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.

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.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. PURPOSE The European Organisation for Research and Treatment of Cancer 10981-22023 AMAROS trial evaluated axillary lymph node dissection (ALND) versus axillary radiotherapy (ART) in patients with cT1-2, node-negative breast cancer and a positive sentinel node (SN) biopsy. At 5 years, both modalities showed excellent and comparable axillary control, with significantly less morbidity after ART. We now report the preplanned 10-year analysis of the axillary recurrence rate (ARR), overall survival (OS), and disease-free survival (DFS), and an updated 5-year analysis of morbidity and quality of life. METHODS In this open-label multicenter phase III noninferiority trial, 4,806 patients underwent SN biopsy; 1,425 were node-positive and randomly assigned to either ALND (n = 744) or ART (n = 681). RESULTS Per intention-to-treat analysis, 10-year ARR cumulative incidence was 0.93% (95% CI, 0.18 to 1.68; seven events) after ALND and 1.82% (95% CI, 0.74 to 2.94; 11 events) after ART (hazard ratio [HR], 1.71; 95% CI, 0.67 to 4.39). There were no differences in OS (HR, 1.17; 95% CI, 0.89 to 1.52) or DFS (HR, 1.19; 95% CI, 0.97 to 1.46). ALND was associated with a higher lymphedema rate in updated 5-year analyses (24.5% v 11.9%; P < .001). Quality-of-life scales did not differ by treatment through 5 years. Exploratory analysis showed a 10-year cumulative incidence of second primary cancers of 12.1% (95% CI, 9.6 to 14.9) after ART and 8.3% (95% CI, 6.3 to 10.7) after ALND. CONCLUSION This 10-year analysis confirms a low ARR after both ART and ALND with no difference in OS, DFS, and locoregional control. Considering less arm morbidity, ART is preferred over ALND for patients with SN-positive cT1-2 breast cancer.

IntroductionAngiosarcomas constitute approximately 2% to 3% of all soft tissue sarcomas, are characterised by an aggressive clinical behaviour and poor outcome. Optimal management of localised angiosarcomas consists of complete surgical resection with or without radiation. However, due to the infiltrating nature of this disease, complete resection is often not possible. Despite optimal management, the outcome of patients with localised disease remains poor. The role of (neo)adjuvant chemotherapy in angiosarcomas remains undefined. The aim of this study is to document the outcome of patients treated with (neo)adjuvant chemotherapy and assess the feasibility of performing a prospective trial by evaluating the number of patients treated at sarcoma referral centres.MethodsA retrospective search within participating EORTC (European Organisation for Research and Treatment of Cancer) sites for patients treated with (neo)adjuvant chemotherapy was made. Patients treated between January 2007 and January 2016 were included.ResultsA total of 15 institutions participated and 86 patients were evaluable, 43 were treated with neoadjuvant, 27 with adjuvant chemotherapy and 16 with both. At the time of analysis, the median follow-up from diagnosis was 4.6 years. Median overall survival (OS) was 4.9 years (2.9 N) and the percentage alive at 4 years was 57.9 (45.5 to 68.4). The median disease-free survival was 1.4 years (0.9 to 1.7) and the percentage disease-free at 4 years was 26.8% (17.9 to 36.5).ConclusionThe outcome of angiosarcoma patients treated with (neo)adjuvant chemotherapy in this case series compares favourably with previously published data. Due to the aggressive nature of angiosarcoma, a prospective trial of neoadjuvant chemotherapy should be considered.

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Objectives: Emergency room (ER) evaluation may differ when physicians see patients in the context of clinical trials compared to routine care. We aimed to determine whether patterns in the use of a systemic pretest probability (PTP) stratification tool and D-dimer testing change over time and whether this influences their clinical utility. Methods: Charts were reviewed of 974 cases that had D-dimer testing for VTE exclusion in two time periods; 474 consecutive patients evaluated between 07/02 and 10/02 and 500 between 07/04 and 10/04. The former cohort was managed by ER physicians that had just participated in a clinical trial on VTE diagnosis including PTP assessment and D-dimer testing, whereas the latter group had received no formal training after 2002. In both cohorts, pretest scoring as low, intermediate or high risk according to Wells criteria for DVT and PE was performed in every case since this was requested from the laboratory. D-dimer testing (Vidas® D-Dimer, Biomerieux) was performed only in the low and moderate risk group after reception of the PTP assessment form. Physicians were also asked to check out a form detailing individual Wells criteria leading to the overall assessment but were not mandated to do so in order to obtain the D-dimer result from the laboratory. Results: Pretest probability was evaluated as low, moderate or high in 66,7%, 31,9% and 1,3% vs. 78,4%, 21,2% and 0% (all comparisons are 2002 vs. 2004). There was a significant increase in proportion of undetailed evaluations of PTP (32,7% vs. 61%). Detailed forms in both cohorts had similar risk distribution (low/moderate risk 51,7/46,4% vs. 59,2/40,8%) whereas undetailed forms were usually quoted as low risk (97,4% vs. 90.5%). Number of D-dimer tests performed per month was stable over the three year period of observation and in the two evaluated cohorts (119/mth vs. 125/mth). D-dimer results were negative in 299/474 cases (63,1%) in 2002 and 359/500 (71,8%) in 2004 (p=0,003), although this difference was less apparent when analysed according to the individual PTP risk groups (low/moderate risk 77,3/51,9% vs. 71,2/48,3%). Incidence of VTE events decreased over time from 5,3 to 1,6% (p=0,002). Incidence in the low/moderate risk groups was 1,6%/10,6% vs. 0,3%/6,6%. Only one false negative result (popliteal vein DVT) was observed in the two cohorts (NPP = 99,9%). Conclusion: Our results show a decreasing incidence in VTE over time in an ER population screened by D-dimer testing and PTP even though the number of tests performed were stable over time. This was accompanied by a decreasing number of cases considered to have an intermediate PTP. These findings suggest a change of practice over time resulting in an increasing use of D-dimer testing for very low risk patients and a decrease in their use for intermediate risk patients. A decrease in the proper use of the PTP tool over time might result in overestimation of the physician perceived risk and therefore lead to an increase in imaging resource utilisation. Broader studies including imaging prescription trends over time will be needed to confirm this hypothesis.

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Twenty-seven patients were enrolled and 25 were eligible and received treatment. The median age was 60.0 years. 88.0% of patients had received other VEGFR therapy prior to lenvatinib. The median dose of lenvatinib at entry was 14 mg daily (10-24 mg). Thirty-six percent of patients had grade 3 adverse events (AEs) and no patients had grade 4 AEs. There were no treatment-related deaths. The most common grade 3 AEs were dyspnea (12%), and hypertension (12%). All other grade 3 AE were 4%. One patient had grade 3 myocarditis and heart failure that was likely related to pembrolizumab therapy. Of 20 evaluable patients, 3 (15%) had a partial response (PR) and 17 (85%) had stable disease (SD), for an ORR of 15% and CBR of 100%. Median PFS was 12.6 months (95% CI: 7.1-18.2). The PFS at 12 months was 56%. Eleven patients (44%) are still on treatment (1.6-16.8 mo). Three patients (15%) had >40% target tumor shrinkage.Conclusions: Adding pembrolizumab to lenvatinib therapy is well tolerated in patients with RAIR DTC. A preliminary primary endpoint of ORR was 15%. The addition of pembrolizumab to patients progressing on lenvatinib has a high CBR and favorable PFS in patients with RAIR DTC.Clinical trial identification: NCT02973997.