1 Tuebingen University Medical Center II, Tuebingen, Germany; 2 Oregon Health Sciences University, Portland, Oregon, USA; 3 Centre Léon-Berard, GETUG, Lyon Cedex, France; 4 The Royal Marsden Hospital, Sutton, UK; 5 Klinikum Großhadern, Munich, Germany; 6 The Norwegian Radium Hospital, Oslo, Norway; 7 Virchow Klinikum, Berlin, Germany; 8 Kaiser Franz Josef Spital, Vienna, Austria; 9 Indiana University, Indianapolis, IN, USA
Received 5 September 2001; revised and accepted 11 February 2002
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Abstract |
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This investigation evaluates prognostic variables in patients with seminomatous and non-seminomatous extragonadal germ-cell tumors (EGCT) in order to identify relevant factors for long-term outcome following cisplatin-based chemotherapy.
Patients and methods:
Patients from six countries treated at 11 centers in Europe and the USA from 1975 to 1996 were evaluated retrospectively. Uni- and multivariate analyses of prognostic variables for survival and for response to chemotherapy were performed.
Results:
Data were available for 635 EGCT patients, 104 with seminomatous and 524 with non-seminomatous EGCT (n = 7 not specified). For non-seminomatous EGCT the following independent adverse factors were identified: presence of either liver, lung or central nervous system metastases, primary mediastinal tumor or elevation of pretreatment ß-human gonadotropin; for extragonadal seminoma (only univariate) adverse factors were: presence of liver metastases, two or greater metastatic sites or International Germ Cell Cancer Collaborative Group (IGCCCG) grouping (intermediate versus good). Integration of these variables produced the following prognostic risk groupings: excellent prognosis, all seminomatous EGCT (89% 5-year survival rate); intermediate low, intermediate high and poor, all non-seminomatous EGCT with a 69, 55 and 17% 5-year survival rate, respectively. The decreased survival among the different groups was due to a lower rate of favorable objective remissions and a higher rate of relapses. Classification and regression tree (CART) modeling confirmed histology and location of primary tumor as the major prognosticators. For the subgroup of patients with mediastinal non-seminoma, the 2-year survival rate ranged from 34 to 84%. Multivariate testing for the probability to respond to chemotherapy revealed non-seminomatous histology, primary mediastinal tumor site, and the presence of liver, lung or CNS metastases as independent adverse factors.
Conclusions:
In EGCT, prognostic variables for the outcome and for the response to chemotherapy could be identified, which in part differ from gonadal GCT. The proposed model might help to better understand the specific prognosis of EGCT and to tailor risk-adapted treatment strategies. In addition, CART analysis demonstrated the heterogenous prognosis of patients with mediastinal non-seminoma.
Key words: chemotherapy, extragonadal germ-cell tumors, mediastinal location, prognostic variables, response, retroperitoneal location
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Introduction |
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Cisplatin-based chemotherapy has demonstrated activity in patients with EGCT and long-term survival rates approach those of patients with advanced-stage metastatic testicular cancer [911]. To better characterize the prognosis of this specific form of disease, a large multicenter database of 635 patients with EGCT has been reviewed. Patients were treated at a time when cisplatin-based chemotherapy was the treatment of choice at 11 cancer centers across six countries in Europe and the USA from 1975 to 1996.
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Patients and methods |
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The contributing centers were internationally recognized for their experience in the treatment of germ-cell tumors: Indiana University, Indianapolis, IN (n = 216; time period 19891996); Institute Gustave-Roussy, Villejuif; Centre Léon-Berard, Lyon; and the Groupe dEtude des Tumeurs Uro-geniales (GETUG), France (n = 93 from these three centers; time period 19751996); Eberhard-Karls University Medical Center II, Tuebingen, Germany (n = 13; time period 19861993); Hannover University Medical School, Hannover, Germany (n = 88; time period 19781995); Norwegian Radium Hospital, Oslo, Norway (n = 48; time period 19801995); Klinikum Großhadern, Munich, Germany (n = 63; time period 19791996); The Royal Marsden Hospital, Sutton, UK (n = 65; time period 19791994); Kaiser-Franz-Josef Spital, Vienna, Austria (n = 19; time period 19751996; and Virchow-Klinikum, Berlin, Germany (n = 30; time period 19871994). A standardized questionnaire was sent to each center and completed by the responsible co-investigator. All patients data were obtained in an anonymous manner. Detailed information on patients characteristics, such as location and histology of the primary tumor; extent of disease including serum tumor marker concentrations of ß-human gonadotropin (ß-HCG), -fetoprotein (AFP) and lactate dehydrogenase (LDH); history of testicular abnormalities; details on diagnostic methods, treatment, response to treatment and follow-up period; and data on secondary testicular cancer and other secondary cancers were acquired. Duration of follow-up and survival in this analysis were calculated based on the date of the first day of treatment until the date of last contact, if the patient was still alive, or the date of death. For all living patients, the status as of August 1998 was verified. Tumor response was classified as follows: complete remission (CR) was defined as a complete disappearance of all clinical, radiological and biochemical evidence of disease with normalization of ß-HCG and/or AFP and/or LDH for at least 1 month. A partial response was defined as a decrease in
50% of the sum of the products of perpendicular diameters of measurable disease lasting for at least 1 month. If elevated markers were the only evidence of disease, a decrease of
90% was required for a partial response. Progressive disease was defined as either residual lesions increasing in size or occurrence of new lesions and/or elevation of tumor markers at repeated controls. Patients who achieved a normalization of tumor markers but an incomplete radiographic response were submitted to postchemotherapy surgery. However, in some patients who had attained serologic complete remission but with persistent minor radiographic abnormalities, individual investigators have chosen to observe such patients without surgery. Those patients were formally coded as partial remissions if their residual abnormalities remained stable or decreased on imaging studies over a 1-year period.
Patients who underwent complete surgical resection of vital carcinoma or mature teratoma were classified as no evidence of disease (NED)carcinoma or NEDteratoma, respectively.
Statistical analysis
All statistical analyses were performed using SPSS for Windows 8.0 (SPSS, Chicago, IL, USA). The overall survival (OS) calculation used death due to any reason as the end point. Various patient characteristics were investigated as potential prognostic factors by univariate analysis, such as: (i) Categorical variables: location of the primary tumor, extent of disease at diagnosis (such as bone, lung, liver, brain and lymph node involvement), age grouping (<20, 2029, 3039, 4049, 50 years of age), tumor marker concentrations at diagnosis (elevated yes/no) or tumor marker grouping (according to the IGCCCG classification) [12], presence of additional metastatic sites, and type of (conventional versus high-dose chemotherapy) and response to first-line treatment (defined as cisplatin sensitive, in case of CR or partial remission (PR) with marker normalization; relative refractory, in case of partial remission without marker normalization or stable disease; absolute refractory, in case of progressive disease during chemotherapy); and (ii) Continuous variables: age and tumor marker concentrations at diagnosis. For survival time, the proportion of survivors was estimated by the KaplanMeier method [13], and the log-rank test was used for comparisons. For ordered categorial variables, the log-rank test for trend was used. A multivariate model was built to evaluate the simultaneous effects of several variables predicting for OS using a stepwise forward selection procedure of the Cox regression. All factors with P <0.05 identified in the proceeding univariate analysis were included in the multivariate analysis [14]. The results of the Cox model were reported with relative risk ratios (hazard ratio, HR) and confidence intervals (CI). In addition, a classification and regression-tree (CART) model was used to explore candidates for further homogenous prognostic subgroups for OS [15]. Advantages of this procedure compared with the proportional hazards model are that the interaction effects can be detected more readily and no prior assumptions need to be made about the form in which distributions of variables should be modeled. For this test, SAS software, version 6.11 (SAS Institute, Cary, NC, USA) was used.
A second end point of this study was to identify predictive factors for response to chemotherapy. Response to treatment was analyzed as a binary variable: patients who achieved a complete or partial remission were considered as responders, and patients with stable disease or progression were considered failures. The proportion of responders was estimated in contingency tables, and the categories were compared using the chi-square test. All factors that presented with a significant or borderline prognostic value were initially included in the Cox regression model [16]. Non-significant factors were subsequently removed. All reported P values were two-sided. The results presented here are based on unadjusted analyses of categorical variables. The final multivariate model were later adjusted by therapeutic regimen. This procedure or the replacement of categorized variables by original variables (tumor marker concentrations at initial diagnosis and at relapse) did not change any conclusion.
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Results |
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The data set contained 104 patients with a pure seminomatous EGCT, which was previously analyzed in detail [17]. The majority [524 patients (83%)] had non-seminomatous EGCT (histology not specified, n = 7). The median age was 37 years (range 1870) for seminoma patients and 29 years (range 1479) for patients with non-seminomatous EGCT.
Two hundred and eighty-seven of 524 non-seminomatous EGCT patients (55%) had a primary mediastinal location. Treatment consisted of chemotherapy in 278 of 287 patients (97%) (for details see Table 1). Additionally, 227 non-seminomatous patients with retroperitoneal location have been included. The majority (n = 223, 98%) has been treated with chemotherapy. Two patients underwent primary resection of retroperitoneal tumor alone (0.9%) (radiation alone, n = 1). Aspects of diagnostic approaches, clinical symptoms, epidemiological data as well as details on treatment of EGCT are reported elsewhere [18].
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Survival
After a median follow-up of 5.1 years (range 1211 months), 12 of 104 seminoma patients (12%) had died. The 5-year OS rate was 88% (Figure 1). For mediastinal non-seminoma the calculated 5-year OS and progression-free survival (PFS) rates were 45% and 44%, respectively. After a median follow-up of 41 months (range 4178 months), 120 patients (42%) had relapsed and 139 of 287 patients (48%) had died. The calculated 5-year OS and PFS rates for patients with retroperitoneal non-seminoma were 62 and 45%. After a median follow-up period of 52 months (range 4203 months) 81 of 227 retroperitoneal non-seminoma patients (36%) had died (Figure 1).
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Multivariate analysis on prognostic factors for survival in EGCT
Classification and regression-tree model (CART) analysis
Primary division of prognostic subgroups was based on histologyseminomatous or non-seminomatous EGCT. Patients with seminomatous histology had a 2-year survival rate of 97% (95% CI 93% to 100%), whereas EGCT patients with non-seminomatous histology had only a 65% 2-year OS rate (95% CI 61% to 70%). Among patients with seminomatous EGCT, no further prognostic subgroups could be identified.
For patients with non-seminomatous histology the next division was performed according to the primary tumor site. Patients with retroperitoneal primaries exhibit a 2-year OS rate of 76% (95% CI 70% to 82%), whereas patients with a primary mediastinal tumor site have a lower chance of cure [2-year OS rate, 57% (95% CI 51% to 63%)]. Interestingly, in this subgroup of patients, further divisions could be determined which lead to survival rates ranging from 34% to 84% at 2 years. Patients with mediastinal germ-cell tumor and presence of visceral metastases achieved the worst 2-year OS rate of 34% (95% CI 17% to 52%). In patients with mediastinal tumor location and absence of visceral metastases [2-year OS rate, 60% (95% CI 54% to 67%)], further subgroups were determined based on the presence of lung metastases, age and serum tumor marker concentration of ß-HCG. For the subgroup of patients 29 years of age with primary mediastinal tumor site having neither visceral metastasis nor lung metastases nor elevated ß-HCG serum values, a favorable outcome of 84% was observed (95% CI 73% to 94%) (Figure 2).
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Discussion |
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Over the past 1520 years several prognostic models have been proposed for patients with metastatic gonadal GCT [2426]. In recent years, the International Germ Cell Cancer Collaborative Group (IGCCCG) classification has replaced these older classifications. One of the major adverse factors identified by the IGCCCG is the presence of a mediastinal primary site in patients with non-seminomatous GCT. Such patients appear to represent a clinically and biologically distinct disease entity [6, 7, 10], associated with lower CR rates, high rates of relapse and failure of salvage chemotherapy [11, 22, 27, 28]. In contrast, patients with mediastinal seminoma prove to have excellent prognosis indistinguishable from that of seminoma patients with bulky metastases and a testicular primary site. In addition, no significant difference in PFS and OS has been demonstrated among patients with primary mediastinal and retroperitoneal seminoma [18]. Patients with mediastinal non-seminomatous EGCT revealed adverse survival rates despite the use of modern cisplatin combination regimens. Retrospective as well as prospective trialsbased on small sample sizesyielded OS rates of 3050% [10, 2022, 2933]. Newer analyses underlined the role of aggressive postchemotherapy surgery [34]. The 284 evaluable patients with primary mediastinal location in the current series had a long-term survival of 48%. However, this detailed analysis demonstrated that this group is composed of patients with heterogeneous prognosis which is dependent on different patient characteristics. Patients, who were of young age, having localized mediastinal disease without elevation of ß-HCG at initial diagnosis revealed a favourable survival chance compared with patients presenting with adverse prognostic variables such as visceral metastases or lung metastases, elevated ß-HCG or being >30 years of age.
The second group of patients with extragonadal non-seminoma comprised patients with retroperitoneal GCT or unknown primary sites with elevated tumor markers. These patients have a prognosis in between mediastinal and testicular primary tumors. But despite this evident difference, the IGCCCG incorporated this group with those patients with a testicular primary site for practical reasons. For these patients, most authors recommend four instead of three cycles of cisplatin-based combination followed by postchemotherapy dissection in the case of residual masses. The 5-year OS for the 227 patients in this series has been determined at 62%. When this subgroup of patients was categorized retrospectively according to the IGCCCG classification, the 5-year OS rates were 59% in the poor prognosis group (expected: 48%) and 61% in the intermediate/good group (expected: 8092%). Taking into account that the serum tumor marker categories used by the IGCCCG were of lower prognostic relevance for EGCT (Table 2) and when the same analysis was performed considering only the variable presence of visceral disease, a significant difference in 5-year OS rates of 16% could be observed between both groups (poor: 50% versus good/intermediate: 66%, P = 0.01). Thus, primary retroperitoneal tumor patients with poor IGCCCG criteria (presence of visceral disease) achieved the expected survival rate, whereas patients with good/intermediate IGCCCG criteria still achieved an inferior outcome compared with patients with gonadal GCT of the same prognostic group.
The identification of prognostic factors in EGCT was primarily limited to the small numbers of patients included in published trials. The current investigation allows for the first time the identification of prognostic factors, due to the large population of EGCT patients included. First, a CART model was used to define a hierarchy of clinical prognostic factors. Histologyseminomatous or non-seminomatoushas been identified as the most important predictor of survival in EGCT. In seminomatous EGCT patients, no further prognostic factors could be identified using both CART and the Cox proportional hazard analysis. For non-seminomatous EGCT, the primary tumor site was the most important predictor according to CART analysis. Subsequently, patients with primary mediastinal tumor could be separated into different subgroups with markedly different OS rates. The Cox proportional hazards model identified the presence of liver, lung or CNS metastases, a primary mediastinal location site and the elevation of ß-HCG as independent factors for OS. The findings that serum tumor marker levels AFP and LDH were less predictive for survival as well as the evidence of lung metastases being relevant for both PFS and OS in non-seminomatous EGCT patients are in contrast to the findings achieved for gonadal GCT patients [13].
Based on the results of the Cox multivariate analysis, prognostic categories for non-seminomatous EGCT patients could be formed using a score that related to the number of risk factors present and to the hazard each risk factor conferred. In these categories, groups of patients with similar response rates and survival were combined. Patients in the poor prognosis category had a significantly lower probability for OS than either intermediate or good prognosis patients. Overall, the differences between these categories were due both to a lower rate of favorable responses and a higher proportion of relapses with increasing score values. In addition, the data set of patients with seminomatous EGCT has been included in the final model. Those patients had an excellent prognosis. The final model consisted of four prognostic categories, excellent (all extragonadal seminomas; overall 17% of patients; 5-year OS rate 89%), intermediate low (extragonadal non-seminomas with a score of 0 or 1; 20% of patients; OS rate 69%), intermediate high (extragonadal non-seminomas with a score of maximum 3; 52% of patients; OS rate 55%) and finally poor (extragonadal non-seminoma with a score >3; 11% of patients; OS rate 17%). Within each prognostic category, we have subsequently tried to examine the influence of different chemotherapeutical treatment regimen on the outcome. However, an unequivocal benefit in terms of increased response rate or improved OS could not be demonstrated.
The multivariate analysis on prognostic factors associated with refractoriness to therapy revealed non-seminomatous histology as the most relevant factor. With the exception of the tumor marker ß-HCG, all other variablespresence of lung, CNS or liver metastases, as well as mediastinal tumor locationhave also been identified to be of prognostic relevance for OS.
In summary, this analysis demonstrates that the prognosis of EGCT patients is in general heterogeneous. Patients with seminomatous histology possess an excellent prognosis comparable to those with metastatic gonadal seminoma, confirming the classification of these patients as proposed by the IGCCCG. For non-seminomatous EGCT, relevant prognostic risk factors have been identified confirming that the outcome of EGCT patients, as suggested earlier, differs from that of gonadal GCT patients even when patients with otherwise similar prognostic characteristics are compared. The knowledge of specific prognostic factors as provided by CART analysis and the Cox proportional model, might help to tailor treatment options in the future considering the individual risk for those patients. The prognosis of mediastinal non-seminoma is worse compared with other subgroups of EGCT; however, patients with localized disease have a substantial chance of cure with the use of modern cisplatin-based combination chemotherapy combined with aggressive surgery.
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Acknowledgements |
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Footnotes |
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