Interpretation of literature published in the 1980s and 1990s was difficult because of the small numbers of patients studied and wide variation in patient selection criteria, treatment policies, and reporting criteria. The publication and acceptance of the IGCCC [13] has led to greater standardization in the description of patient groups. International trial groups are now using the IGCCC classification to determine eligibility for trials and to report their results.

Randomized comparisons performed to date have failed to identify any systemic therapy approach that is clearly superior to four cycles of cisplatin, etoposide, and bleomycin, which was first described in the mid-1980s. The recently reported results of the Intergroup trial that showed no benefit with high-dose chemotherapy and stem cell support add to a sense of frustration at the lack of progress, despite the extensive effort put into developmental and phase III trials. These results also suggest that other attempts to improve outcomes by intensifying therapy are unlikely to result in major improvement. Future opportunities for significantly improving therapy for poor-prognosis patients include the development of new therapeutic agents, particularly approaches targeting molecular mechanisms of resistance. The study of biologic markers to predict outcome and influence the choice of therapy is also warranted.

In the shorter term, three randomized trials are currently underway in Europe. The German Tes-ticular Cancer Study Group has shown that the dose intensity of repetitive cycles of chemotherapy can be escalated significantly [42]. In contrast to the approach used in the Intergroup study, this approach introduces high-dose chemotherapy earlier and dose intensity is ensured by recycling the chemotherapy every 3 weeks. This approach is the subject of a phase III trial being performed by the EORTC group. The C-BOP-BEP regimen has been extensively studied in nonrandomized trials and is currently being compared with standard BEP in a phase III trial in the United Kingdom. Finally, the Genitourinary Group of the French Federation of Cancer Centers will assess the value of changing treatment for those patients who have a slow predicted time to serum tumor marker normalization, according to the paradigm that they have described [22].

The role of surgery and the impact of the treating institution are often underemphasized in discussions of therapy, because they are not the subject of large trials or of the evidence base. Despite this, the surgical resection of residual masses from multiple sites is a vital component of optimal care. Surgery also is potentially effective as a salvage procedure for patients who subsequently relapse. There is convincing evidence that patients who have poor-prognosis germ cell tumors have better outcomes if they are managed at centers that manage a large number of similar cases. It is likely that at least some of this improvement is attributable to the expertise of the surgeons at these centers and their willingness and ability to tackle difficult cases.

The failure to define clear advances in the management of poor-prognosis germ cell tumors in the last 10 years emphasizes the need for well-conceived and carefully conducted randomized studies using standard patient selection and reporting criteria. All patients presenting with poor-prognosis tumors should be encouraged to participate in clinical trials. The expertise and experience of the treating clinicians is likely to be one of the most important factors in determining outcome for this group of patients. Referral to a specialist center is warranted. Attempts to intensify therapy may improve outcomes modestly but the major challenges currently are the identification of molecular mechanisms of resistance and the development of novel molecularly targeted therapeutic approaches.

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