Late Relapse of Germ-Cell Tumor

Germ-cell tumors represent the most common cancer in men aged 15 to 35 years. They account for approximately 95% of all testicular cancers, and their management represents one of the success stories of modern medicine. Today, approximately 90% of men diagnosed with testicular cancer are ultimately cured of their disease.¹ What is particularly impressive is that, with the use of cisplatin-based chemotherapy, 70% to 80% of patients with metastatic disease achieve complete remission. Most patients who relapse after primary treatment present with recurrent disease within 2 years of initial therapy; however, 2% to 3% present with late relapse. In a retrospective analysis, Dr David George and colleagues describe the clinical characteristics and preliminary molecular data in patients with late relapse of germ-cell tumor treated at the University of Indiana.

Update on Late Relapse of Germ Cell Tumor: A Clinical and Molecular Analysis

George DW, Foster RS, Hromas RA, et al.

J Clin Oncol. 2003;21:113–12212506179.

This study reports on 83 patients who were identified between 1993 and 2000 with relapse of germ-cell tumor more than 2 years after initial treatment. Most patients presented with relapse more than 5 years after initial therapy. The median time to relapse was 7 years. Of the 49 patients treated by surgical resection, 43 were rendered disease-free by surgery, and 20 patients (41%) remained free of additional recurrences. Of the 32 patients treated with chemotherapy, only 6 were rendered disease-free, and 5 patients (16%) remained free of additional recurrences. Of these 5 patients, 3 were naïve to chemotherapy. Of the 32 patients treated with chemotherapy for recurrent disease, 18 were disease-free after successful postchemotherapy resection of residual lesions.

Based on these results, the authors make several recommendations. Given the long median interval between initial treatment and relapse of disease, they recommend lifetime follow-up. However, no data are provided to recommend a specific follow-up regimen. The authors do, however, provide the follow-up regimen used at Indiana University and emphasize some key principles. Because most recurrences are identified within the first 2 years after initial therapy, the follow-up intervals should be short during the first and second years. With a longer disease-free interval, the follow-up can be less frequent.

For the treatment of late relapse, the authors recommend surgical resection alone. The most common sites of recurrence in this study were the retroperitoneum and the lungs, with approximately two thirds of all recurrences being solitary. They state that, as a single modality therapy, surgical resection was superior to chemotherapy in producing a durable disease-free state (41% vs 16%, respectively). Of the 81 patients who received treatment, only 2 were able to avoid surgery. The authors point out that surgical resection was performed for multiple sites of relapse in 10 patients. They also argue that the better results seen with surgery alone compared with chemotherapy alone are unlikely to simply reflect more advanced disease in patients receiving chemotherapy. Chemotherapy had a poor response even in patients with minimal disease, which was defined as marker elevation with no radiologic evidence of recurrent tumor.

The authors also present prospectively collected molecular data. Abnormalities of chromosome 12, which are present in nearly all germ-cell tumors, were assessed by fluorescence in situ hybridization analysis. Results confirmed the preservation of chromosome 12p abnormalities in late recurrences. The authors also examined the expression of FoxD3, which is a transcription regulator and repressor of differentiation, and of apurinic/apyrimidinic endonuclease (Ape1), which is involved in deoxyribonucleic acid repair and is thought to be important for resistance to chemotherapy. Only 5 of 21 specimens stained highly for FoxD3, and only 9 patients who received chemotherapy had staining data for Ape1. Therefore, there were insufficient data to draw any clinical conclusions.

The authors make a convincing argument in favor of surgery as monotherapy for patients with late relapse of germ-cell tumor. It is important to understand that late relapses are relatively resistant to chemotherapy. However, it is unclear whether surgery alone is superior to the combination of surgery and chemotherapy. Based on the results presented in this study, it makes sense to perform surgery first when both surgery and chemotherapy are being considered. The results of the surgical pathology may influence the need for further therapy. If surgical resection reveals minimal disease, this study provides a rationale for further management with close observation.