The incidence of testicular recurrence in boys with acute leukemia treated with total body and testicular irradiation and stem cell transplantation

Authors


Abstract

BACKGROUND

The incidence of testicular recurrence of childhood acute leukemia after total body irradiation (TBI) in conjunction with stem cell transplantation (SCT) has been reported to be as high as 24%. The authors studied the incidence of testicular failure in a large series of male patients who underwent SCT using either TBI and a testicular irradiation boost or chemotherapy alone.

METHODS

One hundred thirty-one boys with either acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) were treated with SCT with either TBI with testicular boost (n = 94 patients), TBI without testicular boost (n = 1 patient), or chemotherapy alone (n = 36 patients) between 1991 and 1999.

RESULTS

The median follow-up was 26.5 months (range, 0.6–99.5 months) from the date of bone marrow infusion. Two patients in the study had a primary testicular failure after TBI with testicular boost followed by an umbilical cord blood transplantation. The first patient had ALL, did not engraft, and was rescued with autologous cells. He developed disease in the testicle 15 months afterward and subsequently died. The second patient had Philadelphia chromosome-positive ALL and developed a testicular recurrence 26 months after SCT. He was treated with orchiectomy, further testicular irradiation, and chemotherapy and remained in complete remission > 3 year after his failure. The incidence of testicular failure in boys who received TBI and testicular irradiation who survived ≥ 1 year was 4.2%. There were no primary testicular failures reported in boys who received chemotherapy alone.

CONCLUSIONS

Boys with AML or ALL had a low incidence of primary testicular failure when they were treated with TBI plus a testicular boost or with chemotherapy alone. Cancer 2004. © 2004 American Cancer Society.

Total body irradiation (TBI) is often part of the conditioning regimen prior to stem cell transplantation (SCT) in the management of children with acute leukemias. Early reports1–3 described frequent, isolated testicular failures in boys who received TBI with SCT. Several of those centers reported adding a testicular irradiation boost, with the subsequent elimination of primary testicular failures.3 We studied the incidence of testicular failure in patients with acute myelocytic leukemia (AML) and acute lymphocytic leukemia (ALL) who underwent SCT in our center.

MATERIALS AND METHODS

One hundred thirty-one boys with either AML (n = 51 patients) or ALL (n = 80 patients) were treated initially with SCT with either TBI plus testicular boost (n = 94 patients), TBI alone (n = 1 patient), or chemotherapy alone (n = 36 patients) between 1991 and 1999 at Duke University Medical Center. Eight patients were positive for the Philadelphia chromosome (Ph+). Twenty-one had cerebrospinal fluid disease at the time of diagnosis. Sixty-two patients underwent SCT in second disease remission; 38 patients were considered high-risk and underwent SCT in first disease remission; and 31 patients were either induction failures, were treated in their third disease remission, or were treated in frank recurrence. Thirty patients underwent autologous SCT, 101 patients underwent allogeneic SCT (45 matched-related bone marrow donors, 3 matched-unrelated bone marrow donors, 50 unrelated umbilical cord blood transplantations [UCBTs], 2 related UCBTs, and 1 matched-related peripheral blood stem cell transplantation). Two patients had testicular leukemia prior to SCT. Fourteen patients underwent a second SCT after developing recurrences subsequent to their initial transplantation. Table 1 outlines other salient patient characteristics.

Table 1. Characteristics of 131 Male Patients
CharacteristicAML (n = 51 patients)ALL (n = 80 patients)
  1. AML: acute myeloid leukemia: ALL: acute lymphocytic leukemia; CSF: cerebrospinal fluid; UCB: umbilical cord blood; BM: bone marrow; TBI: total body irradiation.

Age (yrs)  
 Range0.1–19.10.4–21.1
 Mean7.67.8
 Median5.46.6
Follow-up (mos)  
 Range0.6–97.30.8–99.5
 Mean26.425.8
 Median14.512.5
Race: No. (%)  
 White44 (86)63 (79)
 African-American6 (12)15 (19)
 Other1 (2)2 (2.5)
Blood counts at diagnosis  
 Leukocytes (109/L)  
  Median28.134.5
  Range0.5–2540.6–770
 Hemoglobin (g/dL)  
  Median7.08.0
  Range2.4–212.5–13.6
 Hematocrit (%)  
  Median20.626.6
  Range11.5–34,014.2–41.0
 Platelets (109/L)  
  Median6541
  Range12–2176–400
No. CSF positive at diagnosis (%)  
 No42 (82)68 (85)
 Yes9 (18)12 (15)
Transplantation type (%)  
 Autologous14 (27)16 (20)
 Allogeneic37 (73)4 (80)
Allogeneic type  
 Unrelated UCB1737
 Related BM2027
Reason for transplantation (%)  
 First remission25 (49)13 (16)
 Second remission10 (20)52 (65)
 Other16 (31)15 (19)
Treatment modality (%)  
 Chemotherapy only23 (45)6 (7)
 Chemotherapy and TBI19 (37)70 (88)
 Two transplantations9 (18)4 (5)

TBI was comprised of 13.5 gray (Gy) in 9 fractions of 1.5 Gy twice daily by opposed lateral photons. For this treatment, the patient lies supine with knees bent, arms held to the sides, and hands folded over the chest. The lung dose was attenuated to 10 Gy using the patients' arms and brass attenuators (which in most cases were approximately 6-cm thick). In narrow parts of the body (i.e., head and legs), brass attenuators were used to obtain a more homogenous dose. The source-skin distance was 280 cm, and the dose rate was approximately 13 centigray (cGy) per minute. For younger patients, anesthesia was used when necessary.4

The testicular boost was comprised of 2 Gy in 2 daily fractions delivered by 4-megavolt, tangential photons with a half-beam block given concurrently with the TBI on the third and fourth days of treatment. The patient was placed in the supine position with his legs in the frog-leg position. The penis was taped to the abdomen to keep it out of the field, and 1 cm of bolus was applied to the testes (Fig. 1). The dose rate was 200 cGy per minute.

Figure 1.

There are several techniques for external beam irradiation of the testes for leukemia. In the two most commonly used techniques, the penile shaft is taped onto the anterior abdominal wall to exclude it from the treatment field (A). Treatment may be administered with a half-beam, blocked, superior oblique field (B) or with an en face electron field (C). Bolus generally is required in both cases. (Reproduced with permission from: Halperin EC, et al. Pediatric radiation oncology. 4th edition. Philadelphia: Lippincott Williams & Wilkins, In press. © year, Lippincott Williams & Wilkins.)

In addition to their irradiation, patients in the TBI group also received chemotherapy, which was comprised of melphalan (at a dose of 60 mg/m2 daily × 3) with or without cyclophosphamide (at a dose of 60 mg/kg per day × 1 dose), and/or antithymocyte globulin (ATG) (30 g/dose daily × 3). Patients in the chemotherapy-only group were treated with the same agents with the addition of busulfan, typically 16 doses of 1 mg/kg per dose. Patients in both groups received graft-versus-host disease (GVHD) prophylaxis with cyclosporine with or without methotrexate for patients who received bone marrow or peripheral blood SCT, and cyclosporine and corticosteroids for patients who underwent UCBT.

Survival curves were estimated using the Kaplan–Meier method.5 The Cox–Mantel test6 was used to compare survival distributions. The P values reported refer to differences between survival distributions between the two groups as calculated from the Cox–Mantel test.

RESULTS

The median follow-up from the time of infusion of stem cells was 26.5 months (range, 0.6–99.5 months). Overall survival (OS) for the entire group was 52.3% at 1 year and 37.4% at 5 years. The median survival for the entire group was 1.2 years. The disease-free survival (DFS) rates were 45.0% and 29.0% at 1 year and 5 years, respectively.

Patients with AML had a 1-year OS rate of 59.5% and a 5-year OS rate of 41.1%. Patients with ALL had 1-year and 5-year OS rates of 50.0% and 34.6%, respectively. The DFS rate for patients with AML was 50.9% at 1 year and 31.4% at 5 years. For patients with ALL, the DFS rate was 46.5% and 25.0% at 1 year and 5 years, respectively. These differences between patients with AML and patients with ALL were not found to be significant.

Neither of the two patients who presented with a history of testicular leukemia prior to their transplantation at Duke University Medical Center developed a post-SCT testicular recurrence; however, in both patients, their posttransplantation survival was short. The first patient initially was diagnosed at age 9 years with T-cell ALL that manifested as a mediastinal mass with hepatosplenomegaly and bone marrow involvement. He had successful induction, and consolidation included intrathecal prophylaxis and cranial irradiation (24 Gy). He developed disease recurrence 3 years later in his mediastinum and bone marrow. He was treated with induction therapy comprised of vincristine, daunomycin, asparaginase, and prednisone. He was consolidated with 24-Gy mediastinal irradiation and 2 years of chemotherapy, including intravenous methotrexate. Four months after completing this regimen, he developed a recurrence in his right testicle. He was reinduced with vincristine, asparaginase, and prednisone and was treated with 24-Gy bilateral testicular irradiation. A 4:6 cord blood match was found, and he underwent SCT with TBI (without testicular boost), melphalan, and ATG. The lung dose was limited to 8 Gy. The patient died of multiorgan system failure 35 days after transplantation.

The second patient was diagnosed at age 3 years with B-cell ALL that presented with easy bruising, fever, anemia, and hepatosplenomegaly. Induction was obtained with vincristine, prednisone, L-asparaginase, methotrexate, and triple intrathecal medications. Consolidation lasted until age 6 years. He developed recurrent disease 10 months later in his bone marrow and both testes. He was treated with L-asparaginase, vincristine, prednisone, and 36-Gy bilateral testicular irradiation. He underwent matched unrelated bone marrow transplantation, with conditioning that included TBI (with a standard testicular boost) and cyclophosphamide. He died 4 months later from severe complications, including venoocclusive disease, hemorrhagic cystitis, graft-versus-host disease, and leukoencephelopathy.

No patient who was treated with chemotherapy alone developed a primary testicular recurrence. Two patients, both with ALL, who were treated with irradiation did have primary testicular failures. The first patient was a boy age 11 years with ALL who failed induction therapy. He was treated with TBI plus a testicular boost followed by UCBT. He did not engraft and was reconstituted with autologous cells. He developed a recurrence in the testicles 15 months after his initial UCBT. He was treated with 26-Gy testicular irradiation plus further chemotherapy but failed systemically and subsequently died from complications of a second chemotherapy-based UCBT. Because it occurred after reinfusion of autologous cells, it is not possible to determine whether the testicular recurrence represented a failure of the irradiation to sterilize testicular disease, or if it was a result of the reinfusion of leukemic cells after the initial irradiation was complete.

The second patient was a boy age 3 years with Ph+ ALL. He underwent transplantation in first disease remission with TBI plus testicular irradiation and UCBT. He suffered a unilateral testicular recurrence 26 months after SCT. He was treated with unilateral orchiectomy, 24-Gy irradiation to the remaining testicle, and chemotherapy and remained in complete remission > 3 years after his recurrence. The incidence of primary testicular failure in boys who were prepared for SCT with TBI and testicular irradiation and boys who survived for ≥ 1 year was 4.2%.

DISCUSSION

Testicular recurrence has long been a known therapeutic problem for boys with ALL, and recent studies continue to confirm this. Chessels et al. reported on 505 patients with ALL who developed recurrences after their first disease remission.7 Fifty-one of those patients developed recurrences in the testicles only, 24 patients developed bone marrow and testicular recurrences, and 6 patients developed recurrences in the central nervous system and testes. Thus, 16% of the total patient population (the gender of this group was not reported) had testicular involvement as part of their initial recurrence. Four hundred thirty-nine of those patients achieved second disease remission and 152 male patients developed a second recurrence; of these 152 patients, 49 (32%) developed recurrences in the testes only and 22 patients (14%) developed recurrences in the bone marrow and testes. Bordigoni et al. described 55 boys with ALL who were treated in second disease remission; 14.5% of those patients had testicular involvement as a component of their initial recurrence.8 Goldberg et al. reported on 1255 patients with ALL9 but did not report the gender distribution of the patient group. Of 217 recurrences, 7 (3.2%) involved the testicles (3 recurrences in the testes only, 3 recurrences in bone marrow and testes, and 1 recurrence in the testes and other sites).

Testicular recurrences in adult patients with AML are regarded as rare events,10, 11 although the rate of pathologic involvement of the testicles at autopsy has been reported to be 20%.12 Furman et al. reported a 3% incidence of testicular recurrence in boys with AML after primary therapy.13 Information regarding the incidence of testicular recurrence after SCT for patients with AML is scant. However, in the study by Shank et al. of TBI, in which 4 of the first 28 boys who were treated had testicular recurrences, 2 of 4 patients who developed testicular recurrences had AML.14 Lehmann et al. reported another case of a boy age 13 years who developed an isolated testicular recurrence after a busulfan-based SCT.15 In general, fewer testicular failures would be expected in these patients than would be expected in patients with ALL, a supposition consistent with the lack of any such failures in this study.

Primary testicular failure after TBI for SCT has long been recognized as a clinical problem. In 1982, Cairo et al. reported a boy with ALL who failed in the testes 20 months after TBI and SCT.16 Conter et al. reported a child with testicular disease treated with 20-Gy testicular irradiation prior to TBI and SCT who subsequently developed a primary testicular failure and later died of systemic disease.17 Ashford et al. described testicular failures as a component of recurrence in 4 of 33 boys who underwent transplantation with TBI. In two of those patients, the failures were confined to the testicles only.1 The authors advocated consideration of a prophylactic testicular irradiation boost.

Sanders et al. described 72 boys who underwent SCT and TBI for ALL.2 Of those patients, 16 boys had received testicular irradiation prior to transplantation: 14 for treatment of testicular recurrences and 2 for prophylaxis. The dose ranged from 10 Gy to 25 Gy. None of those patients failed in the testicle. Twenty-nine boys without prior testicular irradiation lived for > 150 days after SCT, including 7 boys (24%) who developed a primary testicular failure, 3 of whom died. The authors concluded that the dose of TBI administered was insufficient to sterilize ALL in the testicles.

Shank et al. reported on 42 boys with AML and ALL who were prepared with TBI for SCT.14 The first 28 boys were treated without a testicular boost. Of these, 4 boys (14%) developed a testicular failure. In response to these results, the authors added a testicular boost of 4 Gy in 1 fraction. The 14 boys who were treated in this manner had no primary testicular failures. In a subsequent report, the authors described > 300 patients who were treated with the addition of a testicular boost in whom no primary testicular failures occurred.3

To our knowledge, the first reported case of a patient who was treated with TBI and a testicular boost who developed a primary testicular failure was described by Li et al. from the Chinese University of Hong Kong.18 Their patient was a boy age 7 years with Ph+ ALL in second disease remission who received 12-Gy TBI followed by 4 Gy in 1 fraction testicular boost. He failed in the testicles 17 months after SCT and was reinduced with systemic chemotherapy and treated with 24-Gy testicular reirradiation. He remained in disease remission at the time of their report, 24 months after the testicular recurrence and 40 months after SCT.

Bordigoni et al. recommended against the use of a testicular boost in their report of TBI plus cytosine arabinoside as conditioning for SCT in patients with ALL.8 They reported that, among boys with no previous testicular involvement, those who were treated with a testicular boost had a higher overall recurrence rate (6 of 19 patients; 51.5%) compared with patients who were not given a testicular boost (3 of 28 patients; 16.9%). However, none of the failures in either group was reported to be in the testicles. It is not clear how a boost dose of irradiation to the testicles would have caused a higher rate of bone marrow recurrences.

In our experience, 2 of 94 patients who were treated with TBI plus a testicular radiation boost developed primary testicular failures. In one patient, it was not clear whether it was truly a testicular recurrence or iatrogenic reseeding by infusion of autologous bone marrow. Combined with the data from Shank et al., this indicates that the addition of a small dose of testicular irradiation at the time of TBI results in a very low incidence of primary failure in the testicles.3, 14 However, this risk is not eliminated completely; therefore, close attention must be paid to testicular examination on follow-up. A prior report on testicular failures after TBI without a testicular boost indicated that the failures occurred within the first months after therapy was withdrawn.2 However, the 3 reported cases of testicular failure after a radiation boost occurred at 15 months, 17 months, and 26 months, respectively, after transplantation. This indicates the importance of long-term attention to the possibility of testicular failure. This is emphasized by the fact that, of the three patients currently described in the literature regarding primary testicular failures after SCT, two still were alive in long-term disease remission after chemotherapy and local reirradiation.

There are potential ill effects associated with the administration of a testicular boost. In 1985, Shalet et al. reported on 11 patients who had received testicular irradiation (24–25 Gy) for leukemic recurrence in the testicle.19 Those authors reported significant impairment of Leydig cell function in 9 of 11 boys. In a similar study, Leiper et al. reported on 11 boys who were treated with 24 Gy for testicular recurrence of leukemia and compared them with an unirradiated control group.20 Those investigators reported a significantly decreased response to the human chorionic gonadotropin-stimulation test in irradiated patients, indicating an impaired ability of the Leydig cells to produce testosterone. It must be noted that the patients who received irradiation in both of those studies had overt testicular leukemia, which prompted the 24–25 Gy of daily irradiation. It may not be inappropriate to extrapolate these data to children who are irradiated prophylactically to receive 17.5 Gy in twice-daily fractions.

To approach this question, Sklar et al. reported on leukemic patients (who did not undergo SCT) who were randomized to one of several different treatment regimens, one of which included craniospinal irradiation (CSI) and 18–24 Gy of testicular irradiation, another that included CSI only, and another that included only cranial irradiation.21 All treatment regimens included identical chemotherapy. Leydig cell function, as measured by luteinizing hormone, testosterone, and pubertal development, was found to be unaffected in all three groups. The long-term rate of germ-cell dysfunction (as measured by raised levels of follicle-stimulating hormone and/or reduced testicular volume) was 55% in the CSI plus testicular irradiation group compared with 0% in the cranial irradiation only group. It is worth noting that the CSI only group had a 17% rate of germ cell dysfunction, indicating that cranial irradiation plus scattered radiation from the CSI fields may have influenced germ cell function.

Sanders, in her review of the late effects of TBI, notes that approximately 50% of all males who are treated with fractionated TBI will suffer delayed onset of puberty and other symptoms of primary gonadal failure, whereas preservation of fertility is rare.22 It is reasonable to conclude that the addition of a 4-Gy boost (raising the total testicular dose from 13.5 Gy to 17.5 Gy at our center) will have little marginal detriment, insofar as most patients will be infertile as a result of the TBI. Additional studies will be necessary to determine the incidence of Leydig cell dysfunction as a result of this procedure. We suspect that the risk of additional serious, long-term effects engendered by a 2-Gy × 2 boost is small and is compensated for by the low rate of testicular failure noted in these patients.

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