Outcomes of active surveillance of clinical stage I non-seminomatous germ cell tumors: sub-analysis of the multi-institutional nationwide case series of the Japanese Urological Association

Outcomes of active surveillance of clinical stage I non-seminomatous germ cell tumors:... Abstract Objective To evaluate the survival rate and risk factors of distant metastasis in stage I non-seminomatous germ cell tumor (NSGCT) cases without adjuvant treatments. Methods A national testicular cancer survey of cases newly diagnosed in 2005 and 2008 was conducted by the Japanese Urological Association in 2011. In 159 stage I NSGCT cases, 132 were followed by active surveillance after high orchiectomy. Their recurrence-free survival rate (RFS) was compared with 27 cases that received adjuvant treatments, and clinical and pathological parameters were explored to identify significant risk factors of recurrence. Results Within a median follow-up period of 30.3 months (range: 0.3–65.6 months), 16 (12.1%) of the 132 surveillance cases relapsed at 2.8–51.2 months after high orchiectomy (median: 8.35 months). The 2-year RFS rate was 90%. Eleven (68.8%) cases relapsed within 1 year, and five (31.3%) cases relapsed in 3 years or more. Half (50%) of the recurrences were detected by imaging studies alone, 37.5% by imaging combined with tumor markers, and 12.5% by tumor marker elevation alone. The only significant risk factor of recurrence was the existence of embryonal carcinoma elements in the primary testicular tumor (P = 0.0068). There was no significant difference in RFS between cases with active surveillance and adjuvant treatments. Conclusions The present report is the first large scale study of clinical stage I NSGCTs in Japan. Active surveillance appears to be an effective treatment option for patients with clinical stage I NSGCTs. active surveillance, epidemiology, germ cell tumor, Japanese, nonseminoma Introduction Clinical stage I testicular cancer is the most common presentation of testicular cancer (1,2). Even with modern staging techniques incorporating computed tomography (CT) and monitoring of serum tumor markers, ~30% of patients with clinical stage I non-seminomatous germ cell tumors (NSGCTs) have occult metastatic disease (3,4) and will have a recurrence if they receive active surveillance after high orchiectomy. However, if retroperitoneal lymph node dissection (RPLND) or adjuvant chemotherapy is administered to patients, many patients will be over-treated, and even if recurrence occurs, almost all cases in the surveillance group can be cured by cisplatin-based chemotherapy (5). Therefore, active surveillance is generally recommended, particularly for patients thought to have a low recurrence risk. Because of the inaccuracy of clinical staging methods and the risk of metastasis, clinical research focusing on the development of prognostic risk factors remains one of the most important clinical challenges. Here, we report outcomes of active surveillance for clinical stage I NSGCT and an analysis of risk factors for recurrence in a Japanese population. Methods A testicular cancer registry program was conducted in 2011 by The Cancer Registration Committee of the Japanese Urological Association (JUA) to collect data of testicular cancer patients diagnosed in 2005 and 2008 from the accredited training institutes for board certification in urology. The survey included details such as age, presenting symptoms, physical examination findings, tumor markers, histopathology, clinical stage, initial treatment and clinical outcomes. The survey did not include the presence of lymphovascular invasion because it is difficult to unify the criteria across all institutions. Among 1157 patients with testicular tumors registered from 274 institutions nationwide, 729 patients were diagnosed with stage I testicular tumors. Pathological examination of the specimens of high orchiectomy revealed that 160 were clinical stage I NSGCTs. We could not confirm the follow-up data of one patient, and 27 cases received adjuvant treatments. Therefore, we finally analyzed 132 patients with stage I NSGCT followed by active surveillance. The frequency of follow-up investigations was not unified and depended on each institution. Regarding tumor markers, although recording the human chorionic gonadotropin (HCG) value is encouraged, we excluded it from analysis because in many of the institutions a free HCG-β (ng/ml) measurement kit, which is unsuitable for the International Germ Cell Consensus Classification (6), was used instead of a total HCG (mIU/ml) measurement kit. The normal concentration of α-fetoprotein (AFP) is 20 ng/ml in accordance with JUA Cancer Registration Statistics (1). Lactate dehydrogenase (LDH) was evaluated depending on its normal range for each facility. Pathological details were obtained from reports of each facility. To predict risk factors, we used the previously published cutoff values of these parameters, i.e., the presence of abnormal serum AFP levels (cutoff: 80 ng/ml) before orchiectomy (7,8), pathological tumor (pT) classification (cutoff greater than 1) (9,10), presence of embryonal carcinoma elements (11,12), presence of yolk sac elements (10,13) and age (cutoff greater than 30) (13,14). This retrospective study was approved by the Institutional Review Board with all participating sites providing the necessary institutional data sharing agreements prior to initiation. The variables of the different groups were compared using the chi-squared test or Mann–Whitney U-test. The Kaplan–Meier method was used to estimate recurrence-free survival (RFS) rates that were compared using the log-rank test. RFS was measured from the date of high orchiectomy until the date of diagnosis of recurrence or until the last follow-up. Univariate and multivariate analyses of RFS were performed using the log-rank test or Cox proportional hazards regression models. Significant or marginally significant variables in univariate analyses were chosen for multivariate analysis. Differences among groups were regarded as significant when P < 0.05. These analyses were performed with the Statview version 5.0 statistical software package (SAS Institute, Cary, NC, USA). Results Patient characteristics Median and mean ages of patients were 32.0 and 33.6 years, respectively. Out of 132 patients, 21 patients (15.9%) had a previous history of inguinal or scrotal surgery. One hundred and thirty-one (99.2%) patients presented with a scrotal mass or swelling and 16 (12.1%) patients complained of scrotal pain. One patient presented with gynecomastia. Laterality of the scrotal mass was on the right side in 83 patients (62.9%), the left side in 47 patients (35.6%) and uncertain in 2 patients (1.5%). AFP was examined in 131 patients (99.2%) and found to be abnormally elevated (>20 ng/ml) in 80 (61.1%) of them (Table 1). Two patients showed an extremely elevated AFP value of ≥10 000 ng/ml with a maximum value of 15 537 ng/ml. LDH was examined in 115 patients (87.1%) and found to be abnormally elevated in 34 (29.6%) of them. An extremely elevated LDH value (>10 × upper limit of normal) was not observed. Table 1. The characteristic of the 159 stage I non-seminomatous testicular tumor cases Active surveillance Adjuvant therapy P-value No. patients 132 27 Mean age(±SD) 33.6 ± 11.73 31.8 ± 11.33 0.503 AFP(ng/ml)  <20 51 38.6% 8 29.6% 0.1507  20–80 23 17.4% 2 7.4%  >80 57 43.2% 17 63.0%  Unknown 1 0.8% 0 0.0% LDH(IU/L)  ≤ULN 81 61.4% 16 59.3% 0.6189  >ULN 34 25.8% 10 37.0%  Unknown 17 12.9% 1 3.7% pT classification  Tis 1 0.8% 0 0.0% 0.6297  1 99 75.0% 20 74.1%  2 25 18.9% 7 25.9%  3 4 3.0% 0 0.0%  4 0 0.0% 0 0.0%  Tx 3 2.3% 0 0.0% Histology  Pure embryonal carcinoma 9 6.8% 2 7.4% 0.0305  Pure teratoma 13 9.8% 0 0.0%  Pure yolk sac tumor 5 3.8% 5 18.5%  Pure choriocarcinoma 0 0.0% 0 0.0%  ITGCN 1 0.8% 0 0.0%  Mixed forms 104 78.8% 20 74.1% Elements  Seminoma 61 46.2% 8 29.6% 0.1132  Embryonal carcinoma 78 59.1% 19 70.4% 0.379  Yolk sac tumor 63 47.7% 17 63.0% 0.1491  Teratoma 85 64.4% 11 40.7% 0.022  Choriocaricnoma 25 18.9% 4 14.8% 0.6131  Others 6 4.5% 0 0.0% 0.2588 Adjuvant treatment  no(surveillance) 132  chemotherapy 22  radiation 1  RPLND 3  chemotherapy+RPLND 1 Active surveillance Adjuvant therapy P-value No. patients 132 27 Mean age(±SD) 33.6 ± 11.73 31.8 ± 11.33 0.503 AFP(ng/ml)  <20 51 38.6% 8 29.6% 0.1507  20–80 23 17.4% 2 7.4%  >80 57 43.2% 17 63.0%  Unknown 1 0.8% 0 0.0% LDH(IU/L)  ≤ULN 81 61.4% 16 59.3% 0.6189  >ULN 34 25.8% 10 37.0%  Unknown 17 12.9% 1 3.7% pT classification  Tis 1 0.8% 0 0.0% 0.6297  1 99 75.0% 20 74.1%  2 25 18.9% 7 25.9%  3 4 3.0% 0 0.0%  4 0 0.0% 0 0.0%  Tx 3 2.3% 0 0.0% Histology  Pure embryonal carcinoma 9 6.8% 2 7.4% 0.0305  Pure teratoma 13 9.8% 0 0.0%  Pure yolk sac tumor 5 3.8% 5 18.5%  Pure choriocarcinoma 0 0.0% 0 0.0%  ITGCN 1 0.8% 0 0.0%  Mixed forms 104 78.8% 20 74.1% Elements  Seminoma 61 46.2% 8 29.6% 0.1132  Embryonal carcinoma 78 59.1% 19 70.4% 0.379  Yolk sac tumor 63 47.7% 17 63.0% 0.1491  Teratoma 85 64.4% 11 40.7% 0.022  Choriocaricnoma 25 18.9% 4 14.8% 0.6131  Others 6 4.5% 0 0.0% 0.2588 Adjuvant treatment  no(surveillance) 132  chemotherapy 22  radiation 1  RPLND 3  chemotherapy+RPLND 1 ITGCN, intratubular germ cell neoplasia; RPLND, retroperitoneal lymph node dissection. Table 1. The characteristic of the 159 stage I non-seminomatous testicular tumor cases Active surveillance Adjuvant therapy P-value No. patients 132 27 Mean age(±SD) 33.6 ± 11.73 31.8 ± 11.33 0.503 AFP(ng/ml)  <20 51 38.6% 8 29.6% 0.1507  20–80 23 17.4% 2 7.4%  >80 57 43.2% 17 63.0%  Unknown 1 0.8% 0 0.0% LDH(IU/L)  ≤ULN 81 61.4% 16 59.3% 0.6189  >ULN 34 25.8% 10 37.0%  Unknown 17 12.9% 1 3.7% pT classification  Tis 1 0.8% 0 0.0% 0.6297  1 99 75.0% 20 74.1%  2 25 18.9% 7 25.9%  3 4 3.0% 0 0.0%  4 0 0.0% 0 0.0%  Tx 3 2.3% 0 0.0% Histology  Pure embryonal carcinoma 9 6.8% 2 7.4% 0.0305  Pure teratoma 13 9.8% 0 0.0%  Pure yolk sac tumor 5 3.8% 5 18.5%  Pure choriocarcinoma 0 0.0% 0 0.0%  ITGCN 1 0.8% 0 0.0%  Mixed forms 104 78.8% 20 74.1% Elements  Seminoma 61 46.2% 8 29.6% 0.1132  Embryonal carcinoma 78 59.1% 19 70.4% 0.379  Yolk sac tumor 63 47.7% 17 63.0% 0.1491  Teratoma 85 64.4% 11 40.7% 0.022  Choriocaricnoma 25 18.9% 4 14.8% 0.6131  Others 6 4.5% 0 0.0% 0.2588 Adjuvant treatment  no(surveillance) 132  chemotherapy 22  radiation 1  RPLND 3  chemotherapy+RPLND 1 Active surveillance Adjuvant therapy P-value No. patients 132 27 Mean age(±SD) 33.6 ± 11.73 31.8 ± 11.33 0.503 AFP(ng/ml)  <20 51 38.6% 8 29.6% 0.1507  20–80 23 17.4% 2 7.4%  >80 57 43.2% 17 63.0%  Unknown 1 0.8% 0 0.0% LDH(IU/L)  ≤ULN 81 61.4% 16 59.3% 0.6189  >ULN 34 25.8% 10 37.0%  Unknown 17 12.9% 1 3.7% pT classification  Tis 1 0.8% 0 0.0% 0.6297  1 99 75.0% 20 74.1%  2 25 18.9% 7 25.9%  3 4 3.0% 0 0.0%  4 0 0.0% 0 0.0%  Tx 3 2.3% 0 0.0% Histology  Pure embryonal carcinoma 9 6.8% 2 7.4% 0.0305  Pure teratoma 13 9.8% 0 0.0%  Pure yolk sac tumor 5 3.8% 5 18.5%  Pure choriocarcinoma 0 0.0% 0 0.0%  ITGCN 1 0.8% 0 0.0%  Mixed forms 104 78.8% 20 74.1% Elements  Seminoma 61 46.2% 8 29.6% 0.1132  Embryonal carcinoma 78 59.1% 19 70.4% 0.379  Yolk sac tumor 63 47.7% 17 63.0% 0.1491  Teratoma 85 64.4% 11 40.7% 0.022  Choriocaricnoma 25 18.9% 4 14.8% 0.6131  Others 6 4.5% 0 0.0% 0.2588 Adjuvant treatment  no(surveillance) 132  chemotherapy 22  radiation 1  RPLND 3  chemotherapy+RPLND 1 ITGCN, intratubular germ cell neoplasia; RPLND, retroperitoneal lymph node dissection. The pathological stage was Tis/T1 in 100 patients, T2–4 in 29 and Tx in 3. A solitary histological subtype was observed in 28 patients and a mixed subtype was observed in 104 patients: seminomatous elements in 61 patients, embryonal carcinoma in 78, yolk sac tumors in 63, teratomas in 85 and choriocarcinoma in 25. Prognosis after active surveillance The rate of patients followed by active surveillance was 77.4% in 2005 and 86.6% in 2008. There was no significant difference in the 2-year RFS rate at 88.2% in 2005 and 89.6% in 2008. Within a median follow-up period of 30.3 months (range: 0.3–65.6 months), recurrence occurred in 16 of 132 (12.1%) patients. Sixteen cases of recurrence during active surveillance are summarized in Table 2. Most recurrences (81.3%) were diagnosed within 24 months after initial diagnosis, and there were only three late recurrences (18.7%). The first evidence of recurrence was most commonly identified by imaging alone (50%) or in combination with tumor markers (37.5%; 87.5% overall), and only half of the recurrences had elevated serum markers. The percentage of recurrences detected only by imaging decreased from 54.5% (6 of 11) within the first 12 months to 40% (2 of 5) after 12 months. The percentage of recurrences detected in combination with tumor markers increased from 27.3% (3 of 11) within the first 12 months to 60% (3 of 5) after 12 months. Two recurrences were detected only by increases in tumor markers within 6 months. Out of 16 recurrent patients, all three patients with normal tumor markers at first diagnosis were detected only by imaging and 3 of 13 patients with elevated tumor markers at first diagnosis did not have elevation of tumor markers at recurrence. In 14 patients diagnosed with recurrence by imaging, the recurrent sites were retroperitoneal lymph nodes in all patients, cervical lymph nodes in 2 patients, and the lung and axillary lymph nodes in one patient. There were no cases of recurrence in the chest with normal tumor markers and normal abdominal imaging. Table 2. The characteristic of the 16 relapse cases Number Relapse months  Within 12 months 11 68.75%  12 months–24 months 2 12.50%  24 months–36 months 2 12.50%  >36 months 1 6.25% Method of first relapse detection  CT scan 8 50.00%  Tumor marker 2 12.50%  CT scan+tumor marker 6 37.50% Treatment for initial relapse  Chemotherapy 14 87.50%  Radiation 0 0.00%  RPLND 0 0.00%  Unknown 2 12.50% Current status  Alive without tumor recurrence 11 68.75%  Death of disease 0 0.00%  Death other cause 0 0.00%  AWD 5 31.25% Number Relapse months  Within 12 months 11 68.75%  12 months–24 months 2 12.50%  24 months–36 months 2 12.50%  >36 months 1 6.25% Method of first relapse detection  CT scan 8 50.00%  Tumor marker 2 12.50%  CT scan+tumor marker 6 37.50% Treatment for initial relapse  Chemotherapy 14 87.50%  Radiation 0 0.00%  RPLND 0 0.00%  Unknown 2 12.50% Current status  Alive without tumor recurrence 11 68.75%  Death of disease 0 0.00%  Death other cause 0 0.00%  AWD 5 31.25% The median time to relapse was 8.35 months range from 2.8 to 51.2 month. RPLND, retroperitoneal lymph node dissection; AWD, alive with disease. Table 2. The characteristic of the 16 relapse cases Number Relapse months  Within 12 months 11 68.75%  12 months–24 months 2 12.50%  24 months–36 months 2 12.50%  >36 months 1 6.25% Method of first relapse detection  CT scan 8 50.00%  Tumor marker 2 12.50%  CT scan+tumor marker 6 37.50% Treatment for initial relapse  Chemotherapy 14 87.50%  Radiation 0 0.00%  RPLND 0 0.00%  Unknown 2 12.50% Current status  Alive without tumor recurrence 11 68.75%  Death of disease 0 0.00%  Death other cause 0 0.00%  AWD 5 31.25% Number Relapse months  Within 12 months 11 68.75%  12 months–24 months 2 12.50%  24 months–36 months 2 12.50%  >36 months 1 6.25% Method of first relapse detection  CT scan 8 50.00%  Tumor marker 2 12.50%  CT scan+tumor marker 6 37.50% Treatment for initial relapse  Chemotherapy 14 87.50%  Radiation 0 0.00%  RPLND 0 0.00%  Unknown 2 12.50% Current status  Alive without tumor recurrence 11 68.75%  Death of disease 0 0.00%  Death other cause 0 0.00%  AWD 5 31.25% The median time to relapse was 8.35 months range from 2.8 to 51.2 month. RPLND, retroperitoneal lymph node dissection; AWD, alive with disease. Chemotherapy was carried out in 14 recurrent patients, including bleomycin-etoposide-platinum agent (BEP)/EP in 13 patients: two courses in 3 patients, three courses in 5 patients, four courses in 2 patients, five or six courses in 1 patient, and 1 unknown, and three courses of VIP (vindesine-ifosfamide-platinum agent) in 1 patient. After median follow-up of 18.5 months from recurrence, no patient has died of the disease and 11 of 16 (68.8%) patients are alive without disease. Within a median follow-up period of 37.3 months, recurrence occurred in only 1 of 27 (4%) patients who received adjuvant therapy. The RFS rate is shown in Fig. 1. The survival rate of patients with active surveillance was compared with that patients who received adjuvant therapy. Out of 159 clinical stage I NSGCT patients, 27 patients received adjuvant therapy after high orchiectomy based on the decision of the physicians in charge. As an adjuvant treatment, chemotherapy (BEP/EP) was administered to 22 patients, radiation therapy (25.2 Gy to para-aortic and ipsilateral iliac fields) was administered to one patient, RPLND was carried out in three patients, and one patient received both chemotherapy and RPLND. There were no significant differences in the characteristics of the two groups except for the histology of the primary testicular tumor. There was also no significant difference in RFS between patients with active surveillance and adjuvant treatments (2-year RFS rates for active surveillance and adjuvant therapy were 90% and 96%, respectively, P = 0.1548). Figure 1. View largeDownload slide Recurrence-free survival rate in surveillance and adjuvant. Figure 1. View largeDownload slide Recurrence-free survival rate in surveillance and adjuvant. Assessment of risk factors Table 3 shows the predictive factors of tumor recurrence in 132 patients with active surveillance. Age at orchiectomy, preoperative AFP levels and LDH levels were not significantly associated with the risk of recurrence. Furthermore, the pT classification and presence of yolk sac tumor components were not found to be significant in univariate analysis. Only one factor was identified as a significant risk factor for recurrence, the presence of embryonal carcinoma elements. Of 78 patients with embryonal carcinoma elements, 15 (19.2%) had a recurrence, while only one (1.8%) of 55 patients without embryonal carcinoma elements had a recurrence (P = 0.0068). Table 3. Analyses of variables in terms of relapse Relapse Univariate Analysis Multivariate Analysis % No % Yes P-value HR (95%CI) P-value AFP(ng/ml)*  ≤80 83.8 16.2 0.0941 0.315 (0.099–1.005) 0.0510  >80 93 7 LDH(IU/L)**  ≤ULN 90.1 9.9 0.1238 2.257 (0.789–6.452) 0.1289  >ULN 83.8 16.2 pT classification***  ≤T1 89 11 0.6238  ≥T2 86.2 13.8 Embryonal carcinoma elements  Present 80.8 19.2 0.0068 10.239 (1.336–78.488) 0.0252  Absent 98.1 1.9 Yolk sac elements  Present 90.5 9.5 0.3534  Absent 85.5 14.5 Age  ≤30 87.8 12.2 0.8222  >30 88 12 Relapse Univariate Analysis Multivariate Analysis % No % Yes P-value HR (95%CI) P-value AFP(ng/ml)*  ≤80 83.8 16.2 0.0941 0.315 (0.099–1.005) 0.0510  >80 93 7 LDH(IU/L)**  ≤ULN 90.1 9.9 0.1238 2.257 (0.789–6.452) 0.1289  >ULN 83.8 16.2 pT classification***  ≤T1 89 11 0.6238  ≥T2 86.2 13.8 Embryonal carcinoma elements  Present 80.8 19.2 0.0068 10.239 (1.336–78.488) 0.0252  Absent 98.1 1.9 Yolk sac elements  Present 90.5 9.5 0.3534  Absent 85.5 14.5 Age  ≤30 87.8 12.2 0.8222  >30 88 12 *Unknown:1 case. **Unknown:17 cases. ***Tx:3 cases. Table 3. Analyses of variables in terms of relapse Relapse Univariate Analysis Multivariate Analysis % No % Yes P-value HR (95%CI) P-value AFP(ng/ml)*  ≤80 83.8 16.2 0.0941 0.315 (0.099–1.005) 0.0510  >80 93 7 LDH(IU/L)**  ≤ULN 90.1 9.9 0.1238 2.257 (0.789–6.452) 0.1289  >ULN 83.8 16.2 pT classification***  ≤T1 89 11 0.6238  ≥T2 86.2 13.8 Embryonal carcinoma elements  Present 80.8 19.2 0.0068 10.239 (1.336–78.488) 0.0252  Absent 98.1 1.9 Yolk sac elements  Present 90.5 9.5 0.3534  Absent 85.5 14.5 Age  ≤30 87.8 12.2 0.8222  >30 88 12 Relapse Univariate Analysis Multivariate Analysis % No % Yes P-value HR (95%CI) P-value AFP(ng/ml)*  ≤80 83.8 16.2 0.0941 0.315 (0.099–1.005) 0.0510  >80 93 7 LDH(IU/L)**  ≤ULN 90.1 9.9 0.1238 2.257 (0.789–6.452) 0.1289  >ULN 83.8 16.2 pT classification***  ≤T1 89 11 0.6238  ≥T2 86.2 13.8 Embryonal carcinoma elements  Present 80.8 19.2 0.0068 10.239 (1.336–78.488) 0.0252  Absent 98.1 1.9 Yolk sac elements  Present 90.5 9.5 0.3534  Absent 85.5 14.5 Age  ≤30 87.8 12.2 0.8222  >30 88 12 *Unknown:1 case. **Unknown:17 cases. ***Tx:3 cases. Discussion The majority of patients with NSGCT present with stage I disease. The standard treatment options for patients with clinical stage I disease remain controversial because patients have equally excellent survival with active surveillance, RPLND and primary chemotherapy. Active surveillance is the main option for management of clinical stage I testicular tumors and has been demonstrated as safe and effective in previous studies (15–17). However, because the number of cases in individual facilities is small, outcomes of active surveillance of clinical stage I NSGCTs have not been previously evaluated in Japan. The current study was carried out by the JUA to comprehensively aggregate the national registration for testicular cancer. This is the first large scale study of clinical stage I NSGCTs in Japan based on multi-institutional registry data. The present study showed that more than 80% of clinical stage I NSGCTs were followed by active surveillance, which appears to be widely accepted in Japan. A surveillance strategy for stage I NSGCTs provides optimal treatment results with cause-specific survival of 100%. Recurrence occurred in 12.1% of patients and the rest of the patients were cured by high orchiectomy alone. The recurrence rate (12.1%) in the active surveillance group was relatively shorter than that in previous reports. It cannot be denied that race differences and short follow-up periods have influenced this result. However, considering that many recurrences occur within 2 years, the trend in this follow-up period appears to be reasonable (mean: 30 months). Other causes may be fewer high risk cases because embryonal carcinoma elements were observed in 59.1% of mixed forms in this study (total 61%) and 78% in previous reports. Furthermore, the presence of vascular invasion was not included in our analysis, which has also been indicated as a prognostic factor in previous studies (12,18). We cannot deny the possibility of few cases with vascular invasion in our study. The majority of recurrences occur within the first 2 years after high orchiectomy. Thus, a close follow-up schedule is important during this period. In particular, during the first year, imaging studies are important because half of recurrences are detected by only imaging. Late recurrence from 2 to 5 years after orchiectomy was found in three patients in this study. Only 1–5% of recurrences occur at 5 years or longer after high orchiectomy, and few cases of very late recurrence (>10 years) have been reported (12,19,20). Because the median follow-up period of this study is relatively short compared with that of other studies, a longer observation period is necessary to evaluate the importance of lifelong surveillance. Although active surveillance is useful to avoid adverse effects of adjuvant therapy and maintain patient quality of life, it is important to determine the risk factors for recurrence and select patients to be offered surveillance. In previous studies, vascular invasion, the presence of embryonal carcinoma in an orchiectomy specimen, absence of yolk sac tumor elements, pT stage, age and AFP level have been identified as risk factors for disease recurrence (5,8,10,13,14,18). However, there have been several negative reports regarding the significance of the AFP level as a risk factor (12–14). Vergouwe et al. (13) also reported that AFP is not a valuable predictor for occult metastasis. In this study, the preoperative AFP level was not significantly associated with the risk of recurrence. In contrast, patients with a low AFP level tended to experience tumor recurrence in both univariate and multivariate analyses. We consider that this effect may be caused by understaging of preoperative imaging studies in patients with normal AFP values. In this study, only the presence of embryonal carcinoma elements was identified as a significant risk factor for recurrence. Even in high resolution CT scans, detection of small volume metastases (<10 mm) is unreliable, and ~30% of patients with clinical stage I NSGCTs have occult metastatic disease that is the main cause of recurrence. By RPLND of stage I NSGCTs, Sweeney et al. reported that 32% of clinical stage I embryonal carcinoma-predominant patients had pathological stage II disease. In comparison, only 5.6% of clinical stage I non-embryonal carcinoma-predominant patients had pathological stage II disease. Pathological stage II disease was found to occur statistically more often with embryonal carcinoma-predominance than with non-embryonal carcinoma-predominance (21). Many prior studies have reported the presence of embryonal carcinoma as a risk factor for recurrence, which is in accordance with our results. In this study, 78 (59.1%) patients had embryonal carcinoma elements. Among them, 15 (19.2%) experienced recurrences. However, if RPLND or adjuvant chemotherapy was limited only to patients with embryonal carcinoma elements, ~50% of patients will be over-treated. Therefore, the simple presence of embryonal carcinoma appears to be insufficient to select patients for adjuvant therapy. The presence of vascular invasion has also been indicated as a prognostic factor in previous studies (12,18). Furthermore, Divrik et al. (14) reported that the combination of the presence of vascular invasion and percentage of embryonal carcinoma (>50%) yielded a recurrence risk of ~75%. Although we had no data about the presence of vascular invasion in this study, additional evaluation including vascular invasion is desirable to identify more specific prognostic factors and reduce the risk of unnecessary adjuvant therapy. Acknowledgements These clinicopathological statistics are based on the results from a number of institutions in Japan. We are grateful for the cooperation of many Japanese urologists. This document was created by the Cancer Registration Committee of the JUA. The members of the Cancer Registration Committee of the JUA are: Chikara Ohyama, Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki; Hiroomi Kanayama, Department of Urology, The University of Tokushima Graduate School, Tokushima; Hiroyuki Fujimoto, Urology Division, National Cancer Center Hospital, Tokyo; Tsuneharu Miki, Department of Urology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto (former); Hiroyuki Nishiyama, Department of Urology, Faculty of Medicine, University of Tsukuba, Ibaraki; Kazuhiro Suzuki, Department of Urology, Gunma University Graduate School of Medicine, Gunma; Masatoshi Eto, Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hiroyuki Nakanishi, Department of Urology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto (former); Tomoharu Fukumori, Department of Urology, The University of Tokushima Graduate School, Tokushima; Seiji Naito, Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (former), Japan. Conflict of interest statement None declared. References 1 Miki T , Kamoi K , Fujimoto H , et al. . Clinical characteristics and oncological outcomes of testicular cancer patients registered in 2005 and 2008: the first large-scale study from Cancer Registration Committee of the Japanese Urological Association . Int J Urol 2014 ; 21 : S1 – 6 . Google Scholar CrossRef Search ADS PubMed 2 Sonneveld DJ , Hoekstra HJ , Van Der Graaf WT , Sluiter WJ , Schraffordt KH , Sleijfer DT . The changing distribution of stage in nonseminomatous germ cell tumors from 1977 to 1996 . BJU Int 1999 ; 84 : 68 – 74 . Google Scholar CrossRef Search ADS PubMed 3 Donohue JP , Thornhill JA , Foster RS , Rowland RG , Bihrle R . Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965 to 1989): Modifications of technique and impact on ejaculation . J Urol 1993 ; 149 : 237 – 43 . Google Scholar CrossRef Search ADS PubMed 4 Pizzocaro G , Zanoni F , Salvioni R , et al. . Surveillance or lymph node dissection in clinical stage I non-seminomatous germinal testis cancer? Br J Urol 1985 ; 57 : 759 – 62 . Google Scholar CrossRef Search ADS PubMed 5 Choueiri TK , Stephenson AJ , Gilligan T , et al. . Management of clinical stage I nonseminomatous germ cell testicular cancer . Urol Clin North Am 2007 ; 34 : 137 – 48 . Google Scholar CrossRef Search ADS PubMed 6 International Germ Cell Cancer Collaborative Group . International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers . J Clin Oncol 1997 ; 15 : 594 – 603 . CrossRef Search ADS PubMed 7 Wishnow KI , Johnson DE , Swanson DA , et al. . Identifying patients with low-risk clinical stage I nonseminomatous testicular tumors who should be treated by surveillance . Urology 1989 ; 34 : 339 – 43 . Google Scholar CrossRef Search ADS PubMed 8 Amato RJ , Ro JY , Ayala AG , et al. . Risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis . Urology 2004 ; 63 : 148 – 9 . Google Scholar CrossRef Search ADS 9 Raghavan D , Colls B , Levi J , et al. . Surveillance for stage I non- seminomatous germ cell tumours of the testis: the optimal protocol has not yet been defined . Br J Urol 1988 ; 61 : 522 – 6 . Google Scholar CrossRef Search ADS PubMed 10 Nicolai N , Miceli R , Necchi A , et al. . Retroperitoneal lymph node dissection with no adjuvant chemotherapy in clinical stage I nonseminomatous germ cell tumors: long-term outcome and analysis of risk factors of recurrence . Eur Urol 2010 ; 58 : 912 – 8 . Google Scholar CrossRef Search ADS PubMed 11 Atsu N , Eskicorapci SY , Uner A , et al. . A novel surveillance protocol for stage I non- seminomatous germ cell testicular tumours . BJU Int 2003 ; 92 : 32 – 5 . Google Scholar CrossRef Search ADS PubMed 12 Daugaard G , Gry Gundgaard M , Mortensen MS , et al. . Surveillance for stage I nonseminoma testicular cancer: outcomes and long-term follow-up in a population-based cohort . J Clin Oncol 2014 ; 32 : 3817 – 23 . Google Scholar CrossRef Search ADS PubMed 13 Vergouwe Y , Steyerberg EW , Eijkemans MJ , Albers P , Habbema JD . Predictors of occult metastasis in clinical stage I nonseminoma: a systematic review . J Clin Oncol 2003 ; 21 : 4092 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Divrik RT , Akdogan B , Ozen H , Zorlu F . Outcomes of surveillance protocol of clinical stage I nonseminomatous germ cell tumors-is shift to risk adapted policy justified? J Urol 2006 ; 176 : 1429 – 30 . Google Scholar CrossRef Search ADS 15 Tandstad T , Dahl O , Cohn-Cedermark G , et al. . Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: The SWENOTECA management program . J Clin Oncol 2009 ; 27 : 2122 – 8 . Google Scholar CrossRef Search ADS PubMed 16 Duran I , Sturgeon JF , Jewett MA , et al. . Initial versus recent outcomes with a non-risk adapted surveillance policy in stage I non-seminomatous germ cell tumors (NSGCT) . J Clin Oncol 2007 ; 25 : 240s . 17 Kollmannsberger C , Moore C , Chi KN , et al. . Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: diminishing treatment-related morbidity while maintaining efficacy . Ann Oncol 2010 ; 21 : 1296 – 1301 . Google Scholar CrossRef Search ADS PubMed 18 Albers P , Siener R , Kliesch S , et al. . Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial . J Clin Oncol 2003 ; 21 : 1505 – 12 . Google Scholar CrossRef Search ADS PubMed 19 Hayes JR , Jewett MAS , Hamilton RJ . 28-year late spermatic cord relapse of a testicular non-seminomatous germ cell tumour, managed robotically . Can Urol Assoc J 2016 ; 10 : E257 – 60 . doi:10.5489/cuaj.3492 . Google Scholar CrossRef Search ADS PubMed 20 Arafat W , Albany C , Ulbright TM , Foster R , Einhorn LH . Very late relapse of germ cell tumor as a teratoma: A case report and review of the literature . J Surg Case Rep 2014 ; doi:10.1093/jscr/rju051 . 21 Sweeney CJ , Hermans BP , Heilman DK , Fostern RS , Donohue JP , Einhorn LH . Result and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma-predominant testis cancer . J Clin Oncol 2000 ; 18 : 358 – 62 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Outcomes of active surveillance of clinical stage I non-seminomatous germ cell tumors: sub-analysis of the multi-institutional nationwide case series of the Japanese Urological Association

Loading next page...
 
/lp/ou_press/outcomes-of-active-surveillance-of-clinical-stage-i-non-seminomatous-MBbH1oaM2U
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
ISSN
0368-2811
eISSN
1465-3621
D.O.I.
10.1093/jjco/hyy051
Publisher site
See Article on Publisher Site

Abstract

Abstract Objective To evaluate the survival rate and risk factors of distant metastasis in stage I non-seminomatous germ cell tumor (NSGCT) cases without adjuvant treatments. Methods A national testicular cancer survey of cases newly diagnosed in 2005 and 2008 was conducted by the Japanese Urological Association in 2011. In 159 stage I NSGCT cases, 132 were followed by active surveillance after high orchiectomy. Their recurrence-free survival rate (RFS) was compared with 27 cases that received adjuvant treatments, and clinical and pathological parameters were explored to identify significant risk factors of recurrence. Results Within a median follow-up period of 30.3 months (range: 0.3–65.6 months), 16 (12.1%) of the 132 surveillance cases relapsed at 2.8–51.2 months after high orchiectomy (median: 8.35 months). The 2-year RFS rate was 90%. Eleven (68.8%) cases relapsed within 1 year, and five (31.3%) cases relapsed in 3 years or more. Half (50%) of the recurrences were detected by imaging studies alone, 37.5% by imaging combined with tumor markers, and 12.5% by tumor marker elevation alone. The only significant risk factor of recurrence was the existence of embryonal carcinoma elements in the primary testicular tumor (P = 0.0068). There was no significant difference in RFS between cases with active surveillance and adjuvant treatments. Conclusions The present report is the first large scale study of clinical stage I NSGCTs in Japan. Active surveillance appears to be an effective treatment option for patients with clinical stage I NSGCTs. active surveillance, epidemiology, germ cell tumor, Japanese, nonseminoma Introduction Clinical stage I testicular cancer is the most common presentation of testicular cancer (1,2). Even with modern staging techniques incorporating computed tomography (CT) and monitoring of serum tumor markers, ~30% of patients with clinical stage I non-seminomatous germ cell tumors (NSGCTs) have occult metastatic disease (3,4) and will have a recurrence if they receive active surveillance after high orchiectomy. However, if retroperitoneal lymph node dissection (RPLND) or adjuvant chemotherapy is administered to patients, many patients will be over-treated, and even if recurrence occurs, almost all cases in the surveillance group can be cured by cisplatin-based chemotherapy (5). Therefore, active surveillance is generally recommended, particularly for patients thought to have a low recurrence risk. Because of the inaccuracy of clinical staging methods and the risk of metastasis, clinical research focusing on the development of prognostic risk factors remains one of the most important clinical challenges. Here, we report outcomes of active surveillance for clinical stage I NSGCT and an analysis of risk factors for recurrence in a Japanese population. Methods A testicular cancer registry program was conducted in 2011 by The Cancer Registration Committee of the Japanese Urological Association (JUA) to collect data of testicular cancer patients diagnosed in 2005 and 2008 from the accredited training institutes for board certification in urology. The survey included details such as age, presenting symptoms, physical examination findings, tumor markers, histopathology, clinical stage, initial treatment and clinical outcomes. The survey did not include the presence of lymphovascular invasion because it is difficult to unify the criteria across all institutions. Among 1157 patients with testicular tumors registered from 274 institutions nationwide, 729 patients were diagnosed with stage I testicular tumors. Pathological examination of the specimens of high orchiectomy revealed that 160 were clinical stage I NSGCTs. We could not confirm the follow-up data of one patient, and 27 cases received adjuvant treatments. Therefore, we finally analyzed 132 patients with stage I NSGCT followed by active surveillance. The frequency of follow-up investigations was not unified and depended on each institution. Regarding tumor markers, although recording the human chorionic gonadotropin (HCG) value is encouraged, we excluded it from analysis because in many of the institutions a free HCG-β (ng/ml) measurement kit, which is unsuitable for the International Germ Cell Consensus Classification (6), was used instead of a total HCG (mIU/ml) measurement kit. The normal concentration of α-fetoprotein (AFP) is 20 ng/ml in accordance with JUA Cancer Registration Statistics (1). Lactate dehydrogenase (LDH) was evaluated depending on its normal range for each facility. Pathological details were obtained from reports of each facility. To predict risk factors, we used the previously published cutoff values of these parameters, i.e., the presence of abnormal serum AFP levels (cutoff: 80 ng/ml) before orchiectomy (7,8), pathological tumor (pT) classification (cutoff greater than 1) (9,10), presence of embryonal carcinoma elements (11,12), presence of yolk sac elements (10,13) and age (cutoff greater than 30) (13,14). This retrospective study was approved by the Institutional Review Board with all participating sites providing the necessary institutional data sharing agreements prior to initiation. The variables of the different groups were compared using the chi-squared test or Mann–Whitney U-test. The Kaplan–Meier method was used to estimate recurrence-free survival (RFS) rates that were compared using the log-rank test. RFS was measured from the date of high orchiectomy until the date of diagnosis of recurrence or until the last follow-up. Univariate and multivariate analyses of RFS were performed using the log-rank test or Cox proportional hazards regression models. Significant or marginally significant variables in univariate analyses were chosen for multivariate analysis. Differences among groups were regarded as significant when P < 0.05. These analyses were performed with the Statview version 5.0 statistical software package (SAS Institute, Cary, NC, USA). Results Patient characteristics Median and mean ages of patients were 32.0 and 33.6 years, respectively. Out of 132 patients, 21 patients (15.9%) had a previous history of inguinal or scrotal surgery. One hundred and thirty-one (99.2%) patients presented with a scrotal mass or swelling and 16 (12.1%) patients complained of scrotal pain. One patient presented with gynecomastia. Laterality of the scrotal mass was on the right side in 83 patients (62.9%), the left side in 47 patients (35.6%) and uncertain in 2 patients (1.5%). AFP was examined in 131 patients (99.2%) and found to be abnormally elevated (>20 ng/ml) in 80 (61.1%) of them (Table 1). Two patients showed an extremely elevated AFP value of ≥10 000 ng/ml with a maximum value of 15 537 ng/ml. LDH was examined in 115 patients (87.1%) and found to be abnormally elevated in 34 (29.6%) of them. An extremely elevated LDH value (>10 × upper limit of normal) was not observed. Table 1. The characteristic of the 159 stage I non-seminomatous testicular tumor cases Active surveillance Adjuvant therapy P-value No. patients 132 27 Mean age(±SD) 33.6 ± 11.73 31.8 ± 11.33 0.503 AFP(ng/ml)  <20 51 38.6% 8 29.6% 0.1507  20–80 23 17.4% 2 7.4%  >80 57 43.2% 17 63.0%  Unknown 1 0.8% 0 0.0% LDH(IU/L)  ≤ULN 81 61.4% 16 59.3% 0.6189  >ULN 34 25.8% 10 37.0%  Unknown 17 12.9% 1 3.7% pT classification  Tis 1 0.8% 0 0.0% 0.6297  1 99 75.0% 20 74.1%  2 25 18.9% 7 25.9%  3 4 3.0% 0 0.0%  4 0 0.0% 0 0.0%  Tx 3 2.3% 0 0.0% Histology  Pure embryonal carcinoma 9 6.8% 2 7.4% 0.0305  Pure teratoma 13 9.8% 0 0.0%  Pure yolk sac tumor 5 3.8% 5 18.5%  Pure choriocarcinoma 0 0.0% 0 0.0%  ITGCN 1 0.8% 0 0.0%  Mixed forms 104 78.8% 20 74.1% Elements  Seminoma 61 46.2% 8 29.6% 0.1132  Embryonal carcinoma 78 59.1% 19 70.4% 0.379  Yolk sac tumor 63 47.7% 17 63.0% 0.1491  Teratoma 85 64.4% 11 40.7% 0.022  Choriocaricnoma 25 18.9% 4 14.8% 0.6131  Others 6 4.5% 0 0.0% 0.2588 Adjuvant treatment  no(surveillance) 132  chemotherapy 22  radiation 1  RPLND 3  chemotherapy+RPLND 1 Active surveillance Adjuvant therapy P-value No. patients 132 27 Mean age(±SD) 33.6 ± 11.73 31.8 ± 11.33 0.503 AFP(ng/ml)  <20 51 38.6% 8 29.6% 0.1507  20–80 23 17.4% 2 7.4%  >80 57 43.2% 17 63.0%  Unknown 1 0.8% 0 0.0% LDH(IU/L)  ≤ULN 81 61.4% 16 59.3% 0.6189  >ULN 34 25.8% 10 37.0%  Unknown 17 12.9% 1 3.7% pT classification  Tis 1 0.8% 0 0.0% 0.6297  1 99 75.0% 20 74.1%  2 25 18.9% 7 25.9%  3 4 3.0% 0 0.0%  4 0 0.0% 0 0.0%  Tx 3 2.3% 0 0.0% Histology  Pure embryonal carcinoma 9 6.8% 2 7.4% 0.0305  Pure teratoma 13 9.8% 0 0.0%  Pure yolk sac tumor 5 3.8% 5 18.5%  Pure choriocarcinoma 0 0.0% 0 0.0%  ITGCN 1 0.8% 0 0.0%  Mixed forms 104 78.8% 20 74.1% Elements  Seminoma 61 46.2% 8 29.6% 0.1132  Embryonal carcinoma 78 59.1% 19 70.4% 0.379  Yolk sac tumor 63 47.7% 17 63.0% 0.1491  Teratoma 85 64.4% 11 40.7% 0.022  Choriocaricnoma 25 18.9% 4 14.8% 0.6131  Others 6 4.5% 0 0.0% 0.2588 Adjuvant treatment  no(surveillance) 132  chemotherapy 22  radiation 1  RPLND 3  chemotherapy+RPLND 1 ITGCN, intratubular germ cell neoplasia; RPLND, retroperitoneal lymph node dissection. Table 1. The characteristic of the 159 stage I non-seminomatous testicular tumor cases Active surveillance Adjuvant therapy P-value No. patients 132 27 Mean age(±SD) 33.6 ± 11.73 31.8 ± 11.33 0.503 AFP(ng/ml)  <20 51 38.6% 8 29.6% 0.1507  20–80 23 17.4% 2 7.4%  >80 57 43.2% 17 63.0%  Unknown 1 0.8% 0 0.0% LDH(IU/L)  ≤ULN 81 61.4% 16 59.3% 0.6189  >ULN 34 25.8% 10 37.0%  Unknown 17 12.9% 1 3.7% pT classification  Tis 1 0.8% 0 0.0% 0.6297  1 99 75.0% 20 74.1%  2 25 18.9% 7 25.9%  3 4 3.0% 0 0.0%  4 0 0.0% 0 0.0%  Tx 3 2.3% 0 0.0% Histology  Pure embryonal carcinoma 9 6.8% 2 7.4% 0.0305  Pure teratoma 13 9.8% 0 0.0%  Pure yolk sac tumor 5 3.8% 5 18.5%  Pure choriocarcinoma 0 0.0% 0 0.0%  ITGCN 1 0.8% 0 0.0%  Mixed forms 104 78.8% 20 74.1% Elements  Seminoma 61 46.2% 8 29.6% 0.1132  Embryonal carcinoma 78 59.1% 19 70.4% 0.379  Yolk sac tumor 63 47.7% 17 63.0% 0.1491  Teratoma 85 64.4% 11 40.7% 0.022  Choriocaricnoma 25 18.9% 4 14.8% 0.6131  Others 6 4.5% 0 0.0% 0.2588 Adjuvant treatment  no(surveillance) 132  chemotherapy 22  radiation 1  RPLND 3  chemotherapy+RPLND 1 Active surveillance Adjuvant therapy P-value No. patients 132 27 Mean age(±SD) 33.6 ± 11.73 31.8 ± 11.33 0.503 AFP(ng/ml)  <20 51 38.6% 8 29.6% 0.1507  20–80 23 17.4% 2 7.4%  >80 57 43.2% 17 63.0%  Unknown 1 0.8% 0 0.0% LDH(IU/L)  ≤ULN 81 61.4% 16 59.3% 0.6189  >ULN 34 25.8% 10 37.0%  Unknown 17 12.9% 1 3.7% pT classification  Tis 1 0.8% 0 0.0% 0.6297  1 99 75.0% 20 74.1%  2 25 18.9% 7 25.9%  3 4 3.0% 0 0.0%  4 0 0.0% 0 0.0%  Tx 3 2.3% 0 0.0% Histology  Pure embryonal carcinoma 9 6.8% 2 7.4% 0.0305  Pure teratoma 13 9.8% 0 0.0%  Pure yolk sac tumor 5 3.8% 5 18.5%  Pure choriocarcinoma 0 0.0% 0 0.0%  ITGCN 1 0.8% 0 0.0%  Mixed forms 104 78.8% 20 74.1% Elements  Seminoma 61 46.2% 8 29.6% 0.1132  Embryonal carcinoma 78 59.1% 19 70.4% 0.379  Yolk sac tumor 63 47.7% 17 63.0% 0.1491  Teratoma 85 64.4% 11 40.7% 0.022  Choriocaricnoma 25 18.9% 4 14.8% 0.6131  Others 6 4.5% 0 0.0% 0.2588 Adjuvant treatment  no(surveillance) 132  chemotherapy 22  radiation 1  RPLND 3  chemotherapy+RPLND 1 ITGCN, intratubular germ cell neoplasia; RPLND, retroperitoneal lymph node dissection. The pathological stage was Tis/T1 in 100 patients, T2–4 in 29 and Tx in 3. A solitary histological subtype was observed in 28 patients and a mixed subtype was observed in 104 patients: seminomatous elements in 61 patients, embryonal carcinoma in 78, yolk sac tumors in 63, teratomas in 85 and choriocarcinoma in 25. Prognosis after active surveillance The rate of patients followed by active surveillance was 77.4% in 2005 and 86.6% in 2008. There was no significant difference in the 2-year RFS rate at 88.2% in 2005 and 89.6% in 2008. Within a median follow-up period of 30.3 months (range: 0.3–65.6 months), recurrence occurred in 16 of 132 (12.1%) patients. Sixteen cases of recurrence during active surveillance are summarized in Table 2. Most recurrences (81.3%) were diagnosed within 24 months after initial diagnosis, and there were only three late recurrences (18.7%). The first evidence of recurrence was most commonly identified by imaging alone (50%) or in combination with tumor markers (37.5%; 87.5% overall), and only half of the recurrences had elevated serum markers. The percentage of recurrences detected only by imaging decreased from 54.5% (6 of 11) within the first 12 months to 40% (2 of 5) after 12 months. The percentage of recurrences detected in combination with tumor markers increased from 27.3% (3 of 11) within the first 12 months to 60% (3 of 5) after 12 months. Two recurrences were detected only by increases in tumor markers within 6 months. Out of 16 recurrent patients, all three patients with normal tumor markers at first diagnosis were detected only by imaging and 3 of 13 patients with elevated tumor markers at first diagnosis did not have elevation of tumor markers at recurrence. In 14 patients diagnosed with recurrence by imaging, the recurrent sites were retroperitoneal lymph nodes in all patients, cervical lymph nodes in 2 patients, and the lung and axillary lymph nodes in one patient. There were no cases of recurrence in the chest with normal tumor markers and normal abdominal imaging. Table 2. The characteristic of the 16 relapse cases Number Relapse months  Within 12 months 11 68.75%  12 months–24 months 2 12.50%  24 months–36 months 2 12.50%  >36 months 1 6.25% Method of first relapse detection  CT scan 8 50.00%  Tumor marker 2 12.50%  CT scan+tumor marker 6 37.50% Treatment for initial relapse  Chemotherapy 14 87.50%  Radiation 0 0.00%  RPLND 0 0.00%  Unknown 2 12.50% Current status  Alive without tumor recurrence 11 68.75%  Death of disease 0 0.00%  Death other cause 0 0.00%  AWD 5 31.25% Number Relapse months  Within 12 months 11 68.75%  12 months–24 months 2 12.50%  24 months–36 months 2 12.50%  >36 months 1 6.25% Method of first relapse detection  CT scan 8 50.00%  Tumor marker 2 12.50%  CT scan+tumor marker 6 37.50% Treatment for initial relapse  Chemotherapy 14 87.50%  Radiation 0 0.00%  RPLND 0 0.00%  Unknown 2 12.50% Current status  Alive without tumor recurrence 11 68.75%  Death of disease 0 0.00%  Death other cause 0 0.00%  AWD 5 31.25% The median time to relapse was 8.35 months range from 2.8 to 51.2 month. RPLND, retroperitoneal lymph node dissection; AWD, alive with disease. Table 2. The characteristic of the 16 relapse cases Number Relapse months  Within 12 months 11 68.75%  12 months–24 months 2 12.50%  24 months–36 months 2 12.50%  >36 months 1 6.25% Method of first relapse detection  CT scan 8 50.00%  Tumor marker 2 12.50%  CT scan+tumor marker 6 37.50% Treatment for initial relapse  Chemotherapy 14 87.50%  Radiation 0 0.00%  RPLND 0 0.00%  Unknown 2 12.50% Current status  Alive without tumor recurrence 11 68.75%  Death of disease 0 0.00%  Death other cause 0 0.00%  AWD 5 31.25% Number Relapse months  Within 12 months 11 68.75%  12 months–24 months 2 12.50%  24 months–36 months 2 12.50%  >36 months 1 6.25% Method of first relapse detection  CT scan 8 50.00%  Tumor marker 2 12.50%  CT scan+tumor marker 6 37.50% Treatment for initial relapse  Chemotherapy 14 87.50%  Radiation 0 0.00%  RPLND 0 0.00%  Unknown 2 12.50% Current status  Alive without tumor recurrence 11 68.75%  Death of disease 0 0.00%  Death other cause 0 0.00%  AWD 5 31.25% The median time to relapse was 8.35 months range from 2.8 to 51.2 month. RPLND, retroperitoneal lymph node dissection; AWD, alive with disease. Chemotherapy was carried out in 14 recurrent patients, including bleomycin-etoposide-platinum agent (BEP)/EP in 13 patients: two courses in 3 patients, three courses in 5 patients, four courses in 2 patients, five or six courses in 1 patient, and 1 unknown, and three courses of VIP (vindesine-ifosfamide-platinum agent) in 1 patient. After median follow-up of 18.5 months from recurrence, no patient has died of the disease and 11 of 16 (68.8%) patients are alive without disease. Within a median follow-up period of 37.3 months, recurrence occurred in only 1 of 27 (4%) patients who received adjuvant therapy. The RFS rate is shown in Fig. 1. The survival rate of patients with active surveillance was compared with that patients who received adjuvant therapy. Out of 159 clinical stage I NSGCT patients, 27 patients received adjuvant therapy after high orchiectomy based on the decision of the physicians in charge. As an adjuvant treatment, chemotherapy (BEP/EP) was administered to 22 patients, radiation therapy (25.2 Gy to para-aortic and ipsilateral iliac fields) was administered to one patient, RPLND was carried out in three patients, and one patient received both chemotherapy and RPLND. There were no significant differences in the characteristics of the two groups except for the histology of the primary testicular tumor. There was also no significant difference in RFS between patients with active surveillance and adjuvant treatments (2-year RFS rates for active surveillance and adjuvant therapy were 90% and 96%, respectively, P = 0.1548). Figure 1. View largeDownload slide Recurrence-free survival rate in surveillance and adjuvant. Figure 1. View largeDownload slide Recurrence-free survival rate in surveillance and adjuvant. Assessment of risk factors Table 3 shows the predictive factors of tumor recurrence in 132 patients with active surveillance. Age at orchiectomy, preoperative AFP levels and LDH levels were not significantly associated with the risk of recurrence. Furthermore, the pT classification and presence of yolk sac tumor components were not found to be significant in univariate analysis. Only one factor was identified as a significant risk factor for recurrence, the presence of embryonal carcinoma elements. Of 78 patients with embryonal carcinoma elements, 15 (19.2%) had a recurrence, while only one (1.8%) of 55 patients without embryonal carcinoma elements had a recurrence (P = 0.0068). Table 3. Analyses of variables in terms of relapse Relapse Univariate Analysis Multivariate Analysis % No % Yes P-value HR (95%CI) P-value AFP(ng/ml)*  ≤80 83.8 16.2 0.0941 0.315 (0.099–1.005) 0.0510  >80 93 7 LDH(IU/L)**  ≤ULN 90.1 9.9 0.1238 2.257 (0.789–6.452) 0.1289  >ULN 83.8 16.2 pT classification***  ≤T1 89 11 0.6238  ≥T2 86.2 13.8 Embryonal carcinoma elements  Present 80.8 19.2 0.0068 10.239 (1.336–78.488) 0.0252  Absent 98.1 1.9 Yolk sac elements  Present 90.5 9.5 0.3534  Absent 85.5 14.5 Age  ≤30 87.8 12.2 0.8222  >30 88 12 Relapse Univariate Analysis Multivariate Analysis % No % Yes P-value HR (95%CI) P-value AFP(ng/ml)*  ≤80 83.8 16.2 0.0941 0.315 (0.099–1.005) 0.0510  >80 93 7 LDH(IU/L)**  ≤ULN 90.1 9.9 0.1238 2.257 (0.789–6.452) 0.1289  >ULN 83.8 16.2 pT classification***  ≤T1 89 11 0.6238  ≥T2 86.2 13.8 Embryonal carcinoma elements  Present 80.8 19.2 0.0068 10.239 (1.336–78.488) 0.0252  Absent 98.1 1.9 Yolk sac elements  Present 90.5 9.5 0.3534  Absent 85.5 14.5 Age  ≤30 87.8 12.2 0.8222  >30 88 12 *Unknown:1 case. **Unknown:17 cases. ***Tx:3 cases. Table 3. Analyses of variables in terms of relapse Relapse Univariate Analysis Multivariate Analysis % No % Yes P-value HR (95%CI) P-value AFP(ng/ml)*  ≤80 83.8 16.2 0.0941 0.315 (0.099–1.005) 0.0510  >80 93 7 LDH(IU/L)**  ≤ULN 90.1 9.9 0.1238 2.257 (0.789–6.452) 0.1289  >ULN 83.8 16.2 pT classification***  ≤T1 89 11 0.6238  ≥T2 86.2 13.8 Embryonal carcinoma elements  Present 80.8 19.2 0.0068 10.239 (1.336–78.488) 0.0252  Absent 98.1 1.9 Yolk sac elements  Present 90.5 9.5 0.3534  Absent 85.5 14.5 Age  ≤30 87.8 12.2 0.8222  >30 88 12 Relapse Univariate Analysis Multivariate Analysis % No % Yes P-value HR (95%CI) P-value AFP(ng/ml)*  ≤80 83.8 16.2 0.0941 0.315 (0.099–1.005) 0.0510  >80 93 7 LDH(IU/L)**  ≤ULN 90.1 9.9 0.1238 2.257 (0.789–6.452) 0.1289  >ULN 83.8 16.2 pT classification***  ≤T1 89 11 0.6238  ≥T2 86.2 13.8 Embryonal carcinoma elements  Present 80.8 19.2 0.0068 10.239 (1.336–78.488) 0.0252  Absent 98.1 1.9 Yolk sac elements  Present 90.5 9.5 0.3534  Absent 85.5 14.5 Age  ≤30 87.8 12.2 0.8222  >30 88 12 *Unknown:1 case. **Unknown:17 cases. ***Tx:3 cases. Discussion The majority of patients with NSGCT present with stage I disease. The standard treatment options for patients with clinical stage I disease remain controversial because patients have equally excellent survival with active surveillance, RPLND and primary chemotherapy. Active surveillance is the main option for management of clinical stage I testicular tumors and has been demonstrated as safe and effective in previous studies (15–17). However, because the number of cases in individual facilities is small, outcomes of active surveillance of clinical stage I NSGCTs have not been previously evaluated in Japan. The current study was carried out by the JUA to comprehensively aggregate the national registration for testicular cancer. This is the first large scale study of clinical stage I NSGCTs in Japan based on multi-institutional registry data. The present study showed that more than 80% of clinical stage I NSGCTs were followed by active surveillance, which appears to be widely accepted in Japan. A surveillance strategy for stage I NSGCTs provides optimal treatment results with cause-specific survival of 100%. Recurrence occurred in 12.1% of patients and the rest of the patients were cured by high orchiectomy alone. The recurrence rate (12.1%) in the active surveillance group was relatively shorter than that in previous reports. It cannot be denied that race differences and short follow-up periods have influenced this result. However, considering that many recurrences occur within 2 years, the trend in this follow-up period appears to be reasonable (mean: 30 months). Other causes may be fewer high risk cases because embryonal carcinoma elements were observed in 59.1% of mixed forms in this study (total 61%) and 78% in previous reports. Furthermore, the presence of vascular invasion was not included in our analysis, which has also been indicated as a prognostic factor in previous studies (12,18). We cannot deny the possibility of few cases with vascular invasion in our study. The majority of recurrences occur within the first 2 years after high orchiectomy. Thus, a close follow-up schedule is important during this period. In particular, during the first year, imaging studies are important because half of recurrences are detected by only imaging. Late recurrence from 2 to 5 years after orchiectomy was found in three patients in this study. Only 1–5% of recurrences occur at 5 years or longer after high orchiectomy, and few cases of very late recurrence (>10 years) have been reported (12,19,20). Because the median follow-up period of this study is relatively short compared with that of other studies, a longer observation period is necessary to evaluate the importance of lifelong surveillance. Although active surveillance is useful to avoid adverse effects of adjuvant therapy and maintain patient quality of life, it is important to determine the risk factors for recurrence and select patients to be offered surveillance. In previous studies, vascular invasion, the presence of embryonal carcinoma in an orchiectomy specimen, absence of yolk sac tumor elements, pT stage, age and AFP level have been identified as risk factors for disease recurrence (5,8,10,13,14,18). However, there have been several negative reports regarding the significance of the AFP level as a risk factor (12–14). Vergouwe et al. (13) also reported that AFP is not a valuable predictor for occult metastasis. In this study, the preoperative AFP level was not significantly associated with the risk of recurrence. In contrast, patients with a low AFP level tended to experience tumor recurrence in both univariate and multivariate analyses. We consider that this effect may be caused by understaging of preoperative imaging studies in patients with normal AFP values. In this study, only the presence of embryonal carcinoma elements was identified as a significant risk factor for recurrence. Even in high resolution CT scans, detection of small volume metastases (<10 mm) is unreliable, and ~30% of patients with clinical stage I NSGCTs have occult metastatic disease that is the main cause of recurrence. By RPLND of stage I NSGCTs, Sweeney et al. reported that 32% of clinical stage I embryonal carcinoma-predominant patients had pathological stage II disease. In comparison, only 5.6% of clinical stage I non-embryonal carcinoma-predominant patients had pathological stage II disease. Pathological stage II disease was found to occur statistically more often with embryonal carcinoma-predominance than with non-embryonal carcinoma-predominance (21). Many prior studies have reported the presence of embryonal carcinoma as a risk factor for recurrence, which is in accordance with our results. In this study, 78 (59.1%) patients had embryonal carcinoma elements. Among them, 15 (19.2%) experienced recurrences. However, if RPLND or adjuvant chemotherapy was limited only to patients with embryonal carcinoma elements, ~50% of patients will be over-treated. Therefore, the simple presence of embryonal carcinoma appears to be insufficient to select patients for adjuvant therapy. The presence of vascular invasion has also been indicated as a prognostic factor in previous studies (12,18). Furthermore, Divrik et al. (14) reported that the combination of the presence of vascular invasion and percentage of embryonal carcinoma (>50%) yielded a recurrence risk of ~75%. Although we had no data about the presence of vascular invasion in this study, additional evaluation including vascular invasion is desirable to identify more specific prognostic factors and reduce the risk of unnecessary adjuvant therapy. Acknowledgements These clinicopathological statistics are based on the results from a number of institutions in Japan. We are grateful for the cooperation of many Japanese urologists. This document was created by the Cancer Registration Committee of the JUA. The members of the Cancer Registration Committee of the JUA are: Chikara Ohyama, Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki; Hiroomi Kanayama, Department of Urology, The University of Tokushima Graduate School, Tokushima; Hiroyuki Fujimoto, Urology Division, National Cancer Center Hospital, Tokyo; Tsuneharu Miki, Department of Urology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto (former); Hiroyuki Nishiyama, Department of Urology, Faculty of Medicine, University of Tsukuba, Ibaraki; Kazuhiro Suzuki, Department of Urology, Gunma University Graduate School of Medicine, Gunma; Masatoshi Eto, Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka; Hiroyuki Nakanishi, Department of Urology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto (former); Tomoharu Fukumori, Department of Urology, The University of Tokushima Graduate School, Tokushima; Seiji Naito, Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (former), Japan. Conflict of interest statement None declared. References 1 Miki T , Kamoi K , Fujimoto H , et al. . Clinical characteristics and oncological outcomes of testicular cancer patients registered in 2005 and 2008: the first large-scale study from Cancer Registration Committee of the Japanese Urological Association . Int J Urol 2014 ; 21 : S1 – 6 . Google Scholar CrossRef Search ADS PubMed 2 Sonneveld DJ , Hoekstra HJ , Van Der Graaf WT , Sluiter WJ , Schraffordt KH , Sleijfer DT . The changing distribution of stage in nonseminomatous germ cell tumors from 1977 to 1996 . BJU Int 1999 ; 84 : 68 – 74 . Google Scholar CrossRef Search ADS PubMed 3 Donohue JP , Thornhill JA , Foster RS , Rowland RG , Bihrle R . Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965 to 1989): Modifications of technique and impact on ejaculation . J Urol 1993 ; 149 : 237 – 43 . Google Scholar CrossRef Search ADS PubMed 4 Pizzocaro G , Zanoni F , Salvioni R , et al. . Surveillance or lymph node dissection in clinical stage I non-seminomatous germinal testis cancer? Br J Urol 1985 ; 57 : 759 – 62 . Google Scholar CrossRef Search ADS PubMed 5 Choueiri TK , Stephenson AJ , Gilligan T , et al. . Management of clinical stage I nonseminomatous germ cell testicular cancer . Urol Clin North Am 2007 ; 34 : 137 – 48 . Google Scholar CrossRef Search ADS PubMed 6 International Germ Cell Cancer Collaborative Group . International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers . J Clin Oncol 1997 ; 15 : 594 – 603 . CrossRef Search ADS PubMed 7 Wishnow KI , Johnson DE , Swanson DA , et al. . Identifying patients with low-risk clinical stage I nonseminomatous testicular tumors who should be treated by surveillance . Urology 1989 ; 34 : 339 – 43 . Google Scholar CrossRef Search ADS PubMed 8 Amato RJ , Ro JY , Ayala AG , et al. . Risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis . Urology 2004 ; 63 : 148 – 9 . Google Scholar CrossRef Search ADS 9 Raghavan D , Colls B , Levi J , et al. . Surveillance for stage I non- seminomatous germ cell tumours of the testis: the optimal protocol has not yet been defined . Br J Urol 1988 ; 61 : 522 – 6 . Google Scholar CrossRef Search ADS PubMed 10 Nicolai N , Miceli R , Necchi A , et al. . Retroperitoneal lymph node dissection with no adjuvant chemotherapy in clinical stage I nonseminomatous germ cell tumors: long-term outcome and analysis of risk factors of recurrence . Eur Urol 2010 ; 58 : 912 – 8 . Google Scholar CrossRef Search ADS PubMed 11 Atsu N , Eskicorapci SY , Uner A , et al. . A novel surveillance protocol for stage I non- seminomatous germ cell testicular tumours . BJU Int 2003 ; 92 : 32 – 5 . Google Scholar CrossRef Search ADS PubMed 12 Daugaard G , Gry Gundgaard M , Mortensen MS , et al. . Surveillance for stage I nonseminoma testicular cancer: outcomes and long-term follow-up in a population-based cohort . J Clin Oncol 2014 ; 32 : 3817 – 23 . Google Scholar CrossRef Search ADS PubMed 13 Vergouwe Y , Steyerberg EW , Eijkemans MJ , Albers P , Habbema JD . Predictors of occult metastasis in clinical stage I nonseminoma: a systematic review . J Clin Oncol 2003 ; 21 : 4092 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Divrik RT , Akdogan B , Ozen H , Zorlu F . Outcomes of surveillance protocol of clinical stage I nonseminomatous germ cell tumors-is shift to risk adapted policy justified? J Urol 2006 ; 176 : 1429 – 30 . Google Scholar CrossRef Search ADS 15 Tandstad T , Dahl O , Cohn-Cedermark G , et al. . Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: The SWENOTECA management program . J Clin Oncol 2009 ; 27 : 2122 – 8 . Google Scholar CrossRef Search ADS PubMed 16 Duran I , Sturgeon JF , Jewett MA , et al. . Initial versus recent outcomes with a non-risk adapted surveillance policy in stage I non-seminomatous germ cell tumors (NSGCT) . J Clin Oncol 2007 ; 25 : 240s . 17 Kollmannsberger C , Moore C , Chi KN , et al. . Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: diminishing treatment-related morbidity while maintaining efficacy . Ann Oncol 2010 ; 21 : 1296 – 1301 . Google Scholar CrossRef Search ADS PubMed 18 Albers P , Siener R , Kliesch S , et al. . Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial . J Clin Oncol 2003 ; 21 : 1505 – 12 . Google Scholar CrossRef Search ADS PubMed 19 Hayes JR , Jewett MAS , Hamilton RJ . 28-year late spermatic cord relapse of a testicular non-seminomatous germ cell tumour, managed robotically . Can Urol Assoc J 2016 ; 10 : E257 – 60 . doi:10.5489/cuaj.3492 . Google Scholar CrossRef Search ADS PubMed 20 Arafat W , Albany C , Ulbright TM , Foster R , Einhorn LH . Very late relapse of germ cell tumor as a teratoma: A case report and review of the literature . J Surg Case Rep 2014 ; doi:10.1093/jscr/rju051 . 21 Sweeney CJ , Hermans BP , Heilman DK , Fostern RS , Donohue JP , Einhorn LH . Result and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma-predominant testis cancer . J Clin Oncol 2000 ; 18 : 358 – 62 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Japanese Journal of Clinical OncologyOxford University Press

Published: Apr 17, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off