Japanese Journal of Clinical Oncology Advance Access originally published online on March 4, 2008
Japanese Journal of Clinical Oncology 2008 38(4):281-287; doi:10.1093/jjco/hyn009
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© The Author (2008). Published by Oxford University Press. All rights reserved
Survival of Metastatic Germ Cell Cancer Patients Assessed by International Germ Cell Consensus Classification in Japan
1 Department of Urology, Tohoku University Graduate School of Medicine, Sendai
2 Urology Division, National Cancer Center Hospital, Tokyo
3 Department of Urology, Kyoto University Graduate School of Medicine, Kyoto
4 Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba
5 Department of Urology, Sapporo Medical University School of Medicine, Sapporo
6 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
7 Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan
For reprints and all correspondence: Yoichi Arai, Department of Urology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. E-mail: yarai{at}uro.med.tohoku.ac.jp
Received December 2, 2007; accepted January 29, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendix: List of Other...References |
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Background: As a risk classification system of metastatic germ cell tumors, the International Germ Cell Consensus (IGCC) classification was proposed in 1997 and has received broad approval. Since the IGCC classification was based on patients treated between 1975 and 1990, we aimed to investigate whether survival has improved for more recently treated Japanese patients.
Methods: We analyzed 296 patients with metastatic germ cell tumors treated at seven hospitals in Japan between 1990 and 2001. These cases are classified as good, intermediate or poor prognosis groups by the IGCC classification. The 5-year progression-free and the 5-year overall survivals were calculated for each prognosis group.
Results: The median follow-up period of all patients was 53 months. In 227 non-seminomatous germ cell tumor cases, the 5-year progression-free survival (95% confidence interval) for good (n = 55), intermediate (n = 106) and poor (n = 66) prognosis was 96% (91–100), 71% (62–80) and 52% (39–65) (P < 0.001), respectively. The 5-year overall survival was 94% (88–100), 81% (73–89) and 61% (49–73) (P < 0.001), respectively. In 69 seminoma cases, the 5-year progression-free survival for good (n = 64) and intermediate (n = 5) prognosis was 78% (67–89) and 80% (45–100) (P = 0.98), respectively. The 5-year overall survival was 90% (82–99) and 80% (45–100) (P = 0.49), respectively.
Conclusions: There was a trend of increase in survival for any risk groups and, in particular, large increase in survival for patients with a poor prognosis. This increase is most likely attributed to more effective chemotherapy regimens and more extensive care in the experienced institutes.
Key Words: chemotherapy • etoposide • IGCC classification • prognosis • germ cell tumor
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendix: List of Other...References |
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Since the introduction of cisplatin-based chemotherapy in the 1970s, long-term cure rates of patients with metastatic germ cell tumors have increased up to 80% (1). Progress in cancer chemotherapy regimens such as etoposide, granulocyte-colony stimulating factor (G-CSF) and high-dose chemotherapy with stem cell support have also positively affected cure rates. To further improve treatment outcome, patients with a poor prognosis should be identified at initial diagnosis and treated with a more intensive strategy. The International Germ Cell Consensus (IGCC) classification that was proposed in 1997 has received broad approval as a means of stratifying risk groups (2).
The IGCC classification reviewed germ cell tumors with metastasis in over 5000 patients treated between 1975 and 1990 in 10 European and American countries. However, treatment approaches have changed since the 1990s: such as the BEP regimen (3) as standard first line chemotherapy and the use of G-CSF. Therefore, treatment outcome should be substantially improved among those treated in 1990 or later. We analyzed 296 patients with metastatic germ cell tumors who underwent treatment at seven hospitals in Japan between 1990 and 2001 and assessed whether survival has improved according to the IGCC classification in comparison with that by International Germ Cell Cancer Collaborative Group (IGCCCG).
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PATIENTS AND METHODS |
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The study included 296 men admitted to seven hospitals in Japan, National Cancer Center Hospital, Tohoku University Hospital, Kyoto University Hospital, Tsukuba University Hospital, Sapporo Medical University Hospital, Kyushu University Hospital and Kyoto Prefectural University Hospital, between 1990 and 2001. There were 286 patients with metastatic testicular tumor and 10 with extragonadal germ cell tumors (EGCT).
Of the 286 testicular tumor patients, 279 were treated with high orchiectomy and chemotherapy, and three were treated with chemotherapy without orchiectomy. Four were treated with high orchiectomy, but died before chemotherapy. The 10 cases with EGCT were treated with chemotherapy. Most patients received platinum-based primary combination chemotherapy. A total of 141 patients had post-chemotherapy residual tumor excised surgically. Fifteen patients received additional radiation therapy.
As first line chemotherapy for 292 patients, 127 (43%) were treated by BEP (bleomycin, etoposide and cisplatin) or PEP (peplomycin, etoposide and cisplatin), 72 (25%) by EP (etoposide and cisplatin), 52 (18%) by PVB (cisplatin, vinblastine and bleomycin) or PVP (cisplatin, vinblastine and peplomycin), 15 (5%) by VAB-6 (vinblastine, actinomycin D, bleomycin, cyclophosphamide and cisplatin), 5 (2%) by VIP (etoposide, ifosfamide and cisplatin) or VeIP (vinblastine, ifosfamide and cisplatin), and 14 (5%) by other chemotherapy. Thus, 206 (71%) received first line chemotherapy containing etoposide.
Comparisons of different groups were made using the Student's t-test or the Kruskal–Wallis test for continuous variables and the 
2 test for categorical variables. Disease progression-free survival and overall survivals were estimated by Kaplan and Meier plots and stratified by IGCC classification. Differences of survivals between groups were tested using the log-rank test. P value <0.05 were considered statistically significant.
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RESULTS |
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Patient age ranged from 16 to 73 years (median 30 years and mean 31.7 years). The median follow-up time was 53 months, ranging from 0 to 169 months (Table 1). Among the 10 cases with EGCT, three had mediastinal primary disease and seven had retroperitoneal primary disease.
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Non-Seminomatous Germ Cell Tumor
There were 227 patients with non-seminomatous germ cell tumor (NSGCT) and their ages ranged from 16 to 65 years (median 28 years and mean 29.9 years). Main histology was embryonal carcinoma (40%), teratoma (15%), seminoma (15%), yolk sac tumor (11%) and choriocarcinoma (8%). According to the IGCC classification, 55 (24%) were classified as good prognosis group, 106 (47%) as intermediate prognosis and 66 (29%) as poor prognosis. The median follow-up time was 50 months, ranging from 0 to 169 months from the initiation of treatment (Table 1). Disease progression occurred in 67 (30%) patients, 45 (20%) died of disease and 3 (1%) died of other disease. In the 67 patients with disease progression, the period of relapse was 0 month (no complete response) in 19 (28%) patients, 1–12 month in 23 (34%), 13–24 month in 10 (15%), 25–36 month in 3 (5%), 37–60 month in 4 (6%) and more than 60 month in 3 (5%).
Table 2 lists clinical and pathological features in the three groups of NSGCT patients. There was no statistically significant difference among the three groups in primary tumor site, T classification or main histology. There was statistically significant difference in AFP (P < 0.001), HCG (P < 0.001), LDH (P < 0.001), N classification (P = 0.002), M classification (P < 0.001) and first line chemotherapy (P = 0.047).
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The 5-year progression-free survival and overall survival (95% confidence interval) were, respectively, 96% (91–100) and 94% (88–100) for the good prognosis group, 71% (62–80) and 81% (73–89) for the intermediate prognosis, and 52% (39–65) and 61% (49–73) for the poor prognosis (Fig. 1). There was statistically significant difference both in progression-free and overall survivals among the three groups (P < 0.001).
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Seminoma
The ages of seminoma patients were between 22 and 73 years (median 36 years and mean 37.4 years). Of the 69 patients with seminomatous tumors, 64 (93%) were classified as good prognosis group and 5 (7%) as intermediate prognosis. The median follow-up time was 57 months from the start of treatment. Disease progression occurred in 14 (20%) patients, 6 (9%) died of disease and 1 (1%) died of other disease. In the 14 patients with disease progression, the period of relapse was 0 month (no complete response) in 2 (14%) patients, 1–12 month in 10 (72%) and 25–36 month in 2 (14%).
Table 3 lists clinical and pathological features in the two groups of seminoma patients. There was no statistically significant difference between the two groups in primary tumor site, T classification or first line chemotherapy. There was statistically significant difference in N classification (P = 0.044) and M classification (P < 0.001).
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There was no statistically significant difference in progression-free survival between the good and intermediate prognosis groups (P = 0.982): 5-year progression-free survival (95% confidence interval) of 78% (67–89) and 80% (45–100), respectively (Fig. 2). The 5-year overall survivals were 90% (82–99) and 80% (45–100), respectively, with no statistically significant difference (P = 0.490).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendix: List of Other...References |
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Current surgical remedies combined with chemotherapy using the BEP regimen can cure 80% of all metastatic germ cell tumors (3). This strategy gained widespread acceptance in the late 1980s. In addition, to reduce the side effect of lung toxicity, peplomycin are sometimes administered instead of bleomycin in Japan. For subsequent relapses or tumors that persist despite BEP therapy, the effects of ifosfamide, paclitaxel and more recently, gemcitabine and irinotecan, are being confirmed (4).
The pre-therapeutic prognosis of relapses and persistent disease is gaining greater importance since physicians can devise more effective initial therapeutic strategies. Several traditional classification methodologies have been proposed, as typified by the Indiana classification. Each had advantages and disadvantages, and a universal classification method has not been established. Against this background, the IGCC classification was proposed based on 5202 prognostic analyses of metastatic germ cell cancers conducted in Europe and North America (2).
In Japan, some prognostic analyses of metastatic germ cell cancers have been attempted at several institutions (5), but not using the IGCC classifications for large numbers of patients. We therefore investigated the applicability of the IGCC classification to Japanese patients with metastatic germ cell tumors in a multi-institutional study.
The risk distributions of patients with seminoma were almost identical between the IGCCCG report and the present study. However, fewer NSGCT patients had a good prognosis and more had an intermediate to poor prognosis in the present study than in the IGCCCG report. Whereas the IGCCCG study consisted of 56%, 28% and 16% groups with a good, intermediate and poor prognosis, respectively, the prognostic distribution of our patients was 24%, 47% and 29%, respectively. These figures suggest that fewer testicular tumors are diagnosed early in Japan compared with those in Europe and North America. In addition, whereas the ratios of EGCT patients in the IGCCCG report were 13% of seminoma patients and 6% of non-seminoma patients, our study included 1% and 4%, respectively, of such patients. Furthermore, our series had only 3 (1%) patients with mediastinal primary tumor, whereas the original IGCCCG report had 3% of such cases. The improved survival of the poor risk group may be partly attributable to this lower percentage of EGCT, especially to the fewer cases of mediastinal primary tumor.
The IGCCCG and the present reports do not significantly differ that the group with seminoma had a good prognosis. However, 5-year progression-free survival values were better for our patients with an intermediate prognosis than those of such patients described in the IGCCCG report (80% versus 67%; Table 4). We did not identify any significant difference in prognosis between the groups with good and intermediate prognoses. Although our study included relatively fewer patients, the prognosis of those with seminoma requires further study, including an analysis of other prognostic factors and parameters.
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The prognosis of all prognostic groups of NSGCT patients was better in the present study than in the IGCCCG report. The present study showed that 5-year progression-free and overall survival rates for the good prognosis group was 96% and 94%, respectively, whereas IGCCCG study found 89% and 92%, respectively. Similarly for the poor prognosis group, these values were, respectively, 52% and 61% in the current study, and 41% and 48% in the IGCCCG report (Table 4).
Our patients seemed to have a better overall prognosis than those in the IGCCCG report. Several reasons might account for this. Firstly, etoposide became available in Japan during 1987 and BEP became the first line chemotherapy thereafter. Second, G-CSF became available in Japan during 1991 and its use has allowed chemotherapy to continue without extending the dosage interval. Furthermore, experienced urologists usually diagnose, administer chemotherapy, excise post-chemotherapy residual mass and perform post-treatment follow-up in Japan. These might be partly involved in the improved survival of our patients. In this study there was a significant difference in the first line chemotherapy for NSGCT, but the reason is not clarified because this is a multi-institutional retrospective study.
Whereas the IGCCCG report described patients in Europe and North America between 1975 and 1990, we considered patients treated between 1990 and 2001. That is, approximately 40% of the patients described in the IGCCCG report were treated before the widespread use of BEP. Currently available treatments for germ cell cancers are more effective than those administered at the time of the IGCCCG report. Einhorn (6) reported that the survival of patients with a ‘poor’ prognosis treated with BEP in 2002 was 10% higher than that of corresponding patients in the IGCCCG report. Muramaki et al. (7) reported that the 5-year overall survival of NSGCT patients significantly increased from 72.8% during 1978–1989, to 83.6% during 1990–2001. Similarly, a meta-analysis of NSGCT patients treated after 1989 indicated that the 5-year survival for good (n = 1087), intermediate (n = 232) and poor (n = 456) prognosis groups was 94%, 83% and 71%, respectively, and that the survival of patients with a poor prognosis increased remarkably (8). Therefore, the prognosis of NSGCT patients with a ‘poor’ prognosis considerably differs between now and before 1989. Compared with before 1989, more patients with a serious general status and major metastasis can be saved using appropriate chemotherapy. This progress might be reflected in the statistical data.
To target intensive treatment strategies for patients with a very poor prognosis, subgroups of such patients have been identified among those with a poor prognosis. Mazumdar et al. (9) identified the rate at which the tumor markers of human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) decline during the first two cycles of chemotherapy as an important risk factor, especially in patients with a poor prognosis. Kollmannsberger et al. (10) developed a regression tree using visceral metastasis, primary site and abdominal mass as risk factors for patients with a poor prognosis. This tree classified five subgroups that differed in terms of 2-year survival ranging from 49% to 84%. Using a similar tree procedure, Dijk et al. (11) developed a new tree using number of metastases, primary site, abdominal mass and lung metastasis as risk factors for patients with a poor prognosis from IGCCCG database. This tree classified five subgroups that differed in terms of 2-year survival ranging from 38% to 73%.
In summary, we investigated the survival of metastatic germ cell tumor patients treated between 1990 and 2001 in Japan based on the IGCC classification. Survival tended to increase for any risk group, and significantly increased among patients with a poor prognosis. This increase is most likely attributable to more effective chemotherapy regimens and more extensive care at institutions where staff had accumulated much experience with such patients. The IGCC classification is a useful criterion enabling to distinguish NSGCT patients according to prognosis. To target intensive treatment strategies for patients with a very poor prognosis, other prognostic factors must be identified that will detect the real stage of patients with a poor prognosis at the time of initial diagnosis.
Conflict of interest statement
None declared.
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Appendix: List of Other Authors |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendix: List of Other...References |
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Hideo Saito (Tohoku University), Takashi Kobayashi (Kyoto University), Hiroshi Kitamura (Sapporo Medical University), Masahiko Harano (Kyushu University), Youichi Mizutani (Kyoto Prefectural University).
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendix: List of Other...References |
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7 Muramaki M, Hara I, Miyake H, Yamada Y, Kawabata G, Kamidono S. Advances in the management of non-seminomatous germ cell tumors during the cisplatin era: a single-institution experience. Int J Urol (2004) 11:768–73.[CrossRef][Web of Science][Medline]
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9 Mazumdar M, Bajorin DF, Bacik J, Higgins G, Motzer RJ, Bosl GJ. Predicting outcome to chemotherapy in patients with germ cell tumors: the value of the rate of decline of human chorionic gonadotrophin and alpha-fetoprotein during therapy. J Clin Oncol (2001) 19:2534–41.
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