countries are lacking. Methods: From 2000 to 2015, a retrospective analysis identified 302 pts with aGCT treated at Instituto do Cancer do Estado de São Paulo (ICESP). Kaplan-Meier methods were used for analysis of progression-free survival (PFS) and overall survival (OS) according to the International Germ Cell Consensus Classification Group (IGCCCG). Results: Median follow-up was 46 months and median age was 28 years old. Clinical features and management are detailed in the Table. 54 pts (18%) had ECOG performance status (PS) ≥ 2 at baseline. According to the IGCCCG, 57% were good-, 18.3% intermediate-, and 24.7% poor-risk disease. Median AFP was 2.9, 243, and 3.998 and HCG was 0.4, 113 and 301 in IGCCCG good-, intermediate-, and poor-risk groups, respectively. 5-year PFS and OS were 69% and 85%, respectively, including 83% and 95.3% in good-risk, 70.9% and 83.6% in intermediate-risk and 35.1% and 62.2% in poor-risk pts. Only 3 pts (3%) received high-dose chemotherapy (HDCT) as first salvage therapy. Conclusions: Brazilian pts with advanced GCT in this cohort had similar outcomes as pts in the IGCCCG database. In comparison to contemporary series, pts with intermediate- and poor-risk GCT had slightly inferior PFS and OS, possibly due to a high percentage of pts with poor PS and less use of HDCT. [Table: see text]

Low RBM3 protein expression correlates with clinical stage, prognostic classification and increased risk of treatment failure in testicular non-seminomatous germ cell cancer.

BackgroundExpression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate with favourable clinicopathological parameters and prognosis in several cancer diseases. The aim of this study was to examine the expression and prognostic ability of RBM3 in patients with testicular non-seminomatous germ cell tumours (NSGCT).Patients and MethodsImmunohistochemical RBM3 expression was analysed in tissue microarrays with tumours from 206 patients. Chi-square test was applied to analyze associations between RBM3 expression and clinicopathological parameters. Kaplan-Meier analysis was used to assess the impact of RBM3 expression on cancer-specific survival (CSS) and failure-free survival (FFS). Cox regression proportional hazards models were used to estimate the relative risk for failure.ResultsIn the entire cohort, there was a significant association between clinical stage (p=0.044) and RBM3 expression. Weak RBM3 expression correlated with a significantly reduced FFS [79.3% versus 90.4% (p=0.019)] and CSS [87.5% versus 97.3% (p=0.047)]. For patients with metastatic disease (n = 88), significant associations were found between RBM3 expression and IGCCC group (p=0.007). The FFS was significantly inferior for patients with low tumour-specific RBM3 expression [59.3% versus 79.0% (p=0.013)], and this association remained significant in a multivariable model for patients with metastatic disease (HR=3.67; 95% CI 1.14, 11.89).ConclusionLow RBM3 expression is an independent predictor of treatment failure in metastatic NSGCT, in relation to the prognostic factors included in the International Germ Cell Consensus Classification (IGCCC). These findings suggest that RBM3 may be a potential biomarker for treatment stratification in patients with metastatic non-seminomatous germ cell tumours, and therefore merit further validation.

Application of the International Germ Cell Consensus Classification to the Nova Scotia population of patients with germ cell tumours

The International Germ Cell Consensus Classification (IGCCC) is the internationally accepted, clinically based prognostic classification used to assist in the management and research of metastatic germ cell tumours (GCTs). The goal of this study was to determine whether the IGCCC is applicable to a population-based cohort. We completed a retrospective chart review of patients who received diagnoses of GCT in Nova Scotia between 1984 and 2004 and who received treatment with platin-based chemotherapy for metastatic disease. We assigned the IGCCC to each patient based on the site of the primary lesion, the presence or absence of nonpulmonary visceral metastases and prechemotherapy tumour marker values. We calculated Kaplan-Meier estimates of 5-year progression-free survival (PFS) and overall survival for each IGCCC group. The study cohort comprised 129 patients. The distribution and outcomes in each group of patients in Nova Scotia was similar to that published in the IGCCC. Among patients with nonseminoma GCTs (NSGCT) 61% had good, 22% had intermediate and 17% had poor prognoses. Among those with seminomas, 85% had good and 15% had intermediate prognoses. Among patients with NSGCTs, the 5-year PFS was 90%, 69% and 55%, and the 5-year overall survival was 94%, 84%, 61% in the good, intermediate, and poor prognostic categories respectively. Among patients with seminomas, the 5-year PFS was 95% and 50% and the 5-year overall survival was 94% and 50% in the good and intermediate prognostic categories, respectively. The IGCCC seems applicable to a population-based cohort, with similar distribution of categories and clear prognostic ability.

Protocol for the Examination of Specimens From Pediatric and Adult Patients With Extragonadal Germ Cell Tumors

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the ‘‘Surgical Pathology Cancer Case Summary (Checklist)’’ portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice. The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of these documents.

Stage migration and pilot studies of reduced chemotherapy supported by positron‐emission tomography findings suggest new combined strategies for stage 2 nonseminoma germ cell tumour

To examine the nodal (N+) vs extranodal (M+) staging in each of the International Germ Cell Consensus Classification Group (IGCCCG) subgroups in an audit of 437 patients treated in The Anglian Germ Cell Cancer Group, where chemotherapy was the primary management, as there is an increasingly earlier presentation of patients with less advanced disease who thus face potentially unnecessary treatment. Clinicians from seven centres prospectively registered patients in a central database, and the follow-up was coordinated by one of the authors. Between 1982 and 2002, 436 patients (median follow-up 60 months) were registered; 63% of IGCCCG good risk (298), 42% of intermediate (62) and 8% poor risk (77) were stage II; 79% of N+M0 intermediate and poor risk cases (29) were alive, vs only 60% of M+ stage IV cases (92, P < 0.05). The trend was similar in IGCCCG good risk patients, with 92% of N+ stage II (156) alive vs only 85% (94) of stage IV M+ (not significant). The frequency of retroperitoneal lymph node dissection after chemotherapy increased from 26% (1983-1993) to 34% (1994-2002), and survival from 89% to 94%. There were no relapses in eight patients who elected to stop treatment after two courses. Four of six patients with positive findings on positron emission tomography had a durable complete response, assessed by standard uptake values, when tested at 72-96 h. Extra-lymphatic spread, although prognostically important within the IGCCCG subgroups, is only statistically significant for intermediate and poor risk combined. The observation that there might be N+ patients cured by two chemotherapy courses alone suggests that there might be opportunities to reduce the morbidity of treatment.

Recurrence in Nonseminomatous Germ Cell Testis Tumor Patients with No Viable Tumor at Postchemotherapy Retroperitoneal Lymph Node Dissection

To determine disease-related outcomes in metastatic testis cancer patients with absence of viable cancer in the postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) specimen and determine whether clinical variables can help predict disease progression. Between 1980 and 2003, 195 patients had no viable tumor at the time of PC-RPLND. We retrospectively reviewed their medical records for pertinent clinical and treatment-related outcomes. At a median follow-up of 45 months (range, 6 to 236 months), 35 patients (18%) developed recurrences, and 18 (9%) died of disease. On multivariate analysis, predictors of recurrence-free survival in patients with no viable tumor were advanced clinical stage (P = 0.01) and poor-risk International Germ Cell Consensus Classification (IGCCC) group (P = 0.01), whereas predictors of disease-specific survival included an elevated serum beta-human chorionic gonadotropin (hCG) level before PC-RPLND (P = 0.002), pathologic diameter of the retroperitoneal mass (P = 0.05), and postoperative recurrence (P <0.0001). An hCG level greater than 1.2 mIU/mL before PC-RPLND trended toward statistical significance (P = 0.07), and pathologic diameter of the retroperitoneal mass greater than 2.5 cm was statistically significant (P = 0.05) in predicting a poorer disease-specific survival. Patients with no viable tumor at PC-RPLND remain at risk of recurrence. Several clinical variables, including advanced clinical stage, poor-risk IGCCC group, preoperative serum hCG level, diameter of the retroperitoneal mass on pathology, and postoperative recurrence, help better define which patients are at risk.

Application of the International Germ Cell Consensus Classification (IGCCC) to the Nova Scotia population of patients with germ cell tumors (GCT)

14625 Background: The IGCCC is the internationally accepted, clinically based, prognostic classification used to aid in the management of GCT. The goal of this study was to determine if the IGCCC is applicable to a population based cohort. Methods: A retrospective chart review of all patients diagnosed with GCT in NS between 1984–2004 was completed, and IGCCC classification (good, intermediate, poor) was assigned to each patient based on the site of the primary lesion, the presence or absence of non-pulmonary visceral metastases and pre-chemotherapy tumor marker values. Kaplan-Meier estimates of five year progression free survival (PFS) and overall survival (OS) were calculated for each IGCCC group, for both non-seminomatous GCT and seminomatous GCT. Results: The distribution, PFS and OS are shown below. Conclusions: The IGCCC seems applicable to a population-based cohort, with similar distribution of categories, as well as clear prognostic ability. This project was funded by a Norah Stephen Oncology Scholars Summer Studentship Grant from Cancer Care Nova Scotia. [Table: see text] [Table: see text]

Etoposide and Cisplatin Chemotherapy for Metastatic Good-Risk Germ Cell Tumors

To assess response, overall survival, and relapse-free survival of patients with good-risk metastatic germ cell tumor (GCT) by International Germ Cell Consensus Classification Group (IGCCCG) criteria treated with four cycles of etoposide and cisplatin (EP). Two hundred eighty-nine patients with IGCCCG good-risk GCT were treated with four cycles of EP. EP consisted of four cycles of etoposide 100 mg/m2 and cisplatin 20 mg/m2 on days 1 to 5 every 21 days. Two hundred eighty-two of 289 patients (98%) achieved a complete response; 269 (93%) responded to chemotherapy alone and 13 (5%) responded to chemotherapy plus surgical resection of viable disease (GCT other than mature teratoma). Seventeen (6%) experienced relapse, and nine (3%) died as a result of disease at a median follow-up of 7.7 years (range, 0.4 to 21.1 years). Sixty-two of 204 patients (30%) with nonseminoma had findings of teratoma or viable GCT at postchemotherapy surgery. Four cycles of EP is a highly effective therapy for patients with good-risk GCT, with a high cure rate, low relapse rate, and little evidence of late relapse. Postchemotherapy surgery resection of residual disease remains an important aspect of treatment for these patients. Four cycles of EP is acceptable as a standard regimen for the treatment of good-risk metastatic GCT, and serves as an alternative to three cycles of bleomycin and etoposide before cisplatin.

Etoposide and cisplatin (EP) chemotherapy for good risk germ cell tumors (GCT): The Memorial Sloan-Kettering Cancer Center (MSKCC) experience

4533 Background: Phase 3 trials at MSKCC showed 4 cycles of EP to be effective and tolerable treatment for good risk advanced GCTs (JCO 1997;15:2553). Additional patients (pts) have been treated and follow-up (f/u) updated to detect late relapses. Methods: 379 pts with good risk GCT received EP from 11/82–12/02 on 4 protocols. MSKCC criteria (Cancer 1991;67:28) were used to assign risk status prospectively until 8/1994. Thereafter, the International Germ Cell Consensus Classification Group (IGCCCG) criteria were used. All pts were retrospectively classified according to IGCCCG criteria. EP consisted of 4 cycles of etoposide 100 mg/m2 and cisplatin 20 mg/m2 days 1–5 every 21 days. Results: 295/379 (78%) had nonseminoma; 84 (22%) had seminoma. Primary site was testis-365 (96%), retroperitoneum-8 (2%), mediastinum-6 (2%). By IGCCCG criteria, 291 (77%) were good risk, 75 (20%) intermediate risk and 13 (3%) poor risk. Of 291 IGCCCG good risk pts, 284 achieved a CR [98%; 273 to chemotherapy (c) and 11 to chemo+...

A 20% dose reduction of the original CISCA/VB regimen allows better tolerance and similar survival rate in disseminated testicular non-seminomatous germ-cell tumors: final resultsof a phase III randomized trial

Background: This prospective randomized clinical trial was designed to compare the efficacy of a low-dose regimen of cisplatin, doxorubicin and cyclophosphamide alternated with vinblastine and bleomycin (CISCA/VB) with the original CISCA/VB regimen in patients with disseminated non-seminomatous germ-cell tumors (NSGCT) and a predicted favorable outcome. Patients and methodsOne hundred and twenty-five patients with disseminated NSGCT and a predicted favorable outcome according to the M.D. Anderson Cancer Center classification [testicular primary and human chorionic gonadotropin (hCG) serum level <50000 mIU/ml] were randomized to receive the original CISCA/VB regimen (100% dose) or a low-dose CISCA/VB regimen (80% dose). ResultsAmong the 124 eligible patients, there was no significant difference in the number of patients in the two treatment arms who achieved a complete response to therapy: 53 of 65 patients (82%) on the original CISCA/VB regimen and 53 of 59 patients (90%) on the low-dose CISCA/VB regimen (P = 0.29). Overall, the original CISCA/VB regimen resulted in a significantly higher relative dose intensity (P<0.0001). After a median follow-up of 6.8 years (range 0.37 to 12.94 years), there was no significant difference in disease-free survival (P = 0.87) or in overall survival (P = 0.88) between the two treatment arms. The 5-year overall survival rate was 93.7% [95% confidence interval (CI) 88% to 100%] and 94.1% (95% CI 84% to 100%) in the original CISCA/VB arm and the low-dose CISCA/VB arm, respectively. The 5-year overall survival rate for the entire study population was 98% (95% CI 94% to 100%) and 88% (95% CI 76% to 100%) in the good- and intermediate-prognosis groups, respectively, as defined by the International Germ Cell Consensus Classification Group (IGCCCG). The low-dose CISCA/VB regimen resulted in significantly less neutropenic fever (P <0.001), grade 4 thrombocytopenia (P <0.03) and severe mucositis (P <0.01) than the original CISCA/VB regimen. ConclusionsCISCA/VB is highly efficient in patients with good or intermediate prognosis NSGCT according to the IGCCCG criteria. Although equivalent antitumor efficacy cannot be claimed, the low-dose CISCA/VB regimen appears to be a better mode of delivery than the original CISCA/VB regimen with respect to toxicity, since survival is comparable.

Viable Malignant Cells After Primary Chemotherapy for Disseminated Nonseminomatous Germ Cell Tumors: Prognostic Factors and Role of Postsurgery Chemotherapy—Results From an International Study Group

To assess the value of postsurgery chemotherapy in patients with disseminated nonseminomatous germ-cell tumors (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy. The outcome of 238 patients was reviewed. Tumor markers had normalized in all patients before resection. A multivariate analysis of survival was performed on 146 patients. The 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three factors were independently associated with both PFS and OS: complete resection (P <.001), < 10% of viable malignant cells (P =.001), and a good International Germ Cell Consensus Classification (IGCCC) group (P =.01). Patients were assigned to one of three risk groups: those with no risk factors (favorable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). The 5-year OS rate was 100%, 83%, and 51%, respectively (P <.001). The 5-year PFS rate was 69% (95% confidence interval [CI], 62% to 76%) and 52% (95% CI, 40% to 64%) in postoperative chemotherapy recipients and nonrecipients, respectively (P <.001). No significant difference was detected in 5-year OS rates. After adjustment on the three prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P <.001) but not with better OS. Patients in the favorable risk group had a 100% 5-year OS, with or without postoperative chemotherapy. Postoperative chemotherapy appeared beneficial in both PFS (P <.001) and OS (P =.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group. A complete resection may be more critical than recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells. Validation is necessary.

Improved long term survival of patients with metastatic nonseminomatous testicular germ cell carcinoma in relation to prognostic classification systems during the cisplatin era

The current study reviews chronologic changes in the long term outcome of patients with metastatic nonseminomatous testicular germ cell tumors (NSTGCT) who were treated at a single institution during the past two decades. The 10-year survival of prognostic subgroups according to the classification of the International Germ Cell Consensus Classification Group (IGCCCG) and various other prognostic classifications is examined in time to evaluate whether cumulative experience has led to an improved outcome of patients with metastatic NSTGCT and to explore differences in outcome of prognostic subgroups. Two hundred ninety-nine patients with metastatic NSTGCT who were treated with cisplatin-based polychemotherapy during the period from 1977 to 1996 were staged retrospectively according to the Royal Marsden (RM) classification and the following prognostic classifications: IGCCCG, Indiana, Medical Research Council (MRC), and European Organization for Research and Treatment of Cancer (EORTC). The numbers of patients who were treated during the periods 1977-1986 and 1987-1996 were 146 and 153, respectively. Survival curves were constructed using the Kaplan-Meier method, and disease specific 10-year survival rates of prognostic subgroups treated during the two consecutive 10-year periods were compared using the log rank test. The median follow-up of surviving patients during the periods 1977-1986 and 1987-1996 was 14.7 years (range, 0.2-20.6 years) and 7.0 years (range, 0.4-11.4 years), respectively. The actuarial disease specific 10-year survival rate of patients with metastatic NSTGCT increased from 76% during the period 1977-1986 to 88% during the period 1987-1996 (relative risk [RR], 0.51; 95% confidence interval [95% CI], 0.29-0.89; P < 0.05). The 10-year survival rates of patients with good, intermediate, and poor prognoses according to the IGCCCG classification were 95%, 74%, and 37%, respectively, during the period 1977-1986 and 94%, 87%, and 66%, respectively, during the period 1987-1996. Patients with a poor prognosis according to the IGCCCG classification showed the greatest increase in 10-year survival (RR, 0.43; 95% CI, 0.18-1.04; P = 0.06). Analysis using the RM, Indiana, and EORTC classifications also showed an improved 10-year survival rate of patients with a poor prognosis who were treated during 1987-1996 compared with those who were treated during 1977-1986. The 10-year survival rate of patients with metastatic NSTGCT who were treated with cisplatin-based chemotherapy significantly increased from 76% during the period 1977-1986 to 88% during the period 1987-1996. This improvement during the cisplatin era resulted mainly from an increase in the survival of patients with metastatic disease who had a poor prognosis. These results indicate that the management of patients with NSTGCT is still improving.