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ORIGINAL ARTICLE
Year : 2007  |  Volume : 44  |  Issue : 1  |  Page : 6-11
 

Outcome of patients with stage II and III nonseminomatous germ cell tumors: Results of a single center


1 Gulhane Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey
2 Gulhane Faculty of Medicine, Department of Epidemiology, Ankara, Turkey
3 Gulhane Faculty of Medicine, Department of Radiation Oncology, Ankara, Turkey

Correspondence Address:
S Ataergin
Gulhane Faculty of Medicine, Department of Medical Oncology, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.31161

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 » Abstract 

Background: The prognostic factors in nonseminomatous germ cell tumors have been mainly derived from the analysis of stage I tumors. Aims: The aim of this study was to evaluate some prognostic factors and the outcome of patients with stage II and III nonseminomatous germ cell tumors according to risk groups treated between 1993 and 2002. Settings and Design: Patients were retrospectively classified as good, intermediate and poor risk groups according to International Germ Cell Cancer Consensus Group. Materials and Methods: Biopsy specimens of 58 patients with stage II and III nonseminomatous germ cell tumors were analyzed by means of tumor histopathology, primary localization site of the tumor, relapse sites, initial serum tumor marker levels, the presence of persistent serum tumor marker elevation and the patients' outcome. Statistical Analysis :0 Kruskall Wallis test and Mann-Whitney U test were used to determine the differences between the groups. Kaplan-Meier method was used for survival analysis and log rank test was used to compare the survival probabilities of groups. Cox proportional hazard analysis was used to determine the prognostic factors in univariate and multivariate analysis. Results: Five-year overall and disease-free survival rates were calculated as 85% and 75% in stage II; 44% and 29% in stage III cases, respectively. Fifty-seven percent of patients were classified in good risk, 9% in intermediate risk and 27% in poor risk groups. Five-year overall survival rates were 97%, 75% and 7% ( P <0.001) and disease-free survival rates were 83%, 34% and 7% ( P <0.001) in good, intermediate and poor risk groups, respectively. Analysis of the prognostic factors revealed that the localization site of the primary tumor ( P < 0.001), the initial stage of disease ( P < 0.001), the initial serum AFP level (p: 0.001), the initial β -HCG level (p: 0.0048), the presence of yolk sac and choriocarcinoma components in tumor (p: 0.003 and p: 0.004), relapse sites of tumor (lung versus other than lung) (p: 0.003), persistent elevation of serum tumor markers ( P <0.001) were significant prognostic factors in univariate analysis. However, in multivariate analysis, only the localization site of tumor (p: 0.049) and the relapse site (p: 0.003) were found statistically significant. Conclusions: This retrospective study revealed that in advanced stage of nonseminomatous germ cell tumors, the outcome is essentially related with the localization site of the tumor and the relapse site.


Keywords: Nonseminomatous germ cell tumors, prognostic factors, stage


How to cite this article:
Ataergin S, Ozet A, Arpaci F, Kilic S, Beyzadeoglu M, Komurcu S. Outcome of patients with stage II and III nonseminomatous germ cell tumors: Results of a single center. Indian J Cancer 2007;44:6-11

How to cite this URL:
Ataergin S, Ozet A, Arpaci F, Kilic S, Beyzadeoglu M, Komurcu S. Outcome of patients with stage II and III nonseminomatous germ cell tumors: Results of a single center. Indian J Cancer [serial online] 2007 [cited 2019 Dec 16];44:6-11. Available from: http://www.indianjcancer.com/text.asp?2007/44/1/6/31161



 » Introduction Top


Germ cell tumors respond generally very well to conventional or to salvage chemotherapy, even in advanced stage or metastatic disease.[1] However, some patients are unable to achieve a complete response.[2] Many prognostic factors including the stage of disease,[3] histopathology,[4] the localization site of the primary tumor,[5] serum alfa-feto protein (AFP) and b-HCG levels,[6],[7],[8] visceral metastasis sites and the number of metastatic sites[6] are examined up-to-date especially in early stage tumors either to preview the outcome or to select the best treatment modality for patients carrying poor prognosis.

In the present study, we retrospectively analyzed some prognostic factors and the outcome of patients with stage II and III nonseminomatous germ cell tumors treated between 1993 and 2002 at our institution.


 » Materials and Methods Top


Patients' characteristics

Patients' characteristics are given in [Table - 1]. A total of 58 patients (19-45 years old) with stage II (36 patients) and stage III (22 patients) nonseminomatous germ cell tumors treated with chemotherapy at our university hospital between 1993 and 2002 were retrospectively analyzed. Most of the patients underwent surgery at different centers and then were referred to our center for chemotherapy application. All data were retrieved by the same physician. At initial presentation, clinical staging was done according to AJCC Cancer Staging[9] with computed tomography of the chest, abdomen and pelvis; as well as preoperative serum tumor marker (AFP and b-HCG) levels were noted for each patient. Initial localization sites of the tumor, metastasis sites (lung versus other than lung) and tumor response to first-line chemotherapy were also noted. Patients were classified as good, intermediate and poor risk groups according to International Germ Cell Cancer Collaborative Group (IGCCCG) [Table - 1].[10]

Chemotherapy regimens

All patients were given the same initial BEP chemotherapy (bleomycin 30 mg, days 2, 9 and 16; etoposide 100 mg/m 2, days 1-5 and cisplatin 20 mg/m 2, days 1-5) for four cycles. Salvage chemotherapy regimens were applied in relapsed or refractory cases. The same initial salvage chemotherapy was given independent from the relapse sites. Further salvage regimens were applied when needed.

Follow-up

Patients were assessed periodically by computed tomography of the chest, abdomen and pelvis, by biochemical analysis and by serum tumor marker levels after the last course of chemotherapy. Periodical follow-up exam with computed tomography was done every two months for the first two years, every six months in the third and fourth year and annually thereafter. Patients with residual retroperitoneal lymphadenopathy, despite normal serum tumor marker levels underwent retroperitoneal lymph node dissection along with resection of metastases in selected cases. Response to chemotherapy was assessed as complete response, partial response or progression.

Histopathologic evaluation

All archival tissue blocks from each tumor were initially checked by hematoxylin and eosin-stained sections to select the representative block with available tissue for immunocytochemical staining. Two same pathologists who did not know the initial stage of disease examined a 4-µm thick section from each formalin-fixed paraffin-embedded tumor.

Statistics

The differences between the groups were tested using Kruskall Wallis test and Mann-Whitney U test. The survivals of patients were estimated by using Kaplan Meier method. Log rank test was used to compare survivals of groups. Cox proportional hazard analysis was used to determine the prognostic factors in univariate and multivariate analysis. All statistical calculations were performed with SPSS 10.0 for Windows statistical software package (SPSS Inc., Chicago, IL, USA). A P value less than 0.05 was considered statistically significant in all analysis.


 » Results Top


Patients and histopathologic findings

Thirty-six patients (62%) had stage II and 22 patients (38%) had stage III disease. In 45 patients (78%), the tumor arose from the testis, whereas in 13 patients (22%) from extragonadal sites [in 10 patients (17%) from retroperitoneal areas and from mediastinal areas in three patients (5%)]. Histopathologic examination revealed embryonal carcinoma in 14 patients (24%), teratocarcinoma in 20 patients (34%), mixed germ cell tumors in 19 patients (33%) and other histological types in five patients (9%). Embryonal carcinoma, choriocarcinoma and yolk sac components in the tumor were present in 72%, 19% and 24% of the patients, respectively [Table - 2].

According to IGCCCG risk groups, 33 patients (57%), nine patients (15%) and 16 patients (27%) were included in good, intermediate and poor risk groups, respectively.

Uni and multivariate cox proportional hazard modeling results

The most important prognostic factors were found to be the localization site of tumor (gonadal vs extragonadal) (p: 0.001), the stage of disease ( P <0.001), the initial serum AFP level (p: 0.001), the initial serum b-HCG level (p: 0.0048), the presence of yolk sac and choriocarcinoma component in tumor (p: 0.003 and p: 0.004), the relapse site (lung vs other site than lung) (p: 0.003) and the persistent serum tumor marker elevation ( P <0.001) in univariate analysis. However, in multivariate analysis, only the localization site of tumor (p: 0.049) and the relapse site (p: 0.003) were the most statistically important prognostic factors to predict the survival [Table - 3],[Table - 4].

Response status and survival

The median follow-up was 55.3 months (range: 11.07-120.07) and 25.53 months (range: 1.47-113.80) in patients with stage II and III germ cell tumors, respectively. Five-year overall survival rates were calculated as 85% in stage II and 44% in stage III; whereas five-year disease-free survival rates were 75% in stage II and 29% in stage III patients, respectively [Figure - 1],[Figure - 2]. The five-year overall survival rate and according to risk groups were 97%, 75% and 7% whereas the disease-free survival rate were 83%, 34% and 7% for the same groups, respectively ( P <0.001, log-rank: 48.91 and P <0.001, log rank: 43.02) [Figure - 3],[Figure - 4].

Relapse

The relapse has occurred at a median of 51st month (4.17-120.07) and at 17th month (1.47-113.80) with a percentage of 25% and 63% in stage II and III patients, respectively. The relapse time between the groups was found statistically significant (p: 0.004). Four patients out of nine in stage II and one patient out of 14 in stage III achieved a complete remission after the salvage chemotherapy administration.

Regarding the risk groups, the relapse time was at median 59th month (range: 6.27-120.07) in low risk group, at 48th month (range: 1.47-6.70) in intermediate risk group and at 10th month (range: 3.20-69.57) in high-risk group. The difference on relapse time between the groups was statistically significant ( P <0.001). The complete response has occurred in 31%, 11% and 0% of patients with good, intermediate and poor risk patients, respectively.


 » Discussion Top


The aims of our study were to examine primarily the outcome and secondarily the prognostic factors in stage II and III nonseminomatous germ cell tumors.

In our study, we found that, five-year overall survival rates were 85% and 44% and five-year disease-free survival rates were 75% and 29% in patients with stage II and III disease, respectively. However, according to risk groups, five-year overall survival rates were 97%, 75% and 7%; and five-year disease-free survival rates were 83%, 34% and 7% in good risk, intermediate risk and poor risk groups, respectively. This data shows that the outcome of patients was closely related with risk groups.

According to new IGCCCG classification system, primary mediastinum-originated tumors, nonpulmonary visceral metastases or the presence of elevated tumor markers were associated with poor prognosis.[10] Mediastinum-originated tumors were shown to have the worst prognosis and the prognosis for retroperitoneum-originated germ cell tumors is accepted as intermediate risk.[1] Patients with metastasis other than lung have been reported to have a five-year survival of less than 50%.[10] Our study also revealed that patients with tumors of extragonadal origin (22% of all patients) had poor prognosis; and mediastinum-originated tumors had the worst prognosis. All patients with extragonadal origins have died within the first twelve months after the last chemotherapy due to progression.

On the other hand, we also found the relapse site as an important risk factor. Lung metastasis developed in 39% of patients and visceral organ metastasis other than lung developed in 61% patients. Five-year survival rate was 78% in the group with lung metastasis; while no patients achieved remission in the group with visceral organ metastasis and died at their 37th month of follow-up.

Histopathologic components were also assessed by many investigators as significant prognosticators to determine the risk for metastasis in germ cell tumors.[11],[12],[13],[14],[15],[16],[17],[18] In our study, only yolk sac or choriocarcinoma components in tumor were determined as significant prognosticator in univariate analysis (p: 0.003 and p: 0.004).

AFP and b-HCG levels were found to be closely related to clinical stage and bulky disease.[19] Although, cut-off values are varied in different trials, preoperative increased levels of ser1m tumor markers predicted the prognosis.[20] In our study, the cut-off value was accepted as 1000 U/ml and 10.000 mU/ml for AFP and b-HCG, respectively. On these values, these tumor markers were found to be important prognostic factors by only univariate analysis (p: 0.001 and P <0.001).

Persistent elevation of serum tumor markers was estimated to be crucial in assessing the refractoriness of tumor to treatment and the risk of relapse.(21) In our study, 11 patients had persistent serum tumor marker elevation; and all of them have died at a median time of 18 months due to progression. Our study showed that persistent elevation of serum tumor markers was a significant prognostic factor in univariate analysis ( P <0.001) but not in multivariate analysis (p: 0.59).

In summary, although our study retrospectively examined the patients most of whom underwent their surgery at different centers, their survival rates according to risk groups are similar to the current literature data and the outcome of patients with advanced stage nonseminomatous germ cell tumors is closely related with the localization site and the relapse site of the tumor. Further large prospective randomized studies may identify different prognostic factors in these patients along with responsiveness to different chemotherapy regimens applicable in poor risk patients.

 
 » References Top

1.Suita S, Shono K, Tajiri T, Takamatsu T, Mizote H, Nagasaki A, et al . Malignant germ cell tumors: Clinical characteristics, treatment, and outcome. A report from the study group for Pediatric Solid Malignant Tumors in the Kyushu Area, Japan. J Pediatr Surg 2002;37:1703-6.  Back to cited text no. 1    
2.Bhatia S, Abanour R, Porcu P, Seshadri R, Nichols CR, Cornetta K, et al . High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 2000;18:3346-51.  Back to cited text no. 2    
3.Einhorn LH, Williams SD, Troner M, Birch R, Greco FA. The role of maintenance therapy in disseminated testicular cancer. N Engl J Med 1981;305:727-31.  Back to cited text no. 3  [PUBMED]  
4.Logothetis CJ, Samuels ML, Trindade A , Grant C, Gomez L, Ayala A. The prognostic significance of endodermal sinus tumor histology among patients treated for stage III non-seminomatous germ cell tumors of the testes. Cancer 1984;53:122-8.  Back to cited text no. 4  [PUBMED]  
5.Feun LG, Samson MK, Stephens RL. Vinblastine, bleomycin, cis-diaminedichloroplatinum in disseminated extragonadal germ cell tumors. Cancer 1980;45:2543-9.  Back to cited text no. 5  [PUBMED]  
6.Bosl GJ, Geller NL, Cirrincione C, Vogelzang NJ, Kennedy BJ, Whitmore WF Jr, et al . Multivariate analysis of prognostic variables in patients with metastatic testicular cancer. Cancer Res 1983;43:3403-7.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Prognostic factors in advanced non-seminomatous germ-cell testicular tumours: Results of a multicentre study. Report from the Medical Research Council Working Party on Testicular Tumours. Lancet 1985;1:8-11.  Back to cited text no. 7  [PUBMED]  
8.Stoter G, Sylvester R, Sleijfer DT, ten Bokkel Huinink WW, Kaye SB, Jones WG, et al . Multivariate analysis of prognostic factors in patients with disseminated non-seminomatous testicular cancer: Results from an European Organization for Research on Treatment of Cancer Multi-institutional phase III study. Cancer Res 1987;47:2714-8.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Fleming ID, Cooper JS, Henson DE. AJCC cancer staging manual, 5th ed. Lippincott-Raven: New York; 1997.  Back to cited text no. 9    
10.International Germ Cell Consensus Classification: A prognostic-factor based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997;15:594-603.  Back to cited text no. 10    
11.Klepp O, Olsson AM, Henrikson H, Aass N, Dahl O, Steinwig AE, et al . Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: Multivariate analysis of a prospective multicenter study. J Clin Oncol 1990;8:509-18.  Back to cited text no. 11    
12.Albers P, Bierhoff E, Neu D, Fimmers R, Wernert N, Muller SC. MIB-1 immunohistochemistry in clinical stage I non-seminomatous testicular germ cell tumors predicts patients at low risk for metastasis. Cancer 1997;79:1710-6.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Freedman LS, Parkinson MC, Jones WG, Oliver RT, Peckham MJ, Read G, et al . Histopathology in the prediction of relapse of patients with stage I testicular teratoma treated by orchiectomy alone. Lancet 1987;2:294-8.  Back to cited text no. 13  [PUBMED]  
14.Heidenreich A, Sesterhenn IA, Mostofi FK, Moul JW. Prognostic risk factors that identify patients with clinical stage I non-seminomatous germ cell tumors at low and high risk for metastasis. Cancer 1998;83:1002-11.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Heidenreich A, Sesterhenn IA, Moul JW. Prognostic risk factors in low stage testicular germ cell tumors: Unanswered questions regarding clinically useful prognosticators for extratesticular disease. Cancer 1997;79:1641-6.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Moran CA, Suster S, Koss MN. Primary germ cell tumors of the mediastinum: III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum-a clinicopathologic and immunohistochemical study of 64 cases. Cancer 1997;80:699-707.  Back to cited text no. 16    
17.Pecham MJ, Barrett A, Husband JE, Hendry WF. Orchidectomy alone in testicular stage I non-seminomatous germ-cell tumours. Lancet 1982;25:678-80.  Back to cited text no. 17    
18.Sogani PC, Perotti M, Herr HW, Fair WR, Thaler HT, Bosl G. Clinical stage I testis cancer: Long-term outcome of patients on surveillance. J Urol 1998;159:855-8.  Back to cited text no. 18    
19.Sesterhenn IA, Weiss RB, Mostofi FK, Stablein DM, Rowland RG, Falkson G, et al . Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: A report from the Testicular Cancer Intergroup Study. J Clin Oncol 1992;10:69-78.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Mead GM, Stenning SP, Parkinson MC, Horwich A, Fossa SD, Wilkinson PM, et al . The second Medical Research Council Study of prognostic factors in nonseminomatous germ cell tumors. J Clin Oncol 1992;10:85-94.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]


    Figures

[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]

    Tables

[Table - 1], [Table - 2], [Table - 3], [Table - 4]

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