Testicular Relapse in Lesser, Standard, and High Risk Patients Treated with Frontline Therapy for Childhood ALL. Pediatric Oncology Group Protocols 9201, 9405, 9605, and 9406.
Authors: Harrison Melissa , Bell Beverly , Chauvenet Allen , Kurtzberg Joanne , Camitta Bruce , Devidas Meenakshi 
Published: October 2019

Abstract
From 1984–94, testicular relapse (TR) was reported in 10–20% of boys with ALL. Addition of intermediate and higher dose methotrexate (MTX) in subsequent trials may have reduced this risk. Pediatric Oncology Group (POG) trials 9201, 9405, 9605, and 9406 for B-precursor ALL opened in 1994–6. Protocol 9201 enrolled 365 lesser risk, 9405: 158 standard risk, 9605: 601 standard risk, and 9406: 512 higher risk (total 1,636) boys with ALL. All studies used a common induction protocol of L-asparaginase, vincristine, and prednisone. Doxorubicin was added for higher risk (based on age, initial WBC, and CNS/testicular status). Overt testicular disease at diagnosis was present in only 7/512 (1.4%) boys, all on 9406; they later received radiation therapy to the testicles. After induction, patients were assigned to POG protocols based on NCI risk criteria. Patients on 9201 received 6 courses of IV MTX (1g/m2) during intensification and once or twice daily oral 6-MP during continuation. Patients on 9405 were randomized to 1 or 2.5 g/m2 IV MTX for 12 courses during consolidation and once or twice daily oral 6-MP during continuation. Patients on 9605 received 6 courses of 1g/m2 IV MTX in consolidation and were randomized to +/− 6 months of divided dose oral MTX during intensification and once or twice daily oral 6-MP during continuation. Study 9406 randomized to 6 courses of 1 or 2.5g/m2 IV MTX and to standard or high dose AraC during intensification. TR was overt (physical exam) or occult (biopsy). 99 boys had isolated or combined TR. 0/7 with testicular disease at diagnosis had TR. Of the boys with TR, only 3 did not receive a significant amount of the total therapy. Lesser risk patients had the lowest incidence of TR and lowest overall mortality rate of 1/11(9.1%). Higher risk patients had more relapses during therapy, 11/32(34%) and highest overall mortality rate of 13/32(40.6%). Isolated TR was more common than combined, except on 9406. Median time to TR off therapy was 7.5 months (range 1–52). Median age at relapse was 9.4 years (range 1.8–22). Mortality post any type of second relapse after TR was 60% compared to 25% for those without second relapse(p=0.0124).
Table 1 9201 9405 9605 9406 # Pts. 365 158 601 512 # TR 11(3.0%) 13(8.2%) 43(7.1%) 32(6.3%) Isolated TR, ON Rx/OFF Tx 8(2.2%),1/7 7(4.5%),1/6 30(5.0%),4/26 16(3.1%),6/10 Combined TR, ON Rx/OFF Rx 3(0.8%),0/3 6(3.9%),2/4 13(2.2%),2/11 16(3.1%),5/11 Median(Range)# of mos. off Rx 5(2–46) 11(1–28) 7(1–52) 8(1–42) Median(Range)Age at Relapse (yrs.) 6(4.4–15.6) 8.1(1.8–22) 8.3(3.4–21) 12.4(3–20.4) Table 2 Type of TR Count(%) Second Relapse(%) Overall Mortality(%) *Other includes 6-TR+CNS and 1-TR+Subcutaneous mass in cheek. Isolated TR 61/99 (61.6) 18/61 (13.1) 18/61 (29.5) TR+Marrow 31/99 (31.3) 5/31 (16.1) 10/31 (32.3) TR+Other 7/99 (7.1) 2/7(28.6) 2/7 (28.6)
Overall TR rate on these studies was approximately 6%. Risk stratification, augmentation of therapy and use of intermediate and high dose MTX may have contributed to this reduction.