Japanese Journal of Clinical Oncology Advance Access originally published online on November 2, 2006
Japanese Journal of Clinical Oncology 2006 36(11):723-730; doi:10.1093/jjco/hyl102
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© 2006 Foundation for Promotion of Cancer Research
Treatment Outcome of Metastatic Testicular Cancer at a Single Institution in Japan, a Country with Low Incidence of Germ Cell Tumor
1 Department of Urology
2 Department of Hematology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan
For reprints and all correspondence: Koji Kawai, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki 305, Japan. E-mail: rkawa{at}md.tsukuba.ac.jp
Received May 2, 2006; accepted July 12, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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BACKGROUND: Incidence of testicular cancer is low in Japan. Recent investigations showed that the outcome of metastatic testicular cancer is associated with the experience of the treatment institution. Objectives of the present investigation are to evaluate outcome of a single institution in Japan, and to identify prognostic factors for testicular cancer.
METHODS: We retrospectively analysed the outcome of 74 patients with metastatic testicular cancer who were treated at Tsukuba University Hospital (TUH) between January 1981 and January 2003. Forty-five patients (61%) were referred to the TUH for the treatment of metastatic disease. The progression-free survival (PFS) rates according to the International Germ Cell Cancer (IGCC) classification and the Indiana University classification were used to evaluate the treatment outcome.
RESULTS: The median follow-up period of all patients was 87 months (range, 13–260 months). Forty patients (54%) were classified as having good prognosis, 20 (27%) intermediate, and 14 (19%) poor. The overall 5- and 10-year PFS was 79 and 74%, respectively. The 5-year PFS with good, intermediate and poor prognosis was 90, 70 and 64%, respectively. There was a significant difference between the three groups (P=0.02), but the survival of the intermediate-prognosis group was not statistically different from that of the poor-prognosis group. The Indiana University classification failed to discriminate the prognoses of moderate and advanced disease, but proved to be an independent prognostic factor for progression-free survival in intermediate- and poor-prognosis patients (P=0.025, hazard ratio=5.39).
CONCLUSIONS: Our treatment outcome is not different from that of the institutions participating in the International Germ Cell Cancer Consensus Group (IGCCCG).
Key Words: testicular cancer • IGCCCG classification • Indiana University classification • chemotherapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Testicular cancer is the most common neoplasm in young males. The treatment outcome of metastatic testicular cancer has improved substantially since the late 1970s. The improved treatment outcome has led to the need to stratify the patients with metastatic disease by prognosis. Because differences among prognostic classification systems make it difficult to compare results of clinical trials, the International Germ Cell Cancer Consensus Group (IGCCCG) published a consensus prognostic index for metastatic germ cell cancers in 1997 (1). The IGCC classification, which uses the risk factors of primary site and presence of non-pulmonary visceral metastases, and the tumor markers human chorionic gonadotrophin (hCG), alpha-fetoprotein (AFP), and lactic dehydrogenase (LDH), is easy to use and widely applied. The classification is simple and highly reproducible, and therefore it is useful in the evaluation of the treatment activity of treatment institutions.
Although an increasing tendency is noted, the incidence of testicular cancer in Japan is much lower than in western countries (2,3). Japanese cancer registration data revealed that the annual incidence rate (per 1000000 men) for testicular cancer was 1.4–1.8 (4,5). The incidence of extra-gonadal germ cell tumor is extremely rare. In Japan, which has a population of 120 million people, only 50 patients with newly diagnosed mediastinal malignant germ cell tumor were operated on in 1073 institutions nationwide in 2001 (6). Therefore, there are few specialized centers with high volume experience in comparison with Western countries. Most of the advanced testicular cancer patients are treated in university hospital- or regional cancer center-based urological oncology units, but not in highly specialized centers; therefore, it is critically important to test the treatment activity of each institution.
Recently, several investigations showed that treatment outcome of metastatic germ cell tumor is directly associated with the cumulative experience of the treatment institution (7,8). It has been suggested that a critical number of patients is needed to develop and maintain the experience within a single institution. At our institution, 5–10 new testicular cancer patients were treated each year. The number of patients is relatively small in comparison with that of western countries; however, over half of the patients have metastatic disease. This is due to the referral pattern of community hospitals to our institute. Since the early 1990s, we have recommended that community hospitals refer advanced cases to our hospital.
The objectives of the present investigation are to evaluate outcome of patients with metastatic testicular cancer treated in a single institution in Japan and to identify prognostic factors for testicular cancer. The progression-free survival (PFS) rates according to the IGCC classification and also the Indiana University classification (9) were used to evaluate the treatment outcome. This investigation is one of the largest series for single-institute experience in treatment of metastatic testicular cancer in Japan (10,11).
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Patients
A total of 134 testicular cancer patients were treated at Tsukuba University Hospital (TUH) between January 1981 and January 2003. Of these, 68 patients had metastatic disease at initial diagnosis. The remaining 66 patients were diagnosed with Stage I disease. Eight had a relapse with metastasis after initial management. Six patients had a relapse after surveillance protocol for non-seminomatous germ cell tumor (NSGCT), and two after adjuvant para-aortic radiation therapy for seminoma. Except for two patients, a total of 74 with metastases were treated in the TUH for metastatic disease. Forty-five of 74 patients (61%) were initially diagnosed at the community hospitals and referred to the TUH for treatment of metastatic disease. They consisted of 48 patients with NSGCT and 26 with seminoma. The median age at diagnosis was 31.5 years (range, 18–73 years). The median follow-up period was 87 months (range, 13–260 months). Pre-treatment staging consisted of physical examination, serum tumor marker levels and radiological examination. Patients were classified into the relevant prognostic category in accordance with the IGCC classification and also the Indiana University classification. The characteristics of the 74 patients are summarized in Table 1. The primary endpoints of this study were cause-specific survival and the PFS.
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Treatment
During the 1981–1989 period, all patients except one received PVB protocol consisting of cisplatin, vinblastine and bleomycin as the first-line treatment (12). The remaining one patient received vinblastine, actinomycin D, bleomycin, cyclophosphamide and cisplatin (VAB-6) (13). In the late 1980s, etoposide became available in Japan and therefore the BEP protocol consisting of bleomycin, etoposide and cisplatin was introduced as the first-line chemotherapy in high-risk-prognosis patients (14). Thereafter, since the mid 1990s, the BEP regimen became the first-line chemotherapy for all patients. One patient who had complications with pulmonary embolism received the VIP regimen (etoposide, ifosfamide and cisplatin) (15) instead of the BEP regimen. Up to 1991, our first-line salvage protocol for the refractory or relapsed case was the VIP or VeIP (vinblastine, ifosfamide and cisplatin) regimen (16). Since 1992, we began to treat the refractory or relapsed case with high-dose chemotherapy (HDCT) combined with peripheral blood stem cell support (17,18). In addition to HDCT, the TIP regimen consisting of paclitaxel, ifosfamide and cisplatin was recently adopted as salvage chemotherapy or as a part of induction chemotherapy for poor-risk patients having an incomplete response to the BEP therapy (19,20). The chemotherapy regimens used in salvage therapies are summarized in Table 1 (21–24).
Principally, the patients underwent surgical resection of residual operable masses when all tumor markers normalized with chemotherapy. After the introduction of BEP regimen, some patients with adequately responding retroperitoneal lymph node (RPLN) mass (less than 3cm in diameter in seminoma patients and less than 1cm in diameter in NSGCT patients without teratomatous element) were excluded from surgery and followed up closely. Consequently, 44 patients (59%) underwent post-chemotherapeutic surgery. The retroperitoneal lymph node dissection and thoracotomy were the most common procedures, as shown in Table 1. Additionally, six patients underwent salvage surgery under tumor marker-positive and chemorefractory conditions.
Evaluation of Response and Follow-up
The best responses to initial treatment with first-line chemotherapy or supplementary cycles of salvage chemotherapy were evaluated in accordance with the standard Memorial Sloan–Kettering Cancer Center response criteria (25). Response was categorized as either a complete response (CR) or incomplete response (IR). CR to chemotherapy alone was defined as complete disappearance of all clinical, radiographic and biochemical findings of testicular cancer after either chemotherapy alone or chemotherapy and surgical resection of residual tumor with the pathologic analysis revealing only necrotic debris, fibrosis, or mature teratoma. CR to chemotherapy plus surgery required complete resection of a post-chemotherapy tumor mass with viable malignant germ cell tumor (other than teratoma) in 1 or more specimens and negative markers and margins. All responses less than CR were considered IR. The treatment outcome measures were cause-specific survival and PFS. In the cause-specific survival analysis, deaths that were not caused by testicular cancer or its treatment were considered censoring events. Recurrence was defined by rising tumor marker values or development of new or enlarging metastases on radiological examinations. Patients with residual masses who did not undergo post-chemotherapy surgery were included in PFS analysis, if masses were further regressed with normalized tumor markers.
Statistical Analysis
Survival curves were estimated by the Kaplan–Meier method and compared using a log-rank test. The level of significance was set at P<0.05. The relative influence of different prognostic factors on survival was estimated using Cox's proportional hazards model with multiple variables. We enlisted a purposeful selection of variables in the analysis, used a P value of <0.05 and excluded variables that were not statistically significant. Statistical analysis was performed using JMP software (version 5.1; SAS Institute Inc., Cary, NC) (26), and Microsoft Excel (Microsoft Corp., Redmond, WA) was employed for graphic presentation.
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RESULTS |
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Responses to Treatment
The best responses to the initial treatment are summarized in Table 1. Overall, 59 patients (80%) achieved CR: 47 achieved a CR to chemotherapy alone and 12 to chemotherapy plus surgery. Of the 12 patients, 11 received additional adjuvant chemotherapy after surgery. Of the 59 CR patients, six (10%) relapsed after CR and required salvage treatments. Of them, four patients had a late relapse, which was defined as a recurrence of disease after a more than 2-year remission interval. Currently, five of the six patients are alive with no evidence of disease after salvage therapy. Of 15 patients who were classified as IR, 12 subsequently suffered from disease progression and nine died of cancer. Of the remaining three IR patients, two had unresectable residual mass after marker normalization. One patient was treated with hepatic arterial cisplatin infusion for residual liver metastasis and another patient received radiation therapy for RPLN mass. Both patients are free from progression. The other IR patient, who had refused treatment during first-line chemotherapy, achieved long-term remission.
Overall, 10 patients died of testicular cancer: nine progressed from IR and the remaining one suffered from late relapse after CR. There were two treatment-related deaths, one resulting from bleomycin-induced pulmonary toxicity after four courses of PVB and the other from acute cardiovascular collapse during VIP. Two patients died of other diseases: one, who was in remission for 7 years, developed fatal necrotizing fasciitis complicated by streptococcus toxic shock syndrome (27); the other died of acute thoracic aortic dissection after a 7-year disease remission. One patient developed leukemia with typical etoposide-associated karyotype at 13 months after chemotherapy with BEP and TIP regimens. The patient is currently in remission of both leukemia and testicular cancer. Another patient had acute myocardial infarction (AMI) at 13 years after the termination of treatment for testicular cancer. The patient successfully recovered.
Prognostic Grouping and Survival
The overall 5- and 10-year cause-specific survival rates were both 84%, as shown in Fig. 1. The overall 5- and 10-year PFS was 79 and 74%, respectively (Fig. 1). The 5-year PFS of NSGCT patients and seminoma patients was 77 and 85%, respectively; the difference was not significant (P=0.19). Figure 2 represents the PFS according to IGCC classification. Forty patients (54%) were classified as having good prognosis, 20 (27%) intermediate and 14 (19%) poor. The patients classified into the good-prognosis group had a 5-year PFS of 90%, while the intermediate- and poor-prognosis groups had 5-year PFS of 70 and 64%, respectively. There was a statistically significant difference between the three groups (P=0.02). However, the survival of the intermediate-prognosis group was not statistically different from that of the poor-prognosis group. When the Indiana University classification was applied, 40 patients (54%) were classified as having minimal disease, 11 (15%) as having moderate disease and 23 (31%) as having advanced disease. The 5-year PFS of the minimal, moderate and advanced disease was 92, 64 and 65%, respectively. Again, the difference was significant among the three groups (P=0.04); however, there was no difference in survival rate between the moderate and advanced disease groups. Therefore, both prognostic classification systems efficiently discriminate the good (minimal) group from high-risk groups. However, they were considered not to be efficient tools for discrimination of the intermediate (moderate) group and poor (advanced) group in the case of germ cell tumor of testicular (but not extra-gonadal) origin.
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Prognostic Factors of Intermediate- or Poor-Prognosis Patients
To identify the prognostic factors of 34 testicular germ cell tumor patients classified into the intermediate- or poor-prognosis group by the IGCC classification, we evaluated seven prognostic variables. These were the Indiana University Classification category (minimal, moderate or advanced disease), histology of primary site (seminoma, NSGCT), presence of teratoma or choriocarcinoma elements at the primary site (present, absent), diameter of RPLN mass (<10cm,
10cm), number of lung metastases (<10 metastases in both lung fields, 10 metastases in both lung fields), presence of non-pulmonary visceral metastases (present, absent) and induction chemotherapy protocol (BEP, other than BEP). Each potential prognostic predictor was examined in univariate analyses using Kaplan–Meier plots of progression-free survival, and subgroups of patients were compared using a log-rank test. As shown in Table 2, the 5-year PFS of patients classified as having minimal disease by the Indiana University classification was some what higher than those of moderate and advanced disease, but the difference was not significant. The other variables were also not significant predictors. On the basis of the results of univariate analysis, we performed a multivariate Cox's proportional hazards analysis using the Indiana University classification, the presence of teratoma and/or choriocarcinoma elements and the induction chemotherapy protocol. The results indicated that the Indiana University classification was an independent prognostic factor for progression-free survival (P=0.025, hazard ratio=5.39) (Table 3). The hazard ratio of presence of teratoma and/or choriocarcinoma elements was 1.70 (95% confidence interval: 0.93–3.35), but it was not found to be a significant independent prognostic factor (P=0.09). In addition, the induction chemotherapy was not an independent risk factor in this analysis (P=0.103). The other variables investigated in this model were not statistically significant.
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The results of multivariate analysis suggest that the estimation of the volume of metastases might be a practical method for individualization of testicular cancer management, especially for patients in the intermediate-prognosis group. In the present investigation, seven of the 20 intermediate-prognosis patients were classified as having minimal disease by the Indiana University classification. The metastases of these patients were generally limited to non-bulky RPLN. The increased tumor markers were AFP and LDH, but not hCG. With the favorable clinical features, all patients achieved CR with the standard induction chemotherapy and surgery: six are free from disease progression; and the remaining one received salvage chemotherapy for late relapse (10 years after initial CR) and currently presents no evidence of disease. Of the remaining 13 patients with intermediate prognosis, four and nine were classified as having moderate and advanced disease by the Indiana University classification, respectively. Disease progression after initial treatment was observed in seven of the 13 patients; ultimately four died of disease. As expected, 12 of 14 patients with poor prognosis were classified as having moderate or advanced disease.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The present retrospective review of patient care shows that outcome of patients with metastatic testicular cancer at this single Japanese university hospital is not different from that of the institutions which participated in IGCCCG. In metastatic germ cell tumor, there is increasing evidence suggesting that institutional experience of chemotherapy is associated with treatment outcome. However, there is some controversy as to the critical number of patients that is needed to allow expertise to accumulate (7, 8,28). Harding et al. suggested that 10–15 new patients each year might be a reasonable estimate (7). Collette et al. reported a poorer outcome in institutions entering fewer than five patients in clinical trial for ‘poor-prognosis’ germ cell tumor, as compared with institutions entering five or more patients (8). The trial recruited 380 advanced germ cell tumor patients over a 4-year period. According to the IGCC classification, 65% of the patients were classified as having poor prognosis and 32% as having intermediate prognosis. Indeed, the total number of patients was relatively small in our hospital. In recent years, however, the number of patients with metastatic disease has been increasing. We have treated 44 patients with metastatic disease over the past 12 years, during the latter half of this investigation. Of these, 20 patients were classified as having intermediate or poor prognosis. This is due to the referral pattern of community hospitals to our institute. We have recommended that community hospitals refer advanced cases to our hospital.
It is likely that the introduction of BEP together with the cumulative treatment experience contributes to the improvement of treatment outcome particularly in poor-prognosis cases. In the present investigation, three of six patients with poor-prognosis achieved durable remission with PVB therapy; in contrast, six of eight patients initially treated with BEP achieved durable remission (statistically not significant). Several investigations by single institutional analysis conducted during the cisplatin era, including those from Japan (11,29,30), reported similar improvement in treatment outcome.
Our data confirms that IGCC classification clearly discriminates good-prognosis cases among metastatic testicular tumor patients. In contrast, the survival of the intermediate-prognosis group was not statistically different from that of the poor-prognosis group. The 5-year PFS of the intermediate- and poor-prognosis groups was 70 and 64%, respectively. The prognosis of the poor-prognosis group was somewhat better than the original IGCC data: the 5-year PFS was 42%. This is partly due to the lack of extra-gonadal cases in the present analysis, because of our limited experience with the disease. Kollmannsberger et al. reported unfavorable outcome for the mediastinal-primary case compared with the gonadal-primary poor-prognosis case (31). In their analysis, 2-year PFS of gonadal or retroperitoneal-primary cases was 63%, while that of the mediastinal-primary cases was 49%. It is certain that the IGCC classification is a simple and valid way to classify patients with whole germ cell tumor into three prognostic groups. A recent review with Cox regression and recursive partitioning also supports the usefulness of the IGCC classification (32). However, in testicular-primary germ cell tumor, a more flexible methodology appears to allow more accurate estimation of each patient's individual prognosis.
We therefore evaluated several other variables to identify prognostic factors for 34 testicular germ cell tumor patients classified into intermediate- or poor-prognosis groups by the IGCC classification. Although univariate analysis failed to identify a significant predictor, multivariate analysis revealed that the Indiana University classification was an independent prognostic factor for progression-free survival. The patients subgrouped as having moderate or advanced disease had a significantly higher risk for disease progression compared with patients subgrouped as having minimal disease (P=0.025, hazard ratio=5.39) (Table 3). In this investigation, it cannot be clarified why Indiana University classification was useful to separate intermediate- or poor-prognosis patients according the IGCC classification. However, there is a possibility that size and number of metastases might become additional information especially in separating intermediate-risk patients. Indeed, the intermediate-risk patients with low volume metastases appeared to have a favorable prognosis. All seven intermediate-risk patients subgrouped as having minimal disease by the Indiana University classification achieved CR with standard induction chemotherapy and surgery. In contrast, the prognosis of the intermediate subgroup having high volume metastases (moderate or advanced disease) was unfavorable. Four of 13 patients in this subgroup ultimately died of cancer. These findings suggest that the estimation of the volume of metastases might be a practical method for individualization of the management of intermediate-risk patients.
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References |
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