Factors Influencing the Response Rate and Survival of Testicular Germ Cell Tumors: A Single Institution Experience from Egypt

Background: Testicular germ cell tumors (TGCTs) are the most common cancer in young adult males, and they represent one of the most curable solid tumors. The treatment modalities of different stages are variable among centers. Aim: To describe the management of TGCTs and its outcome in an Egyptian cancer center. Methods: The medical records of patients with TGCT treated between January 2012 and December 2016 were retrospectively reviewed. Thirty-two patients were included. Demographic, clinical, treatment, and outcome data were analyzed. Results: The median age of the patients was 34.5 years. The most common presentation was unilateral painless testicular mass (87.5%). Seminoma represented 53% of cases and almost half of them had Stage I disease. For all patients, the clinical stage and International Germ Cell Cancer Collaborative Group (IGCCC) risk classification were significantly associated with survival outcomes. Five-year overall survival for stage I patients was 100%, compared to 87.5% for stage II (p<0.0001). Patients with good risk had a 5-year OS of 87.4% while none of the poor risk group survived for 5 years (p =0.002). The 5-year disease-free survival for stage I was 83% for those who remained under active surveillance versus 87.5% for those who received adjuvant carboplatin (p=0.364). Conclusions: Stage I TGCTs has an excellent overall survival regardless of the treatment modality received. In advanced disease, the clinical stage and IGCCC risk stratification remain valid prognostic risk factors.


Introduction
Testicular cancer is the most commonly diagnosed malignancy in young adult men 1 . There is marked geographical variation in the agestandardized incidence rate for testicular cancer, ranging from as low as 1.86/100,000 in Egypt 2 to as high as 9.2/100,000 in Denmark 3 .
Although the overall incidence of testicular tumors is rare (about 1% of all male malignancies), testicular germ cell tumors (TGCT) are the most common among them. In post pubertal males, 95% of testicular tumors arise from germ cells and the majority of cases occur between the ages of 20 to 35 years 4 .
There is a paucity of data on testicular germ cell cancer management in Egypt. In the present study, our objective was to describe the treatment of these rare tumors in a single Egyptian institution and to determine factors that may impact survival results. This is expected to guide further improvement in the quality of care of our patients.

Methods
This is a retrospective study of the medical records of patients with pathologically proven TGCTs who had been treated at Kasr Al-Ainy Center of Clinical Oncology and Nuclear Medicine (NEMROCK) from January 2012 to December 2016. Only patients with complete clinical data were enrolled in the present study.
The Radiotherapy for para-aortic lymph nodes was given as 3D conformal RT using A-P/P-A fields on a LINAC machine. The dose ranges from 21.6 Gy/12 fractions to 30 Gy / 15.
Regarding response assessment, complete remission (CR) was defined as the absence of tumor mass by computerized tomography scan after chemotherapy or residual mass <3cm in seminoma or <1cm in NSGCT, with normal tumor markers. Partial remission (PR) was defined as having residual mass after chemotherapy that did not match the definition of CR, while progressive disease (PD) was defined as growing mass or increasing markers.

Statistical analysis
Categorical variables were described as numbers and percentage and compared between groups using Chi-square / Fisher exact test. Abnormally-distributed continuous variables were described as median and range. The Kaplan-Meier method was used for survival analysis and survival curves were compared using the log-rank test. Disease-free survival (DFS) was calculated as the time of months elapsed between the date of achieving complete remission (after surgery and / or chemoradiotherapy) and the date of recurrence / death. Overall survival (OS) was calculated from the date of diagnosis to the date of death. A p-value less than 0.05 was considered significant.
The IBM SPSS software, version 23.0. (Armonk, NY: IBM Corp.) was used for data management and analysis.

Results
During the study period, 46 patients presented to our institute with the diagnosis of TGCT. Fourteen patients were excluded due to incomplete data and the remaining 32 patients were included.
All patients underwent a thorough clinical examination, scrotal ultrasound, computed tomography scan of the chest, abdomen, and pelvis with contrast and measurement of AFP, B-HCG, and LDH levles. All patients underwent upfront unilateral inguinal orchiectomy. The delay period from surgery to presentation to our department ranged from 3 to 62 days, with a median of 21 days. Details on the clinical and pathological characteristics of the studied population are presented in Table 1.
The first-line treatment received and the response to it according to different stages are presented in Table 2. In the 3 patients with stage II who did not achieve CR, the retroperitoneal lymph nodes were the only site of residual disease. Those patients were successfully managed as follows: one patient with NSGCT underwent retroperitoneal lymph node dissection while the other 2 patients with seminoma, were treated by radiotherapy.
In patients with stage III diseases who did not achieve CR (3 with PR and 1 with progression); three patients with NSGCT had retroperitoneal residual disease and retroperitoneal lymph node dissection was performed, while the remaining patient developed brain metastasis and died from disease progression.
At the time of data analysis (June 2020), the median follow up of patients was 42.5 months (95% CI: 23.0 -63.1 months). Four (12.5%) patients died; two from chemotherapy toxicity (septic shock) and the other 2 from disease progression (liver cell failure and respiratory failure).
The 5-year DFS and OS for the entire group was 76 % and 84%, respectively. The median DFS and OS were not yet reached. As shown in Table 4, the stage of disease and the IGCCC risk stratification were the only factors that had a significant impact on survival. Disease-free survival and OS for patients with stage I were 86% and 100%, vs 79% The relationship between achieving CR and the studied variables is shown in Table 3. The clinical stage was the only significant factor.
As presented in Figure 1, the 5-year DFS was 87.5% in patients who received adjuvant chemotherapy vs. 83% in patients kept on active surveillance only, with no statistically significance difference between the 2 groups (p=0.364).
Three patients (out of 17) with stage I had relapse (relapse rate 17.6%). Two of them were under active surveillance, and one patient received adjuvant carboplatin. The median time to relapse was 20 months and para-aortic lymph nodes was the only site of relapse. All the 3 patients were successfully salvaged by BEP.    Prospective studies are required for patients with poor risk NSGCT to improve their outcome.