Patients with stage II germ cell tumors of the testes have high survival rates when treated with surgery and adjuvant chemotherapy; the OS rates in several studies have been over 95%[4,7,9,11–13]. In a POG/CCG study, 17 pediatric patients with stage II testicular MGCT received 4 cycles of PEB chemotherapy post-surgery, and both the 6-year EFS and OS rates were 100%[7]. In an earlier United Kingdom Children’s Cancer Study Group (UKCCSG) study, children with stage II testicular MGCT had a 5-year OS rate of 86% when treated with surgery and PEB chemotherapy[13]. Another UKCCSG study demonstrated that the 5-year EFS and OS rates of children with stage II testicular MGCT were both 100%, when children received 4 to 6 cycles of adjuvant JEB (carboplatin, etoposide, and bleomycin) chemotherapy’91. In a German study, 22 children with stage II testicular MGCT were treated with CVB (cisplatin, vinblastine, and bleomycin) chemotherapy, and the 5-year OS rate was 95%’111. A previous study in our center showed that the 3-year OS rate was 100% after 4 to 6 cycles of PEB chemotherapy in children with stage II testicular MGCT’141. Nevertheless, most children with MGCT are quite young at disease onset, with the first peak incidence occurring before the age of 2 years. Adjuvant chemotherapy is routinely recommended for these young patients with stage II disease whose serum tumor markers fail to normalize after an appropriate period of half-life time and who have no evidence of residual disease. However, concerns regarding toxicity often prompt parents to decline chemotherapy for these patients. Indeed, in the present study, the parents of 21 patients refused adjuvant chemotherapy. The relapse rate was high at 76.2%. Although there was no imaging or pathologic evidence of residual disease, failed post-surgical normalization of the serum tumor markers AFP and HCG after an appropriate period of time indicated the presence of residual tumor cells that secrete these marker proteins[10,15]. The 3 patients in the present study who received orchiectomy and adjuvant chemotherapy had a 3-year EFS rate of 100%. Thus, children with stage II disease with tumor markers that failed to normalize need to receive adjuvant chemotherapy to eliminate residual tumor cells, and thereby reduce recurrence and improve survival. At the time this protocol was designed, tumor marker decline during chemotherapy had demonstrated in a retrospective analysis a strong relationship with treatment outcome[16]. AFP has a half-life of 7 days, and β-HCG has a half-life of 3 days. Thus, for an AFP level of 400 ng/mL after surgery, the level should fall below 25 ng/mL at 28 days after surgery. We suggest that post-surgery, AFP should be monitored weekly until it reaches normal levels, which refers to a measurement less than 25 ng/mL. If serum tumor markers fail to normalize after an appropriate period of time, the patient should be treated with chemotherapy.
The level of AFP at diagnosis is closely related to prognosis. Two studies revealed that patients with an AFP level ⩾ 10,000 ng/mL had a poor prognosis[17,18]. In the present study, 12 patients had AFP levels >10,000 ng/mL. We compared the 3-year EFS rates between patients with AFP levels <10,000 ng/mL and AFP levels ⩾ 10,000 ng/mL, and the difference was not statistically significant (41.7% vs. 18.2%, P = 0.061). This may be due to the limited number of cases in this study. In contrast, the 3-year EFS rate for the 21 children who underwent surgery alone was higher when the time to AFP normalization was <1 month compared with ⩾ 1 month (75.0% vs. 11.8%, P = 0.044). The rate of AFP decline to normalization was therefore associated with prognosis. If the AFP level does not decline to normal 1 month after surgery, the patient should receive adjuvant chemotherapy. Nevertheless, AFP levels in most patients do not decline to normal, probably due to residual tumor cells, though potentially due to liver damage or false positives caused by treatment medications’191. Here, the relapse rate was very high when AFP was high after the appropriate time for decline or did not fall to a normal level more than 1 month after surgery. Barring possible false positives, the results suggest that patients who exhibit these characteristics should be treated with adjuvant chemotherapy.
In the present study, PEB was the regimen for both adjuvant chemotherapy and chemotherapy after relapse. Children who were treated with orchiectomy followed by 4 cycles of adjuvant chemotherapy had an excellent outcome. The 3-year OS rate of children with relapse and metastasis remained high (90%) after salvage treatment. Patients in this group received more cycles of chemotherapy. In this study, the median number of cycles after relapse was 6, and the maximum number was 10. The main adverse reaction observed in this study was bone marrow suppression. The rates of grade IV bone marrow suppression for initial adjuvant chemotherapy and chemotherapy after relapse were 0% and 7.7%, respectively, and the rates of grades I–II gastrointestinal reaction were 2.6% and 61.5%, respectively. Toxicity became more severe as the number of chemotherapy cycles after relapse increased. Renal toxicity, ototoxicity, and lung toxicity were not observed. A study from UKCCSG showed that the rates of renal toxicity and ototoxicity were 45% and 10%, respectively, and 1 patient died of secondary leukaemia[13]. Therefore, there is a relatively high level of toxicity after recurrence, even with a high survival rate.
Most cases of recurrence are detected using tumor markers or abdominal CT scan[20, 21]. In this study, recurrence was detected by using CT scan in 87.5% (14 of 16) patients. Furthermore, a report showed that 80% of events occurred in the first year post-surgery, and more than 90% of events occurred during the first 2 years[22]. In a large study of children with stage I testicular MGCT, 80% of recurrences occurred in the first year after surgery, 12% occurred in the second year, 6% occurred in the third year, and approximately 1 % occurred in the fourth and fifth years, with occasional occurrences in subsequent years[23, 24]. In this study, the median time from surgery to relapse was 4 months (range, 0.5 to 14.3 months). Consequently, close follow-up is essential for patients in the first 5 years. Tumor markers should be monitored, and abdominal CT scan should be obtained periodically.
Patients with recurrent disease can still achieve long-term survival with salvage therapy. Of the 16 children who experienced relapse and metastasis in this study, 11 underwent salvage chemotherapy, 2 underwent second-look surgery and salvage chemotherapy, 2 received salvage chemotherapy first and then underwent second-look surgery, and 1 received 1 cycle of salvage chemotherapy followed by second-look surgery and additional salvage chemotherapy. Except for 1 patient who stopped treatment after 1 cycle of chemotherapy, the remaining 15 patients had normalized AFP levels following salvage treatment and achieved CR. Fourteen patients were alive after salvage treatment. In the case of stage I disease, all patients with relapse or progression appeared to be cured with further surgical excision and chemotherapy[9,10]. Few studies have evaluated the survival rate of children with stage II MGCT treated with surgery alone. One report of patients with yolk sac tumors showed AFP normalization in 72%, persistent elevation in 8%, and relapse in 16% of patients who experienced transient lowering after radical orchiectomy[25]. All 6 patients who showed either elevation or relapse of AFP received salvage chemotherapy. This therapy rescued all but 1 patient, who was further treated with peripheral blood stem cell transplantation. None of the patients experienced relapse after these treatments. Thus, patients who experience relapse still have a high chance of survival with salvage therapy
In conclusion, to reduce recurrence and improve survival of children with stage II MGCT, adjuvant chemotherapy should be given to those whose serum tumor markers increase or fail to normalize after an appropriate period of half-life time following surgery even if there is no imaging or pathologic evidence of residual disease. Tumor markers should be monitored periodically post-surgery. If serum tumor markers fail to normalize after an appropriate period of half-life time, the patient should be treated with chemotherapy as soon as possible.