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

2021 ◽  
pp. JCO.20.03292
Author(s):  
Jörg Beyer ◽  
Laurence Collette ◽  
Nicolas Sauvé ◽  
Gedske Daugaard ◽  
Darren R. Feldman ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Germ Cell ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Good Prognosis ◽  
Collaborative Group ◽  
Prognostic Impact ◽  
Major Advance ◽  
Adverse Prognostic Factor ◽  
Upper Limit

PURPOSE The 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 METHODS Data 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. RESULTS Compared 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. CONCLUSION PFS 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.

International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.

1997 ◽  
Vol 15 (2) ◽  
pp. 594-603 ◽  
Keyword(s):  
Survival Rate ◽  
Prognostic Factor ◽  
Germ Cell ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Staging System ◽  
Lactic Dehydrogenase ◽  
Good Prognosis ◽  
Collaborative Group ◽  
Data Set

PURPOSE Cisplatin-containing chemotherapy has dramatically improved the outlook for patients with metastatic germ cell tumors (GCT), and overall cure rates now exceed 80%. To make appropriate risk-based decisions about therapy and to facilitate collaborative trials, a simple prognostic factor-based staging classification is required. MATERIALS Collaborative groups from 10 countries provided clinical data on patients with metastatic GCT treated with cisplatin-containing chemotherapy. Multivariate analyses of prognostic factors for progression and survival were performed and models were validated on an independent data set. RESULTS Data were available on 5,202 patients with nonseminomatous GCT (NSGCT) and 660 patients with seminoma. Median follow-up time was 5 years. For NSGCT the following independent adverse factors were identified: mediastinal primary site; degree of elevation of alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactic dehydrogenase (LDH); and presence of nonpulmonary visceral metastases (NPVM), such as liver, bone, and brain. For seminoma, the predominant adverse feature was the presence of NPVM. Integration of these factors produced the following groupings: good prognosis, comprising 60% of GCT with a 91% (89% to 93%) 5-year survival rate; intermediate prognosis, comprising 26% of GCT with a 79% (75% to 83%) 5-year survival rate; and poor prognosis, comprising 14% of GCT (all with NSGCT) with a 48% (42% to 54%) 5-year survival rate. CONCLUSION An easily applicable, clinically based, prognostic classification for GCT has been agreed on between all the major clinical trial groups who are presently active worldwide. This should be used in clinical practice and in the design and reporting of clinical trials to aid international collaboration and understanding.

Actionable targets in patients with cisplatin-resistant advanced germ cell tumors.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 473-473 ◽  
Author(s):  
Aditya Bagrodia ◽  
Samuel D. Kaffenberger ◽  
Byron Lee ◽  
William Lee ◽  
Eugene K. Cha ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Germ Cell ◽  
Cell Cancer ◽  
Significant Proportion ◽  
Germ Cell Tumors ◽  
Targeted Sequencing ◽  
Collaborative Group ◽  
First Line ◽  
Kras Mutations ◽  
Cell Functions

473 Background: Approximately 30% of patients with advanced germ cell tumor (aGCT) will progress after first-line chemotherapy. Nearly half of these patients will die of progressive GCT. We describe potentially actionable mutations in a cohort of patients with platinum-resistant aGCT through targeted sequencing. Methods: 76 patients with cisplatin-resistant (CR) disease were sequenced using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay that examines 341 cancer-related genes. Patients were categorized as CR if they met any of the following criteria: 1) incomplete response to first-line cisplatin-based chemotherapy; 2) nonteratomatous tumor progression after standard chemotherapy; 3) nonteratomatous GCT identified at postchemo surgery. We grouped all somatic mutations into core signal transduction pathways or canonical cell functions to identify potential precise targets for therapy. Results: The majority of patients had nonseminoma histology (n = 64, 84%). International Germ Cell Cancer Collaborative Group risk was good, intermediate, and poor in 34%, 13%, and 53% of patients. 17 patients died of disease. In total, 51 potentially actionable alterations were identified in 36/76 (47%) patients. In the TP53 pathway, 7 MDM2 amplifications and 4 MYCN amplifications that may sensitize to nutlin-3 inhibitors were identified. Within the receptor tyrosine kinase pathway, 3 KIT mutations, 1 KDR amplification, and 1 MET amplification were seen that may sensitize to tyrosine kinase inhibitors. Eleven KRAS mutations, 3 NRAS mutations, 3 BRAF mutations, and 2 RAC1 mutations were see among the RAS pathway with preclinical data suggesting efficacy towards respective inhibitors. Actionable targets were also among the PI3-K, WNT, and cell cycle pathways. Potential targets with chromatin modifying or tumor suppressor functions were also seen. Conclusions: We describe actionable alterations that may guide treatment selection in a significant proportion of patients with CR aGCT. Targeted sequencing of these patients may allow us to enrich future clinical trials with patients whose tumors harbor alterations in the drug target of interest.

scholarly journals Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell Tumors

2016 ◽  
Vol 34 (33) ◽  
pp. 4000-4007 ◽  
Author(s):  
Aditya Bagrodia ◽  
Byron H. Lee ◽  
William Lee ◽  
Eugene K. Cha ◽  
John P. Sfakianos ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cisplatin Resistance ◽  
Residual Disease ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Collaborative Group ◽  
Resistant Disease ◽  
Exon Capture ◽  
Whole Exome ◽  
Risk Of Cancer

Purpose Owing to its exquisite chemotherapy sensitivity, most patients with metastatic germ cell tumors (GCTs) are cured with cisplatin-based chemotherapy. However, up to 30% of patients with advanced GCT exhibit cisplatin resistance, which requires intensive salvage treatment, and have a 50% risk of cancer-related death. To identify a genetic basis for cisplatin resistance, we performed whole-exome and targeted sequencing of cisplatin-sensitive and cisplatin-resistant GCTs. Methods Men with GCT who received a cisplatin-containing chemotherapy regimen and had available tumor tissue were eligible to participate in this study. Whole-exome sequencing or targeted exon-capture–based sequencing was performed on 180 tumors. Patients were categorized as cisplatin sensitive or cisplatin resistant by using a combination of postchemotherapy parameters, including serum tumor marker levels, radiology, and pathology at surgical resection of residual disease. Results TP53 alterations were present exclusively in cisplatin-resistant tumors and were particularly prevalent among primary mediastinal nonseminomas (72%). TP53 pathway alterations including MDM2 amplifications were more common among patients with adverse clinical features, categorized as poor risk according to the International Germ Cell Cancer Collaborative Group (IGCCCG) model. Despite this association, TP53 and MDM2 alterations predicted adverse prognosis independent of the IGCCCG model. Actionable alterations, including novel RAC1 mutations, were detected in 55% of cisplatin-resistant GCTs. Conclusion In GCT, TP53 and MDM2 alterations were associated with cisplatin resistance and inferior outcomes, independent of the IGCCCG model. The finding of frequent TP53 alterations among mediastinal primary nonseminomas may explain the more frequent chemoresistance observed with this tumor subtype. A substantial portion of cisplatin-resistant GCTs harbor actionable alterations, which might respond to targeted therapies. Genomic profiling of patients with advanced GCT could improve current risk stratification and identify novel therapeutic approaches for patients with cisplatin-resistant disease.

scholarly journals Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial.

1997 ◽  
Vol 15 (5) ◽  
pp. 1844-1852 ◽  
Author(s):  
A Horwich ◽  
D T Sleijfer ◽  
S D Fosså ◽  
S B Kaye ◽  
R T Oliver ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cell Cancer ◽  
Survival Rates ◽  
Germ Cell Tumors ◽  
Good Prognosis ◽  
Cancer Trial ◽  
European Organization ◽  
To Receive ◽  
Nonseminomatous Germ Cell Tumors ◽  
Good Risk

PURPOSE This prospective randomized multicenter trial was designed to evaluate the efficacy of carboplatin plus etoposide and bleomycin (CEB) versus cisplatin plus etoposide and bleomycin (BEP) in first-line chemotherapy of patients with good-risk nonseminomatous germ cell tumors. PATIENTS AND METHODS Between September 1989 and May 1993, a total of 598 patients with good-risk nonseminomatous germ cell tumors were randomized to receive four cycles of either BEP or CEB. In each cycle, the etoposide dose was 120 mg/m2 on days 1, 2, and 3, and the bleomycin dose was 30 U on day 2. BEP patients received cisplatin at 20 mg/m2/d on days 1 to 5 or 50 mg/m2 on days 1 and 2. For CEB patients, the carboplatin dose was calculated from the glomerular filtration rate to achieve a serum concentration x time of 5 mg/mL x minutes. Chemotherapy was recycled at 21-day intervals to a total of four cycles. RESULTS Of patients assessable for response, 253 of 268 (94.4%) of those allocated to receive BEP achieved a complete response, compared with 227 of 260 (87.3%) allocated to receive CEB (P = .009). There were 30 treatment failures in the 300 patients allocated to BEP and 79 in the 298 allocated to CEB (log-rank chi 2 = 26.9; P < .001), which led to failure-free rates at 1 year of 91% (95% confidence interval [CI], 88% to 94%) and 77% (95% CI, 72% to 82%), respectively. There were 10 deaths in patients allocated to BEP and 27 in patients allocated to CEB (log-rank chi 2 = 8.77; P = .003), which led to 3-year survival rates of 97% (95% CI, 95% to 99%) and 90% (95% CI, 86% to 94%), respectively. CONCLUSION With these drug doses and schedules, combination chemotherapy based on carboplatin was inferior to that based on cisplatin. This BEP regimen that contains moderate doses of etoposide and bleomycin is effective in the treatment of patients with good-prognosis metastatic nonseminoma.

scholarly journals Low Survival in Poor Prognosis Metastatic Germ Cell Cancer in Belarus

2021 ◽  
pp. 63-71
Author(s):  
Alexander I. Rolevich ◽  
Denis M. Borodin ◽  
Anton N. Rabcheuski ◽  
Tatsiana A. Ivanitskaya ◽  
Sviataslau A. Semenov ◽  
...  
Keyword(s):  
Germ Cell ◽  
Poor Prognosis ◽  
Clinical Stage ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Progression Free Survival ◽  
Germ Cell Cancer ◽  
High Income ◽  
Collaborative Group ◽  
Entire Cohort

PURPOSE Since the development of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification in a 1997 study, high-income countries have reported a significant increase in survival for poor prognosis patients. There are scant data on IGCCCG risk-stratified survival from low- and middle-income countries. We assessed the progression-free survival (PFS) and overall survival (OS) rates in a contemporary cohort of Belarusian patients with advanced germ cell cancer (GCC) stratified by the IGCCCG prognostic classification and analyzed prognostic factors for survival. MATERIALS AND METHODS The consecutive cohort of patients with clinical stage IIb-III testicular GCC or extragonadal germ cell tumors who received treatment or consultation in our two centers between 2010 and 2015 was included. All patients underwent primary chemotherapy. The patients were divided into seminoma and nonseminomatous germ cell carcinoma (NSGCC) subgroups. The Kaplan-Meier method was used to estimate 5-year PFS and OS. RESULTS This study included 111 patients with a median age of 32 years, 95% of whom were diagnosed with testicular cancer. Seminoma and NSGCC were identified in 32 (29%) and 79 (71%) patients, respectively. The median follow-up was 6.1 years. The 5-year PFS and OS rates for the entire cohort were 70% and 77%, respectively. In patients with good prognosis seminoma and good, intermediate, and poor prognosis NSGCC, the estimated PFS rates were 76%, 88%, 74%, and 39% and those for OS were 83%, 97%, 83%, and 38%, respectively. CONCLUSION In our cohort of Belarusian patients with advanced germ cell tumors, we failed to demonstrate an improvement in PFS and OS compared with the 1997 IGCCCG study. Moreover, survival in poor prognosis group is inferior to that in IGCCCG and all contemporary series from high-income countries.

Chemotherapy for Advanced Germ Cell Tumors

2006 ◽  
Vol 24 (35) ◽  
pp. 5493-5502 ◽  
Author(s):  
G. Varuni Kondagunta ◽  
Robert J. Motzer
Keyword(s):  
Clinical Trials ◽  
Germ Cell ◽  
Cell Cancer ◽  
Palliative Therapy ◽  
Germ Cell Tumors ◽  
Collaborative Group ◽  
High Dose ◽  
Group Model ◽  
Treatment Choices ◽  
Risk Patients

Purpose Germ cell tumors constitute the most curable of all cancers. Standard treatment of previously untreated and treated patients has evolved on the basis of prospective clinical trials and prognostic factors. This review summarizes the prognostic criteria on which treatment decisions may be based, and outlines the current treatment approaches. Patients and Methods Randomized and nonrandomized trials of first-line, salvage, and palliative therapy and the role of surgery after chemotherapy were reviewed. In the treatment of previously untreated patients, emphasis was placed on interpretation of data of trials according to the International Germ Cell Cancer Collaborative Group model, which has evolved into a universally accepted classification algorithm for determining appropriate risk-directed chemotherapy. This system permits treatment choices based on the balance between benefit and toxicity and allows comparison of results across multiple clinical trials. Results Standard therapy for good-risk patients is four cycles of etoposide plus cisplatin or three cycles of cisplatin, etoposide plus bleomycin (BEP × 3); both approaches cure approximately 90% of patients. After chemotherapy and normalization of markers, patients should generally undergo resection of residual masses. Approximately 75% of intermediate-risk and 45% of poor-risk patients group achieve a durable complete response with BEP × 4. Potentially curative options in the salvage setting include ifosfamide plus cisplatin-containing standard dose therapy and high-dose carboplatin plus stem-cell rescue. Surgery remains an essential component of care. Conclusion Curative therapy exists even in patients with resistant disease, and treatment choices can be based on established clinical criteria. Serum tumor markers and surgery after chemotherapy have essential roles in patient management.

Improved outcomes in testicular germ cell tumor patients treated at the referral center in Slovakia in the last decade.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16059-e16059
Author(s):  
Michal Chovanec ◽  
Katarina Rejlekova ◽  
Zuzana Sycova-Mila ◽  
Jana Obertova ◽  
Patrik Palacka ◽  
...  
Keyword(s):  
Germ Cell ◽  
National Cancer Institute ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Treatment Strategies ◽  
Collaborative Group ◽  
Rank Test ◽  
Poor Risk ◽  
Before And After ◽  
Group 2

e16059 Background: Treatment at expert centers results in superior survival in patients with germ cell tumors (GCTs). This study evaluated outcomes in patients treated at National Cancer Institute in Slovakia before and after the year 2008 after refining the treatment strategies. Methods: Our institutional database was searched for GCT patients treated at National Cancer Institute in Slovakia between 1992 and 2016. A year of 2008 was selected for cutoff to compare changes in outcomes before and after this time-point due to refining treatment strategies such as centralization of post-chemotherapy surgery and incorporation of granulocyte-colony stimulating factor (G-CSF) for routine prophylaxis of febrile neutropenia. Kaplan-Meier product limit and log-rank test were used for statistical analysis. Results: This retrospective study included 485 patients treated for metastatic GCT. Two hundred and sixty-three patients (54%) were treated before 2008 (group 1) and 222 patients (46%) were treated after 2008, including (group 2). Progression-free survival (PFS) and overall survival (OS) was significantly improved in group 2 vs 1 (HR = 0.63, 95% CI 0.46-0.87; P= 0.0039 for PFS and HR = 0.44, 95% CI 0.30-0.65; P = 0.0003 for OS, respectively). In a subgroup analysis of International Germ Cell Cancer Collaborative Group criteria, favorable change in survival was observed in good-risk GCTs (HR = 0.40, 95% CI 0.24-0.67; P = 0.0009 for PFS, and HR = 0.20, 95% CI 0.10-0.38; P = 0.0002 for OS), but nor in intermediate or poor risk group. Conclusions: Treatment outcomes of GCTs have significantly improved in the last decade at our institution. We hypothesize that changes in treatment approach contributed to this improvement including centralization of post-chemotherapy retroperitoneal lymph-node dissections and routine use of granulocyte-colony stimulating factors that have been implemented in 2007. Referral bias for extremely poor risk patients in recent years may be an accounting factor for lack of improvement in this subgroup.

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

2021 ◽  
pp. JCO.20.03296
Author(s):  
Silke Gillessen ◽  
Nicolas Sauvé ◽  
Laurence Collette ◽  
Gedske Daugaard ◽  
Ronald de Wit ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Germ Cell ◽  
Prognostic Model ◽  
Lung Metastases ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Progression Free Survival ◽  
Collaborative Group ◽  
Data Set ◽  
Nonseminomatous Germ Cell Tumors

PURPOSE The 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 METHODS Data 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. RESULTS Compared 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 ). CONCLUSION The 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.

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