Prognostic factors

Determination of treatment based on pretreat-ment clinical characteristics was proposed early in the development of effective chemotherapy [3]. In the 1980s, several major groups identified factors

* Department of Medical Oncology, Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia.

E-mail address: [email protected]

predictive of a poor outcome, including tumor marker elevation, extent or bulk of metastatic disease, visceral organ involvement, histopathology, and primary site [4-9]. The most common finding was that tumor bulk and levels of tumor markers were the most important prognostic variables. Ex-tragonadal primary site was also identified as an adverse prognostic factor, particularly for medias-tinal primary nonseminomatous germ cell tumors, which seem to have distinct clinical characteristics and respond poorly to treatment [10,11]. Although most analyses identified similar factors, unfortunately many trial groups or individual centers produced their own prognostic classification systems and used them exclusively in the design and reporting of clinical trials. All of these analyses and classifications were open to criticism for their small numbers, exclusion of certain variables found important by other groups, and lack of consensus.

The impact of the variability in prognostic classification between different centers was demonstrated by Bajorin and colleagues [12]. This study showed that patient selection criteria could make the results of a treatment seem better than an equally effective alternative used in a more stringently selected patient population. This study demonstrated the need for uniform criteria for prognostic classification in clinical trial design and demonstrated clearly the problems of comparison of small phase II trials using differing patient selection criteria.

The International Germ Cell Consensus Classification

An international group pooled data from more than 6000 cases of germ cell tumors undergoing chemotherapy and published a prognostic factor-based staging system in 1997 [13]. The IGCCC identifies three groups with good, intermediate, and poor prognoses. The classification includes seminomas and nonseminomas along with testicular and extragonadal primary sites. The intermediate- and poor-prognosis categories are described in Table 1. The intermediate-prognosis category included 26% of germ cell tumors and achieved 79% overall survival at 5 years. The poor-prognosis group made up 14% of germ cell tumors and had a 48% survival at 5 years.

Since it was published in 1997, the IGCCC classification has been widely accepted. The IGCCC groupings should be used to select the most appropriate treatment for patients requiring chemotherapy. Recently reported clinical trials have successfully used the classification to determine eligibility [14]. This use promises to allow better analysis of results and comparability with other studies. Unless an improved and widely accepted classification is developed, all clinical trial results should be reported using the IGCCC criteria.

Several studies have assessed prognostic factors within the poor-prognosis group [15] or in groups that commonly have a poor prognosis, such as those with an extragonadal primary site [10,16]. Within the IGCCC poor-prognosis group, patients who had a mediastinal primary nonseminoma with metastases had the worst outlook, whereas those who had a testis or retroperitoneal primary site and no visceral metastases other than lung metastases had the best prognosis [15]. A recent evaluation of the international experience with extragonadal germ cell tumors confirmed the findings of the IGCCC with extragonadal seminomas having a good prognosis and mediastinal nonseminoma clearly having the worst outcomes [16].

Serum tumor marker decline during chemotherapy

Investigators at Memorial Sloan Kettering Cancer Center (MSKCC) retrospectively reviewed serum tumor marker data and found that a slower-than-expected decline in either human chorionic gonadotropin (HCG) or a-fetoprotein (AFP) allowed early prediction of subsequent failure in patients who had both good- and poor-prognosis tumors [17]. Similar results were found in the salvage setting [18]. Slow decline of markers has been used in clinical trials at MSKCC to identify patients for early crossover to high-dose chemotherapy with bone marrow transplant [19]. The initial surge in tumor marker levels after initiation of chemotherapy was also found to be prognostic in one study [20]. Assessment of marker decline has been assessed by other investigators with variable results [21], including a recent large study that suggested particular value in poor-prognosis IGCCC patients [22]. The latter approach is being studied prospectively by the French in a randomized trial for poor-prognosis patients to assess the value of changing chemotherapy in those cases with a predicted slow marker normalization [22]. Although there is increasing evidence of the potential value of assessing the pattern of change of serum tumor markers, there remains no consensus as to the most appropriate methodology. At present, it should remain an investigational tool and awaits confirmation by prospective data [21].

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