To assess the prognosis of overt testicular disease at diagnosis of acute lymphoblastic leukemia, and any therapeutic role of irradiation for this involvement, we reviewed the data of 811 boys treated on St Jude studies Total X–XI (early period) and Total XII-XIV (recent period). In all, 19 boys (2.3%) had testicular disease at diagnosis. In the early period, patients with testicular leukemia had a poorer overall survival (OS) (P=0.003), event-free survival (EFS) (P=0.064), and higher cumulative incidence of relapse (P=0.041) than did other patients. During the recent period, patients with and without overt testicular leukemia did not differ in OS (P=0.257), EFS (P=0.102), or cumulative incidence of relapse (P=0.51). In a multivariate analysis, OS was lower for patients with testicular disease than for those without the involvement in the early period (P=0.047) but not in the recent one (P=0.75). Both patients who received irradiation for residual testicular disease at the end of induction subsequently died of leukemia. Of the other 17 patients who did not receive irradiation, only one developed testicular relapse in combination with bone marrow relapse. In conclusion, the prognostic impact of overt testicular disease has diminished. Irradiation appears to provide no survival advantage to this patient population.
Overt testicular involvement occurs in about 2% of boys at the time of diagnosis of childhood acute lymphoblastic leukemia (ALL) and has been reported to be associated with a poor outcome.1, 2 The survival rate of patients with ALL has improved considerably in recent years;3, 4, 5, 6 however, the prognostic significance of overt testicular disease treated with contemporary therapy is unknown. Furthermore, little is known about the role of irradiation of the testes in providing local control and in achieving a high survival rate. In this retrospective review, we analyzed the records of boys with ALL treated on consecutive studies over the past 20 years at St Jude Children's Research Hospital (St Jude) to evaluate the prognostic significance of testicular disease at diagnosis and to determine whether local irradiation provides a survival advantage.
Patients and methods
Patients and protocols
The St Jude Institutional Review Board approved this retrospective study. We analyzed data from 811 boys with newly diagnosed ALL treated on St Jude Total Therapy studies (Total X, XI, XII, XIIIA, XIIIB, and XIV) conducted from 1979 to 2000. During this time period, information about overt testicular disease was recorded prospectively in the database. The details of these treatment regimens have been previously published.4, 7, 8, 9, 10, 11, 12 Total X, which enrolled 257 boys, investigated the efficacy of high-dose methotrexate and of the combination of teniposide and cytarabine.8 Total XI,9 which recruited 193 boys, evaluated the efficacy of early intensification and the alternating use of non-cross-resistant drug pairs. Total XII10 investigated whether individualized dosing of chemotherapy improves treatment outcome; 102 boys participated in this trial. Total XIIIA,11 on which 92 boys were enrolled, featured early intensification of intrathecal therapy. Total XIIIB4 enrolled 144 boys and included more stringent risk classification, early intensification of intrathecal treatment, reinduction therapy, and postremission therapy that included dexamethasone.
In Total XIV,12 on which 23 boys were enrolled, patients received the same six-drug induction therapy as that given in Total XIIIB. Consolidation therapy consisted of daily oral administration of 6-mercaptopurine and weekly administration of high-dose methotrexate (2 g/m2) for 2 weeks. The continuation therapy used rotational drug pairs similar to that in Total XIIIB, but consisted of higher (2.5 g/m2 for lower-risk patients and 5 g/m2 for higher-risk patients) and fewer doses (4 instead of 8) of high-dose methotrexate used in Total XIIIB. The cumulative dose of high-dose methotrexate was 15 g/m2 in Total X, 4 g/m2 in Total XI, 7.5 g/m2 in Total XII, 20–21 g/m2 in Total XIIIA, 20–21 g/m2 in Total XIIIB, and 15–37 g/m2 in Total XIV.4, 7, 9, 10, 11
Overt testicular involvement was diagnosed by physical examination (increased size and firm consistency of the testes). Ultrasonography was used to confirm the diagnosis in more recent years. In protocols Total X through XIIIB, patients with overt testicular involvement underwent biopsy of the testes during hematologic remission and received testicular irradiation at the beginning of continuation therapy only if there was microscopic evidence of leukemia. Patients enrolled on Total XIV underwent biopsy before continuation therapy only if testicular size was persistently abnormal, and patients received irradiation only if leukemic infiltrate was present. Overt testicular involvement was considered to be a characteristic of higher risk disease in Total XIIIB and XIV.
All patients who completed therapy were examined at least annually at St Jude. To assess disease and treatment effects on gonadal function, we analyzed information collected during annual off-therapy evaluations, including information about growth, Tanner stage, testicular volume, and laboratory test results.
Overall survival (OS) was defined as the time from diagnosis until the date of death or the last follow-up date. Event-free survival (EFS) was defined as the time from diagnosis until the date of failure (relapse, death, or second malignancy) or until the last follow-up date for all event-free survivors. Treatment failures at time zero were those cases in which complete remission was not achieved. OS and EFS functions were estimated by the methods of Kaplan and Meier. Standard errors were calculated by the methods of Peto et al13 The Mantel–Haenszel test14 was used to compare OS and EFS estimates for patients with and without testicular disease at diagnosis in the early period (Total X–XI, 1979–1988); the same test was also used to conduct the same type of comparison involving patients with and without testicular disease at diagnosis in the recent period (Total XII–XIV, 1988–2000). The Cox proportional hazards model15 was used to determine whether testicular disease is an independent risk factor for OS and EFS after adjustments were made for other risk factors: age <1 years or >10 years, leukocyte count ⩾50 × 109/l, CNS status other than CNS-1, and T-cell immunophenotype.
The cumulative-incidence function of all relapses was estimated by the method of Kalbfleisch and Prentice.16 The impact of testicular disease on the cumulative-incidence function of relapse was compared by Gray's test with the incorporation of competing events.17 The analysis was performed for the early period and for the recent period. Death during remission and cases of second malignancies were treated as competing risks. Failure to achieve complete remission was considered to be a competing event at time zero. The Fine and Gray's estimator with the incorporation of competing events18 was applied to determine whether testicular involvement is an independent risk factor for relapse after adjustments for other risk factors in the early period and in the recent period. Only data collected before or on June 24, 2004, were analyzed.
Patients with overt testicular involvement at the time of diagnosis
In total, 19 (2. 3%) of 811 boys had overt testicular disease at the time of diagnosis of ALL (Table 1). Cases 1–13 have been previously reported,1 and their updated outcomes are reported here. The median age of the 19 boys at diagnosis was 8.7 years (range, 0.2–16.3 years), and the median leukocyte count was 118.2 × 109/l (range, 3.6–581 × 109/l). Of the patients, 12 had B-lineage ALL, and seven had T-cell ALL. Bilateral testicular disease was present in 14 patients. In eight patients (patients 7, 11, 13, 14, 15, 16, 18, and 19), testicular disease was confirmed by ultrasonography. No patient underwent testicular biopsy at the time of diagnosis.
All except patient 17 achieved complete hematologic remission. After the conclusion of induction therapy, patients 9, 10, 13, 16, 18, and 19 did not undergo biopsy of the testes because the physicians chose not to conduct the test (three patients), because no abnormality was found by untrasonography (one patient), or because biopsy was not a requirement of the protocol (two patients). Patients 1 and 15 received 2000 and 2400 cGy to the testes, respectively, after testicular biopsy during hematologic remission revealed occult leukemia. None of the 19 patients underwent orchiectomy.
Outcome after testicular leukemia
In all, 12 patients experienced adverse events (Table 1) during follow-up (median length, 4.9 years; range, 0.3–19.7 years): hematologic relapse in four patients; isolated CNS relapse in three; testicular relapse, combined hematologic and CNS relapse and induction failure in one case each; and second malignancy in two patients (acute myeloid leukemia and glioblastoma multiforme , respectively). Of the 12 patients, nine died of refractory or relapsed leukemia, and one died of secondary acute myeloid leukemia.
Prognostic significance of testicular involvement in different treatment periods
Table 2 illustrates the differences in OS and EFS estimates and cumulative incidences of relapse for groups with and without testicular disease treated during the early (Total X and XI) and recent (Total XII–XIV) periods. In the early period, patients with testicular disease (n=10) had a significantly higher cumulative incidence of relapse and a significantly lower OS estimate than did those without testicular disease (n=440) during the same period. In the recent period, the cumulative incidence of relapse and EFS and OS estimates did not differ significantly between patients with testicular disease (n=9) and without (n=352).
Cox regression analysis adjusted for age, leukocyte count, CNS involvement, and immunophenotype indicated that the group with testicular disease at diagnosis had a significantly higher hazard ratio for OS (2.20 [95% confidence interval (CI), 1.01–4.83], P=0.047) than did the group without testicular involvement during the early period but not during the recent period (1.21 [95% CI, 0.37–4.00], P=0.75). There was no significant difference in EFS (hazard ratio, 1.48 [95% CI, 0.68–3.20], P=0.33 in the early period and 1.23 [95% CI, 0.48–3.12], P=0.67 in the recent period) or in cumulative incidence of relapse (1.62 [95% CI, 0.66–3.97], P=0.30 in the early period and 0.89 [95% CI, 0.23–3.25], P=0.86 in the recent period) between patients with and without testicular disease.
Gonadal functions of long-term survivors
As a result of the relatively young age of the surviving patients (median age at the time of analysis, 26.5 years, range 4.7–32.1 years), there was limited information that could be used to assess gonadal function of the cohort. One patient (patient 19) was in full puberty at the time of diagnosis and has not had any signs of hypogonadism. Seven other patients who were prepubertal (patients 7, 9, 14, and 18) or in early puberty (patients 6, 11, and 12) at the time of diagnosis subsequently underwent age-appropriate pubertal development. Another patient (patient 16) was prepubertal at the time of this analysis. One patient (patient 6) has fathered children. Two patients (patients 9 and 11) underwent testing of gonadotropin levels, and both had normal values.
The prognostic significance of overt testicular disease at diagnosis of ALL and the optimal treatment of this condition have not been well studied. In a previous report from St Jude, patients with testicular disease had significantly poorer survival estimates than did patients without testicular disease.1 The adverse prognosis of testicular disease was attributed partly to its more frequent occurrence in infant or adolescent boys and its association with leukocytosis.
The 811 boys in the present study were treated on six consecutive treatment protocols. The outcome of all patients, with or without testicular disease, improved significantly in the recent period (data not shown). Our evaluation only showed a trend of improved outcome between patients with testicular disease in the early period and those with testicular disease in the recent period (data not shown); the lack of a significant difference is probably due to the small sample sizes. Further comparison showed that patients with testicular disease in the early period had a lower OS estimate, a lower EFS estimate, and a higher cumulative incidence of relapse than did those without testicular disease during the same period (Total X and XI), but significant differences were not observed between the two groups of patients during the recent treatment period. Although our results are limited by the relatively small number of patients with testicular involvement in each era, this latter finding indicates that the difference in outcome between patients with and without testicular disease has lessened with improved treatment.
The recent improvement in outcome was achieved by advancement of systemic chemotherapy but not of local therapy. In our study of 19 patients with testicular disease, radiation therapy was administered to the testes of only two patients (patients 1 and 15) because of detectable residual leukemia after the completion of induction therapy. Both patients who received irradiation experienced relapse outside of the testes and died of disease. Of the 17 patients who did not receive testicular irradiation, only one (patient 8) experienced testicular relapse. This patient had negative results of testicular biopsy at the time of first hematologic remission, but testicular relapse developed during continuation therapy. At that time, his bone marrow also contained 22% blast cells. Although a second remission was attained, he eventually died of leukemia. On the basis of his clinical course, we believe that this patient had systemic drug-resistant disease and, therefore, testicular irradiation during the first remission would not have helped.
Isolated testicular relapse in patients without testicular disease at diagnosis was very rare when they were treated on more recent protocols. While isolated testicular relapse occurred in 15 patients (5.8%) without testicular disease at diagnosis on Total X,8 this complication developed in only one patient (patient 8 in this study, 0.5%) on Total XI,9 two patients (2.0%) on Total XII,10 zero patients on Total XIIIA,11 one patient (0.7%) on Total XIIIB,4 and zero patients on Total XIV (unpublished data). The results indicate an association between an improved control of testicular disease and the use of more effective systemic chemotherapy, although the results should be interpreted cautiously because the sample numbers were small. The complications associated with testicular irradiation, for example, severe gonadal atrophy and gonadal and sexual dysfunction, are well recognized.19, 20 Thus, we believe that local irradiation of the testes is of little value and should be abandoned.
Treatment with high-dose methotrexate is widely accepted as a means of reducing the risk of testicular relapse.21, 22, 23 In successive protocols conducted at St Jude, the cumulative dose of high-dose methotrexate has increased; the greater dose intensity conceivably contributes to the better outcome. Although the cumulative dose of high-dose methotrexate used during the Total X study (15 g/m2) was higher than that used in Total XI or XII (4 and 7.5 g/m2, respectively), each individual dose (1 g/m2) was lower than that used during later studies (2 g/m2 or more) and was followed by higher and more frequent doses of leucovorin than those used during later studies,8 which may have caused the undesirable rescue of leukemic cells. Moreover, high-dose methotrexate was given only in one of two randomized arms for lower-risk disease in Total X,8 and five of seven patients with testicular disease on this protocol did not receive it (Table 1).
Risk-adapted therapy lessens the predictive strength of prognostic factors.24 It is plausible that the inclusion of testicular disease as a criterion of higher-risk ALL also helped to improve the outcome. A previous St Jude report that showed the adverse prognosis associated with testicular disease.1 Therefore, since the start of Total XIIIB, patients with testicular disease at St Jude have been classified as having higher-risk ALL. Although testicular involvement was not included in the criteria for the higher-risk group until Total XIIIB, all patients with overt testicular leukemia who were enrolled on Total XI, XII, or XIIIA were treated as though they had higher-risk ALL because other risk factors (high leukocyte counts, age, and T-cell phenotype) (Table 1) were present. Two of three patients who were treated as though they had lower risk in the early period died. Although this number is too small for any meaningful statistical analysis, all the results presented in the preceding text suggest the necessity of intensified systemic treatment for patients with overt testicular disease at diagnosis.
In conclusion, the predictive strength of overt testicular disease in childhood ALL has diminished in recent years because of the use of contemporary risk-stratified and intensified systemic chemotherapy that has included high-dose methotrexate. Local irradiation of the testes in patients with overt testicular disease at diagnosis appears to be unnecessary for achievement of survival rates comparable to those of patients without testicular disease.
Gajjar A, Ribeiro RC, Mahmoud HH, Sandlund JT, Liu Q, Furman WL et al. Overt testicular disease at diagnosis is associated with high-risk features and a poor prognosis in patients with childhood acute lymphoblastic leukemia. Cancer 1996; 78: 2437–2442.
Donadieu J, Auclerc MF, Baruchel A, Leblanc T, Landman-Parker J, Perel Y et al. Critical study of prognostic factors in childhood acute lymphoblastic leukaemia: differences in outcome are poorly explained by the most significant prognostic variables. Fralle group. French Acute Lymphoblastic Leukaemia study group. Br J Haematol 1998; 102: 729–739.
Pui CH, Relling MV, Downing JR . Acute lymphoblastic leukemia. N Engl J Med 2004; 350: 1535–1548.
Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 2004; 104: 2690–2696.
Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 2000; 95: 3310–3322.
Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001; 97: 1211–1218.
Pui CH, Dodge RK, Look AT, George SL, Rivera GK, Abromowitch M et al. Risk of adverse events in children completing treatment for acute lymphoblastic leukemia: St Jude Total Therapy studies VIII, IX, and X. J Clin Oncol 1991; 9: 1341–1347.
Pui CH, Simone JV, Hancock ML, Evans WE, Williams DL, Bowman WP et al. Impact of three methods of treatment intensification on acute lymphoblastic leukemia in children: long-term results of St Jude total therapy study X. Leukemia 1992; 6: 150–157.
Rivera GK, Raimondi SC, Hancock ML, Behm FG, Pui CH, Abromowitch M et al. Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet 1991; 337: 61–66.
Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH . Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 1998; 338: 499–505.
Pui CH, Mahmoud HH, Rivera GK, Hancock ML, Sandlund JT, Behm FG et al. Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 1998; 92: 411–415.
Kishi S, Griener J, Cheng C, Das S, Cook EH, Pei D et al. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol 2003; 21: 3084–3091.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer 1977; 35: 1–39.
Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–170.
Cox DR . Regression models and life tables. J Roy Stat Soc Ser B 1972; 20: 187–220.
Kalbfleisch JD, Prentice RL . The Statistical Analysis of Failure Time Data. New York: John Wiley & Sons, 1980.
Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.
Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.
Grundy RG, Leiper AD, Stanhope R, Chessells JM . Survival and endocrine outcome after testicular relapse in acute lymphoblastic leukaemia. Arch Dis Child 1997; 76: 190–196.
Castillo LA, Craft AW, Kernahan J, Evans RG, Aynsley-Green A . Gonadal function after 12-Gy testicular irradiation in childhood acute lymphoblastic leukaemia. Med Pediatr Oncol 1990; 18: 185–189.
Abromowitch M, Ochs J, Pui CH, Fairclough D, Murphy SB, Rivera GK . Efficacy of high-dose methotrexate in childhood acute lymphocytic leukemia: analysis by contemporary risk classifications. Blood 1988; 71: 866–869.
Dordelmann M, Reiter A, Zimmermann M, Fengler R, Henze G, Riehm H et al. Intermediate dose methotrexate is as effective as high dose methotrexate in preventing isolated testicular relapse in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 1998; 20: 444–450.
Freeman AI, Boyett JM, Glicksman AS, Brecher ML, Leventhal BG, Sinks LF et al. Intermediate-dose methotrexate versus cranial irradiation in childhood acute lymphoblastic leukemia: a ten-year follow-up. Med Pediatr Oncol 1997; 28: 98–107.
Pui CH, Campana D, Downing JR . Childhood acute lymphoblastic leukaemia-current status and future perspectives. Lancet Oncol 2001; 2: 597–607.
We thank Julia Cay Jones, PhD, for her expert editorial review; James Boyett, PhD, and Deo Kumar Srivastava, PhD, for helpful suggestions concerning the statistical analysis; Imella Smith Herrington for her assistance in manuscript preparation; Jeana Cromer for her administrative assistance; and Annette Stone and Gena Durham for data collection. This work was supported in part by a Cancer Center Support Grant (CA21765) from the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC). Ching-Hon Pui is the American Cancer Society FM Kirby Clinical Research Professor.
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Hijiya, N., Liu, W., Sandlund, J. et al. Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19, 1399–1403 (2005). https://doi.org/10.1038/sj.leu.2403843
- high-dose methotrexate
- gonadal function
Overt testicular disease at diagnosis in childhood acute lymphoblastic leukemia: prognostic significance and role of testicular irradiation
The Indian Journal of Pediatrics (2010)