Epidemiology and Treatment Outcomes of Testicular Germ Cell Tumor at Tertiary Care Center in Patna, India: A Retrospective Analysis

Malignant testicular neoplasm constitutes about 1% of all cancers in male [1], but malignant germ cell tumors (GCT) are most common tumors in adolescents and young adult males [2]. It has been seen that the incidence of testicular GCT has doubled in past 40 years [3]. India has the lowest incidence of testicular carcinoma that is about 1.7% [4]. Age standardized incidence in highest in New Zealand (7.8) followed by UK (6.3) and Australia (6.1) per 100000 men. Maldescended testis and cryptorchidism is the most common factor associated with testicular carcinoma, which increases the risk by 2-4 times [5]. GCTs are divided into seminoma and Abstract

Introduction outcome, survival and prognosis.

Materials and Methods
This study was conducted in department of Radiotherapy, All India Institute of Medical Sciences, Patna from August 2014 to September 2019. It was single institution based retrospective study in which data was retrieved from the recorded files & analysed after approval from Institutional Ethics Committee. The study focused on demographic profile as well as clinical presentation with respect to age, presenting complaints, histological types & tumours markers, surgical procedures, systemic chemotherapy, toxicity and disease free and overall survival outcomes. Data retrieved included details of clinical presentation, examination findings, radiological details, per operative findings, post operative histopathological report, adjuvant treatment details, and tumor markers AFP (alpha fetoprotein), βHCG (β Human chorionic gonadotropin), LDH (lactate dehydrogenase).

Statistical analysis
Statistical evaluation was done using SPSS version 25. Chi-square test and Kaplan Meier survival curves were plotted for recurrence free and overall survival. Recurrence free survival was defined as time from diagnosis till recurrence whereas overall survival was defined as time from diagnosis to death.

Results
In this study we analyzed 38 patients (n=38), histologically confirmed cases of germ cell tumor, of which seminoma and nonseminoma were 50% (19) and 50% (19) respectively. The median age of presentation was 31 years (1 -61). The most common affected age group was 31 to 40 (31.6%) of the cases followed by age group of 21 to 30 years (28.9%) and least number of cases (7.9%) were seen in age group of > 50 years. Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0 in 31.6% of patients, ECOG PS 1 in 39.5%, ECOG PS 2 in 15.8% and ECOG PS 3 in 13.2%. Testicular swelling was the most common symptom and seen in 71.1% of patients. Other presenting symptoms were abdominal pain, abdominal pain with lump, hemoptysis, neck node and sacral mass seen in 5.3%, 5.3%, 5.3%, 7.9% and 5.3% respectively. Metastasis was observed in 50% of patients at initial work up, most common site of metastasis was lung (26.3%), liver in 7.9%, inguinal lymph nodes in 7.9% and supraclavicular lymph nodes in 7.9%. Post operative staging revealed that 50% of patients were in stage III followed by stage II and stage I in 28.9% and 21.1% respectively. Seminoma presented most commonly in stage II (21.1%) and non seminoma in stage III (34.2%). The median tumor size was 6 (3.2 -12.3) cm. Upfront surgery was performed in 78.9% of cases and all consisted of high inguinal orchidectomy, 21.1% of cases were not able to undergo upfront surgery and these cases were considered for high inguinal orchidectomy after neoadjuvant chemotherapy.
As per International Germ Cell Consensus Classification (IGCCCG) classification risk group we found in this study that good risk, intermediate risk and high risk were in 65.8%, 13.2% and 21.1% respectively. Among the good risk patients, 28% having metastatic disease and 72% with local disease at presentation while 87.5% of high risk patients presented with metastatic disease and 12.5% with local disease. In this study serum tumor marker groups were S0, S1, S2 and S3 in 2.6%, 60.5%, 26.3% and 10.5% respectively. We found that in seminoma the median value of AFP was 4 ng/ml (1.3 -56), βHCG 638 mIU/ml (246 -1200), LDH 486 U/L (212 -1563) and in nonseminoma AFP was 380 ng/ml (0.5 -1500), βHCG 316 mIU/ml (1.0 -69399), LDH 558 U/L (312 -3261). The median volume of locoregional disease was 65 cc in seminoma and 120 cc in nonseminoma, these were measured on the basis of radiological parameters of largest locoregional lymph node from CT scan ( Table 1) Response to chemotherapy after surgical intervention, showed that response evaluation criteria in solid tumors 1.1 (RECIST) of target lesion complete response (CR) in 15.8%, partial response (PR) in 63.2 % and radiological response could not be assessed in 21.1% of cases, similarly RECIST of non target lesion or of metastatic site were showing CR in 21.1%, PR in 21.1% and stable disease in 5.3% while RECIST could not be evaluated in 50% of cases. Systemic chemotherapy was indicated in 94.7% and not indicated in only 5.3% of patients. Pre-chemotherapy pulmonary

Discussion
There is a lack of recent data from India on epidemiology of germ cell tumor (GCT) except for few small series [7]. There is a recent publication on epidemiological study on GCT by Joshi et. al. [8]. In our study the median age of patients with seminoma and nonseminoma were 36 (25-61) and 24 (1-60) years respectively. Joshi et. al. found similar age distribution among the seminomatous and non seminomatous in their study as median age in seminoma and nonseminoma 39 and 28 years respectively [8]. Similar findings regarding function test (PFT) was done in 65.8% while status of PFT was not known in 23.7% and not performed in 10.5% of cases. Neoadjuvant chemotherapy was considered in 21.1% of cases and these are the patients not able to undergo upfront surgery. Adjuvant chemotherapy was not taken or defaulted by 18.4% of patients and 81.6% of patients completed their scheduled chemotherapy. Neutropenia was the most common complication followed by diarrhoea and pulmonary toxicity was least common. Grade III diarrhoea was seen in 8.7% of patients, grade III mucositis in 2.6%, grade III neutropenia in 13.1%, febrile neutropenia in 5.7%, anaemia in 4.3% and pulmonary toxicity in 3.9% of patients respectively. Grade I or II complication of was seen in 22.3% of cases. Toxicities of the chemotherapy led to the delay in treatment schedule, 39.5% patients took their chemotherapy on schedule, 34.2% of patients were in delay in group of 1-10 days, 21.1% were in delay group of 11-20 days and 5.3% were in delay group of 21-30 days. The median number chemotherapy cycles were 4 (4-6). Baseline epidemiological characteristics are given in Table 2 on the basis of (histological category) seminoma and non seminoma. In this study on Kaplan Meier survival analysis we found that median duration of recurrence free survival (RFS) was 52 months (95% CI; 26.7 -76.3 months) (Figure 1), duration of median overall survival (OS) was 71 months (95% CI; 35.1 -106.8) months (Figure 2), the OS rates at 1, 3 and 5 years were 100%, 71.4%     [9]. In this study we found that median pre-chemotherapy value of AFP, HCG and LDH in seminomatous GCT were 4 ng/ml, 638 mIU/ml and 212 U/L respectively. The median pre-chemotherapy value of AFP, βHCG and LDH in nonseminomatous GCT were 380 ng/ml, 316 mIU/ml and 558 U/L respectively. We found in our study that tumor markers S group as S0, S1, S2 and S3 were 0%, 73.6%, 21% and 5.2% respectively in seminomatous GCT while in nonseminomatous GCT S0, S1, S2 and S3 were 5.2%, 47.3%, 26.3% and 21% respectively. The serum tumor markers S group results were different from the findings of the study by Joshi et. al. [8]. Assessment of response to chemotherapy according to RECIST [12].
In conclusion, testicular germ cell tumor is predominantly a disease of young adults and it presents as a testicular mass in almost all cases for which consultation to physician was sought. Most of the cases presented with advanced stage and majority of them have undergone high inguinal orchidectomy which is the standard surgical procedure for testicular germ cell tumor. The high nodal burden disease presentation at our center and most of the patient showed partial response to standard chemotherapy it seems that there is the need of alternative chemotherapy regimen in expectation to good response especially in nonseminomatous germ cell tumors to achieve complete response. Patients presented with disease confined to locoregional lymph nodes or local disease having good prognosis as compared to metastatic disease which was reflected in both recurrence free survival and overall survival. Overall survival in our study was not matching to the data of western studies the reason for this may be advanced disease at presentation, bulky retroperitoneal nodal disease, treatment abandonment, failure to maintain dose intensity and lost to proper follow up.