Recent Refinements in the Management of Testicular Cancer
Clinical Review
Recent Refinements in the Management of Testicular Cancer
The treatment of testicular cancer is frequently used as an example of the success of clinical trial methodology in medical oncology. More than 80% of all patients are curable with available therapy. Despite this high level of success, recent progress has led to improved methods of separating good risk from poor risk patients, and this permits the field to focus on important remaining questions. The improved staging methods help in defining the minimal effective doses of treatment for the good risk patients to minimize toxicity. In addition, more reliable recognition of poor risk patients permits the justifiable use of more aggressive and more toxic treatment approaches in an effort to increase the fraction of patients cured.
Staging
The tumor, node, metastasis (TNM) classification has not been very helpful in defining risk groups. However, the International Germ Cell Cancer Consensus Group (IGCCCG) has generated criteria for defining the risk group of an individual patient that should assist in standardizing the eligibility criteria for protocol treatments and facilitate the comparison of different studies. There are two major histologic forms of testicular cancer: seminoma and non-seminoma. Stage for stage, seminoma has a better prognosis. The new IGCCCG criteria include histology as a prognostic factor.1
For seminomas, there are two risk categories: good risk and intermediate risk. The difference between these two risk groups is that intermediate risk patients have nonpulmonary visceral metastases. Any patient without nonpulmonary metastases is considered good risk regardless of the levels of tumor markers or the primary site of disease.
By contrast, there are three risk categories for nonseminomas: good, intermediate, and poor risk. These three groups are determined by the primary site (testes or retroperitoneal vs mediastinum), the presence or absence of nonpulmonary visceral metastases, and the serum levels of three tumor markers, alphafetoprotein (AFP), beta-human chorionic gonadotropin (betaHCG), and lactate dehydrogenase (LDH). Specific criteria for defining risk are shown in the Table.
Treatment of Good Risk Patients
Patients with good risk seminoma are treated with radiation therapy and nearly 100% of patients are cured.
Since the demonstration that about 90% of good risk nonseminomatous testicular cancers are curable with cisplatin-based combination chemotherapy, clinical research in the last decade has been focused on defining how little therapy can be given and still preserve the high rate of curability. The standard regimen for these patients is bleomycin, etoposide, and cisplatin (BEP). The Indiana group has shown that three cycles is as equally effective as four cycles; thus, standard therapy is three cycles of BEP.2 The results obtained by the Memorial Sloan Kettering Cancer Center group with four cycles of etoposide and cisplatin (EP)3 are said to be comparable to the results obtained with three cycles of BEP at Indiana.4 However, no direct comparison has been made between three cycles of BEP and four of EP. An EORTC study comparing BEP and EP with the etoposide dose at 360 mg/m2 rather than 500 mg/m2 showed a significantly lower complete response rate to EP, but bleomycin toxicity was noted on the BEP arm.5 Studies in which carboplatin has been substituted for cisplatin seem to obtain poorer results.6,7
Table
IGCCCG Risk Classification for Nonseminomatous Germ Cell Tumors
Good Risk |
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Intermediate Risk |
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Poor Risk |
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Treatment of Intermediate and Poor Risk Patients
Patients with intermediate risk seminoma (that is, those with nonpulmonary visceral metastases) are treated with four cycles of BEP. A recent study suggests that the subset of "good risk" patients with extragonadal primary tumors and those with retroperitoneal masses larger than 5 cm in diameter, should also receive chemotherapy rather than radiation therapy.8 There is no defined poor risk group for seminoma. More than 90% of intermediate risk patients are cured with BEP.
Patients with intermediate risk nonseminomatous germ cell tumors are usually treated with four cycles of BEP and about 70% of them are cured. BEP results in the cure of about 35% of poor risk patients. Efforts to improve the treatment success, by augmenting the dose intensity of the chemotherapy and adding other active agents, have not made a significant impact.9,10 Kaye and colleagues9 compared an intensive induction-sequential chemotherapy schedule using bleomycin, vincristine, and cisplatin (BOP) followed by etoposide, ifosfamide, cisplatin, and bleomycin (VIP-B) to alternating BEP/EP. The intensive regimen was more toxic but not more effective. Similarly, Nichols and colleagues10 substituted ifosfamide for bleomycin and showed that BEP and VIP (etoposide, ifosfamide, and cisplatin) were comparably active, but, that VIP was more toxic. Thus, BEP remains the standard regimen even for poor risk patients. BEP myelotoxicity can be abetted to some extent by the use of colony-stimulating factors, but this does not permit the delivery of higher doses of therapy.11
Based upon promising phase II data from several centers (e.g., See reference 12), ongoing clinical trials in poor risk patients are evaluating high-dose therapy as a component of treatment. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Memorial Sloan Kettering Cancer Center are evaluating four cycles of BEP vs. two cycles of BEP followed by high-dose therapy with carboplatin, etoposide, and cyclophosphamide. Less than one in 10 patients has poor risk characteristics. Thus, it is important to consider entering such patients on clinical trials to speed the development of more effective treatments.
References
1. IGCCCG International Germ Cell Consensus classification. J Clin Oncol 1997;15:594-603.
2. Saxman S, et al. J Clin Oncol 1998;16:702-706.
3. Xiao H, et al. J Clin Oncol 1997;15:2553-2558.
4. Bosl G. J Clin Oncol 1998;16:1244-1247.
5. De Wit R, et al. J Clin Oncol 1997;15:1837-1843.
6. Bajorin D, et al. J Clin Oncol 1993;11:598-606.
7. Horwich A, et al. J Clin Oncol 1997;15:1844-1852.
8. Warde P, et al. J Clin Oncol 1998;16:290-294.
9. Kaye SB, et al. J Clin Oncol 1998;16:692-701.
10. Nichols CR, et al. J Clin Oncol 1998;16:1287-1293.
11. Fossa S, et al. J Clin Oncol 1998;16:716-724.
12. Motzer R, et al. J Clin Oncol 1996;14:1098-1105.
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