TESTICULAR SEMINOMA : CORRELATION BETWEEN STAGING AND CHEMOTHERAPY RESPONSE , TWO YEARS OVERALL SURVIVAL RATE

Objective: to determine the patient’s characteristics, correlation between staging and chemotherapy response, furthermore two years overall survival rate. Methods: a retrospective analytic study was conducted. Data were obtained from medical records in January 2008 to December 2014 and analyzed using SPSS 17.0. All of correlation between staging and chemotherapy response, primary tumor staging (pT) and metastasis (M), regional lymph nodes staging (N) and metastasis (M), serum tumor marker and chemotherapy response were tested by Spearman correlation test. Two years overall survival rate was analyzed by Kaplan-Meier. Data ratio with normal distribution was tested by Paired T-test. Results: the mean age of patients were 31.03 ± 13.751 years, with seven patients (15.6%) had previous history of undescended testis. Based on TNM staging, we found that most patients had already develop into stage pT3 (46.7%), N3 (57.7%), and M0 (57.7%). A significant correlation between staging and chemotherapy response was shown with stage I of testicular seminoma had completely chemotherapy response (100%) and two years overall survival rate in stage I was 100%, whereas in metastatic seminoma (stage II and III) was 60%, with Hazard Ratio 0.63 (p=0.294; 95%CI 0.276-1.476). Conclusion: patients in early stage of testicular seminoma will give a better response to chemotherapy and will have better survival rate compared to those with metastatic seminoma.


INTRODUCTION
Testicular cancer accounts for 1% of malignancies in men, and 5% of all urogenital tumors. 1 Ninety-four percent of testicular tumors are Germ Cell Tumors (GCT). 2 Prevalence rate of testicular tumor tend to increase, 55% in 1973 became 73% in 2001.About 10% until 30% of the cases will come with far metastasis.The data from Surveillance Epidemiology and End Result (SIER) Program (1973-1998)  shows that the risk of having seminoma among Caucasian men in United States of America is increasing. 3In USA about 8400 people had testicular cancer and 380 people died because of it.GCT can be categorized as seminoma and nonseminoma (NSGCT) based on its pathology and treatment.The incidence of testicular seminoma is increasing compared to that of non-seminoma GCT. 4 GCT incidence is also increasing around the world.In USA, its prevalence rate among patient with age 15 until 49 years old increased from 2.9 per 100,000 in 1975 became 5.1 per 100,000 in 2004. 3Based on a study about testicular cancer at dr. Soetomo General Hospital in 2008 until 2013, there were 37 testicular seminoma cases (80%), 4 yolk sac tumor cases (9%), 1 embryonal tumor case (2%), 1 teratoma case (2%), and 3 mixed germ cell tumor cases (3%). 5he aim of this study was to determine the characteristics of the patients, correlation between testicular seminoma staging and the response to chemotherapy, as well as two years overall survival rate of patients with testicular seminoma that were managed in our department.

METHODS
This was a cohort retrospective study.The data of the subject age, tumor stage and location, tumor marker serum level, and type/response/side effect of chemotherapy were obtained from medical records in dr.Soetomo General Hospital Surabaya from January 2008 to December 2014, and analyzed using SPSS 17.0.
Patients diagnosed with testicular seminoma based on the histopathology of the specimen taken from the surgery and get chemotherapy BEP (Bleomycin, Etoposide, and Cisplatin) as many as 1 to 4 cycles, with 30 units of intravenous bleomycin on days 2, 9, and 16; 100 mg/m 2 intravenous etoposide on days 1-5; and 20 mg/m 2 intravenous cisplatin on days 1-5 with the interval 21 days.The chemotherapy response was evaluated based on the Response Evaluation Criteria In Solid Tumor (RECIST) criteria. 6The subject was categorized to have a complete response if the mass reduced completely, partial response if there was at least 30% of reduction in the size of lesion, progressive response if there was at least a 20% increase in the sized of the lesion; and stable or no response if there was no or insufficient reduction of the lesion size.The tumor staging was categorized based on the standardized TNM staging classification.
Data were analyzed by descriptive statistic.Correlation between staging and response to chemotherapy, correlation primary tumor staging (pT) and metastasis (M), correlation regional lymph nodes staging (N) and metastasis (M), correlation serum tumor marker level before operation and response to chemotherapy was tested by Spearman correlation test.Two years overall survival rate was analyzed by Kaplan-Meier and hazard ratio was analyzed by cox-regression, we divided staging group into 2 category, stage I and metastatic seminoma (stage II and III).Laboratory results pre and post chemotherapy is a data ratio with normal distribution and tested by Paired T-test.Statistically significant if p<0.05.
The value of rho (r) and p for the correlation between chemotherapy response and tumor marker serum are r=0.296and p=0.067.It means there is a weak correlation between chemotherapy response and tumor marker serum and it's not statistically significant (Table 8).In patients with stage I testicular seminoma, 10 patients had complete responses (100%), while in patients with stage II there were 1 patients with complete response (25%) and 2 patients with partial responses (75%), while in patients with stage III there were 4 patients with complete response (15.4%), 17 patients with partial response (65.4%), and 5 patients with no response (19.2%) with r=0.685 and p=0.001.This shows a significant correlation between the staging of testicular seminoma and the response to chemotherapy (Table 9).
Based on this study, percentages of having 2 years overall survival rate in stage I patients is 100%, while in metastatic seminoma patients (stage II and III) is 60% (Figure 1). 10 patients with metastatic seminoma died during 2 years follow up, the hazard rate value is 0.63, it means that patients with metastatic seminoma tend to have fatal possibility 0.63 times comparing to those with stage I testicular seminoma.But it is not statistically significant (HR=0.63,95%CI 0.26-1.476,p=0.294).

DISSCUSION
Testicular cancer is the most common cancer found in men age 15-35 years old. 3 Testicular seminoma often occurred in the 4 th decade of life, while non-seminoma often happens in the 3 rd decade of life. 5he incidence is rare in men age under 15 years old or over 60 years old.Its prevalence among children only 0.5-2.0 per 100,000 population. 6The age distribution in children also different than in adult. 7Based on study result, there are 45 testicular seminoma patients with average age in stage I is 31.45± 13.67 years old and in metastatic seminoma is 30.90 ± 13.97 years old.Testicular cancer often occurs in the right side rather than left side, and it also happens in patient with cryptorchidismus. 8he most important factor that considered having correlation with testicular cancer is cryptorchidism history on the testis.About 7-10% testicular cancer patients have cryptorchidism history, seminoma is the common testicular cancer that happen among this kind of patients.Cryptorchidism raises the chance of having testicular cancer 4 until 6 times higher.The risk is higher in testis located intra-abdominal (1 in 20 cases), and significantly lower in testis located in inguinal (1 in 80 cases). 9Based on study result, tumor located in right testis is more common, 23 patients (51.1%), than left testis, 18 patients (40.0%), and intraabdominal testis, and 4 patients (8.9%).History of undescended testis presences in 7 patients (15.6%).
Although fetal AFP serum level is high, after 1 year old, it becomes very low. 9AFP will not increase in pure seminoma or choriocarcinoma. 3Increasing level of β-hCG did not occurred in pure embryonal cell carcinoma, this cancer cell does not contain syncytiotrophoblast, increasing level of AFP in pure embryonal cell carcinoma is rare and if it is occurred, it usually accompanied by yolk sac tumor. 4here are many combinations of mixed tumor, usually it consists of embryonal cell carcinoma, seminoma, yolk sac, teratoma or synctiotrophoblast. 10 Based on the previous study, seminoma was said to be highly sensitive to platinum-containing chemotherapy. 11However, the present data show contrary result.Majority of the subjects showed partial response (42.2%).Regardless of that, the recurrence of seminoma was high.These masses resolve slowly over months, and although residual masses are commonly present one month after completion of chemotherapy. 12n stage IIA/B seminoma, radiotherapy could provide excellent results, as the majority of patient will be cured with this treatment alone.Chemotherapy is the treatment of choice for stage IIC seminoma. 13he cause of neutropenia, leucopenia, and thrombocytopenia are side effect of etoposide and cisplatin which is suppression of bone marrow so leucocytes and thrombocytes production is decreasing. 14Alopecia is the most common side effect of bleomycin and etoposide, this is happened because the chemotherapy drugs blocking cellular absorption in hair follicle so hair growth is disturbed. 15n the analysis of tumor size or T category, this study showed the tumor size was correlated neither with clinical substage nor relapse rate.There was a poorer 3-years survival for anaplastic seminomas as compared to that of classical seminoma, the difference was not significant. 16A risk adapted chemotherapy policy for advanced seminoma yielded an excellent outcome with a 3 years overall survival rate was 96% and 5-years overall survival rate was 92%. 17n this study, no correlation between pT staging with M and serum tumor marker after the operation with chemotherapy response.Significant correlation between N and M staging, which means the higher N staging it will be followed by an increase in M staging and vice versa.In this study also found a positive correlation between staging and response to chemotherapy, it is means patient in advanced stage cancer will give a poor response to chemotherapy.In this study, 2 years overall survival rate for patients with stage I seminoma testicular better when compared with metastatic seminoma, but this was not statistically significant.

CONCLUSION
Testicular seminoma mostly appears in younger males.Testicular seminoma is chemosensitive.Patients in early stage will give a better response to chemotherapy compared to those with advanced stage.After chemotherapy, evaluation should be done to the patient's complaints and complete blood count to detect side effects.Patients with stage I testicular seminoma have a better two years overall survival rate compared to those with metastatic seminoma, but the difference was not significant.

Table 4 .
Side effect of chemotherapy.

Table 6 .
Correlation between staging pT and M.

Table 7 .
Correlation between staging N and M.

Table 8 .
Correlation between tumor marker serum and chemotherapy response.

Table 9 .
Correlation between staging and chemotherapy response.