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Poor-Prognosis Germ Cell Tumors: We Have Not Yet Crossed the Finish Line

Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA

During the 2006 meeting of the American Society of Clinical Oncology, Lance Armstrong received the Special Recognition Award for his tireless efforts on behalf of people with cancer. The remarkable story of his recovery from poor-prognosis germ cell tumor (GCT) to the pinnacle of competitive cycling inspires all who are touched by cancer. Despite his successful outcome and the significant advances that have been made in the management of advanced GCT over the last three decades, poor-prognosis GCT continues to be a major challenge. Although the 5-year survival for patients with good-risk GCT, as defined by the International Germ Cell Consensus Classification, is approximately 90%, 5-year survival for intermediate-risk GCT and poor-risk GCT is only approximately 80% and 50%, respectively.¹

Clinical investigations have attempted to overcome the issue of drug resistance inherent in poor-prognosis GCT. Phase III randomized studies of investigational approaches in poor-prognosis GCT, such as doubling the dose of cisplatin,² substituting ifosfamide for bleomycin,³ or using a dose-intensive sequential chemotherapy regimen,⁴ have demonstrated no improvement in survival compared with standard therapy. However, patients with relapsed GCT can have successful salvage treatment with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation (ASCT). Presently, this approach is a standard treatment for patients with relapsed disease. Therefore, moving HDCT to first-line treatment of poor-prognosis GCT was a logical and reasonable next step. Nonrandomized studies of first-line HDCT and ASCT in poor-prognosis GCT demonstrated preliminary results that compared favorably to what had been achieved historically.^5-8

In this issue of the Journal of Clinical Oncology, Motzer et al⁹ report the results of a phase III randomized trial investigating first-line HDCT in poor-prognosis GCT (intermediate or poor risk). All patients were treated with standard-dose bleomycin, etoposide, and cisplatin (BEP) for two cycles and then were randomly assigned to either two cycles of high-dose carboplatin, etoposide, and cyclophosphamide with ASCT or to standard BEP for two additional cycles. The 1-year durable complete response (CR) rate, the primary end point of the trial, did not differ between the two groups (52% v 48%; P = .53). In addition, with a median follow-up of 51 months, no differences in event-free or overall survival were demonstrated. We agree with the investigators' conclusion that standard first-line treatment for these patients remains four cycles of BEP. Once again, promising preliminary noncomparative results of HDCT for the treatment of a solid tumor have not withstood rigorous randomized testing.

Does this trial definitively reject first-line HDCT for poor-prognosis GCT patients? The trial was designed to detect a 20% improvement in durable CR at one year. A similarly powered trial is ongoing at the European Organisation for Research and Treatment of Cancer to compare sequential HDCT plus ASCT with standard BEP in patients with poor-prognosis GCT. Yet, neither trial is large enough to detect smaller (eg, 5% or 10%) differences in outcome that might be clinically relevant for this group of young men. Given the rarity of poor-prognosis GCT, it seems unlikely that a trial large enough to detect differences this small will be performed. This underscores two important points. First, we need to recruit more patients to well-designed scientifically sound clinical trials, especially in relatively uncommon cancers like GCT. Second, it may take international collaboration in the future to accomplish meaningful clinical trials in this patient population.

The experience of the treating institution has been previously demonstrated to have prognostic importance in patients with poor-prognosis GCT.¹⁰ In a trial at the European Organisation for Research and Treatment of Cancer, patients at institutions that treated fewer than five patients on the trial had a worse outcome than patients at institutions that treated five or more patients. The reason for this is not entirely clear, but it may be related to protocol deviations such as chemotherapy dose reductions or delays. In addition, the quality of postchemotherapy surgery and the expertise in managing treatment-related toxicity also could play a role. In this trial, no information is presented concerning the proportion of patients in each arm, treated by more experienced centers. It is concerning that nearly one fourth of patients randomly assigned to the HDCT arm never received this treatment. In addition, 12 of the 111 patients in the BEP arm received two or fewer cycles of treatment. Also noteworthy is the lack of difference in treatment-related mortality between the two arms; most treatment-related deaths occurred during the BEP portion of therapy. Information on the experience of the treating institutions, dose-intensity, dose reductions and delays, and completeness of postchemotherapy surgery in each arm would help clarify whether outcomes were influenced by these potential sources of bias.

A unique aspect of GCT management is the ability to assess treatment response on the basis of serial measurements of serum alpha-fetoprotein and human chorionic gonadotropin levels. Studies have demonstrated that the rate of serum tumor marker decline has prognostic significance.^11-14 In this trial, the prognostic importance of marker decline during the first two cycles of BEP in poor-prognosis GCT was assessed prospectively. Unsatisfactory marker decline was defined as an alpha-fetoprotein half-life of more than 7 days or human chorionic gonadotropin half-life of more than 3.5 days. Patients with satisfactory marker decline demonstrated a 1-year durable CR rate and a 2-year survival that was better than that of patients with unsatisfactory marker decline. The clinical implication is that if a patient with unsatisfactory marker decline is identified, treatment could be modified such that the outcome could be improved. Indeed, for patients with unsatisfactory marker decline, the 1-year durable CR rate was 61% for the HDCT arm and 34% for the BEP arm (P = .03). This raises the possibility that patients with poor-prognosis GCT who have unsatisfactory marker decline during the first two cycles of BEP might benefit from switching to HDCT. Because of the inherent bias in subset analysis, this result cannot be considered definitive, but continued investigation of HDCT and other novel approaches in patients with unsatisfactory marker decline is warranted.

Why do patients with poor-prognosis GCT fare so much worse than their good-prognosis counterparts? The factors that influence chemotherapy sensitivity and, conversely, chemotherapy resistance in patients with GCT are not fully understood. Studies examining the role of p53, bcl-2, and DNA repair mechanisms have not provided a clear explanation.¹⁵ As mechanisms of GCT chemotherapy sensitivity and chemotherapy resistance in patients are better understood, perhaps in the future, with molecular profiling, clinicians will be able to predict accurately which poor-prognosis GCT patients are likely to be cured with standard chemotherapy and which are not. Incurable patients would be candidates for first-line investigational approaches. Increased understanding of this biology also may lead to the development of targeted therapies for chemotherapy-resistant disease. Although the high cure rate of patients with good-risk GCT is a tremendous achievement, we need to continue to focus our research efforts on the poor-prognosis subgroup. We have not reached the finish line, but the race is well under way.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: David J. Vaughn, Edward A. Stadtmauer

Manuscript writing: David J. Vaughn, Edward A. Stadtmauer

Final approval of manuscript: David J. Vaughn, Edward A. Stadtmauer

REFERENCES

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8. Schmoll HJ, Kollmannsberger C, Metzner B, et al: Long-term results of first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem-cell support for patients with advanced metastatic germ cell cancer: An extended phase I/II study of the German Testicular Cancer Study Group. J Clin Oncol 21:4083-4091, 2003[Abstract/Free Full Text]

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