Treatment of Isolated Testicular Relapse in Childhood Acute Lymphoblastic Leukemia: An Italian Multicenter Study By Cornelio Uderzo, Maria Grazia Zurlo, Luigia Adamoli, Luigi Zanesco, Maurizio Aric6, G. Calculli, Adele Comelli, Luca Cordero di Montezemolo, Maria Teresa Di Tullio, Carlo Guazzelli, A. Donfrancesco, and Beate Werner for the Associazione Italiana Ematologia ed Oncologia Pediatrica Between May 1980 and April 1987, 49 children with acute lymphoblastic leukemia (ALL) in isolated testicular and first leukemia relapse (ITR) were enrolled in the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) multicenter study REC80-ITR. According to the Rome Workshop criteria, 77% were at standard and 23% at high initial prognostic risk. In 33% of the cases, ITR occurred during first treatment. The REC80-ITR protocol consisted of an induction phase regimen of vincristine (VCR), cytarabine (ARAC), methotrexate (MTX), and asparaginase (L-asp), and bilateral testicular irradiation, and CNS prophylaxis with intrathecal MTX and a maintenance phase with a multidrug rotating regimen. Total treatment duration was 30 months. The median time of observation after ITR was 51 months. The Kaplan-Meier estimates of survival and disease-free survival (DFS) at 4 years were 67.7% and 41%, respectively. Patients who had an ITR on therapy or within the first
THE TESTES are one of the most common extramedullary sites of relapse in childhood acute lymphoblastic leukemia (ALL). The reported incidence of isolated testicular relapse (ITR) varies from 3% to 16% in patients on therapy and from 7% to 40% in those off thera-
off-therapy year showed the poorest outcome. The DFS at 3 years was 20%, 47.6%, and 100%, respectively, for children who had an ITR on treatment (n = 16), within the first year of treatment withdrawal (n = 22), or later (n = 10) (P = .001). Pa-
tients with an asymptomatic occult testicular infiltrate at treatment discontinuation had a very unfavorable prognosis. Eighty-one percent of second relapses involved the bone marrow. In our experience, children presenting an early ITR (ie, within 6 months of treatment withdrawal) need a very aggressive treatment because of the high probability of an underlying systemic disease. On the other hand, patients with a late ITR seem to have a truly local recurrence and can apparently be cured by standard protocols, as shown in protocol REC80-ITR. J Clin Oncol 8:672-677. © 1990 by American Society of Clinical Oncology.
In 1980, the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) started a multicenter study, AIEOP REC80-ITR, based on the treatment of first isolated testicular relapse in childhood ALL. The results of this study are the subject of this report.
py.1-4 In recent years, the increasing intensity of
front-line therapies has apparently reduced these figures.5,6 ITR is usually a relatively late relapse, presenting mainly in the first year following treatment withdrawal.7' Its prognosis is definitely better in patients relapsing off therapy. 1,9
From the ClinicaPediatricaUniversithdi Milano, Monza; Clinica Pediatrica,Padova, Clinica Pediatrica,Pavia; Clinica Pediatrica,Brescia; Istituto G. Gaslini, Genova; Clinica PediatricaIII, Torino; Clinica Pediatrica,Napoli; Clinica PediatricaIII, Firenze; OspedaleBambino Gesfi, Roma; and the Clinica Pediatrica,Roma, Italy. Submitted December 5, 1988; accepted November 9, 1989. Address reprintrequests to Cornelio Uderzo, MD, Clinica Pediatrica,Nuovo Ospedale San Gerardo,via Donizetti 106, 20052 Monza, MI Italy. © 1990 by American Society of ClinicalOncology. 0732-183X/90/0804-0004$3.00/0
672
PATIENTS AND METHODS Patients From May 1980 to April 1987 all 49 children followed in the 19 participating institutions who had a histologically confirmed isolated testicular and first ALL relapse were enrolled in this study. Median age at first ALL diagnosis was 5 years 7 months (range, 5 months to 10 years 11 months); 89.8% of the patients were between 1 and 9 years, and 10.2% less than 1 or more than 10 years old. Initial WBC count was above 50 x 109/L in 15% of the cases. Since the first leukemia diagnosis was made between 1974 and 1984, some other data such as immunophenotype and French-American-British (FAB) morphology at diagnosis are not available for all the children. According to the criteria proposed at the Rome Workshop'0 38 (77.6%) patients were at standard and 11 (22.4%) at high initial prognostic risk. Previous treatment was not uniform. Thirty-five patients were treated with multidrug regimens for standard-risk leukemia, including a two-(vincristine [VCR] plus prednisone [PRD]) or three-drug (plus asparaginase [L-asp]) induction,
Journalof ClinicalOncology, Vol 8, No 4 (April), 1990: pp 672-677
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TREATMENT OF ISOLATED TESTICULAR RELAPSE IN ALL prophylaxis to the CNS with intrathecal methotrexate (MTX) plus cranial radiation, followed in the majority of the cases by a consolidation phase (cytarabine [ARA-C], thioguanine, and daunomycin [daunorubicin]) and a classic mercaptopurine plus MTX maintenance, and in 15 cases with pulses of VCR plus PRD. The remaining 14 patients were treated with more aggressive protocols, with anthracyclines and cyclophosphamide. None of the front-line protocols adopted required a testicular biopsy at the time of treatment withdrawal. That notwithstanding, of the 33 of 49 patients who continued treatment until the time the initial therapy was to be discontinued, 27 underwent this procedure. The diagnosis of ITR was made on an open-wedge testicular biopsy, bilateral in 37 cases. At the same time, a bone marrow (BM) aspirate and a CSF sample were examined and found negative in all the cases. Clinical remission (CR) of overt ITR was evaluated at the end of the induction (chemotherapy plus local radiation) and was defined as the return of testicular size to normal in a well boy with normal counts and no other signs or symptoms of disease. Remission was evaluated with a second testicular biopsy in only two patients.
Treatment The REC80-ITR therapeutic protocol consisted of: induction chemotherapy, VCR 1.5 mg/sqm intravenously (IV), ARA-C 150 mg/m2 IV push and 300 mg/sqm IV in 24 hours, MTX 150 mg/m2 IV over 4 hours on days 1 and 15, and L-asp 5,000 IU/m 2 intramuscularly (IM) on days 2 to 4 and 16 to 18; radiotherapy, bilateral testicular irradiation, starting from the first day of the induction (dose, 20 Gy in 10 fractions); CNS prophylaxis, intrathecal administrations of MTX (standard dose per age) plus ARA-C (30 mg/m2) once a week for the first month and then every 6 weeks until treatment withdrawal; maintenance chemotherapy, multidrug rotating regimen according to LSA2-L2 protocol maintenance" for 30 months.
Evaluation and StatisticalMethods The Kaplan-Meier method and log-rank tests 12 were used respectively to estimate and compare survival, disease-free survival (DFS), and disease-free interval (DFI) curves. Time on study or time to terminal event were calculated from the date of testicular relapse. Terminal events considered were for survival, death; for DFS, death in second CR and second relapse; for BM DFI, second relapse involving the BM. Patients who underwent BM transplantation (BMT) in second CR were censored from the analysis at the time of BMT. All analyses are based on follow-up to April 30, 1988.
RESULTS In 16 of 49 patients (32.7%), ITR presented during treatment, in five (10.2%) at therapy suspension (occult infiltrate at routine testicular biopsy), and in 28 (57.1%) after treatment with-, drawal (13 of these in the first 6 months, five in 6
673
to 11 months, and ten 1 or more years after therapy suspension). In 22 of 28 patients who were off therapy when ITR occurred, a routine testicular biopsy was performed at therapy suspension and was negative. In eight of these patients, ITR was observed within 6 months from treatment withdrawal, in five of these patients it was observed in the following 6 months, and in the remaining nine, thereafter. Thus, if only the 43 patients assessable for testicular biopsy at treatment withdrawal are considered, the proportion of boys with an occult infiltrate-all from the standard initial prognostic risk group-is 11.6%. All the patients completed the induction phase of protocol REC80-ITR. In one patient with an occult testicular infiltrate, the routine BM performed at the end of REC80-ITR induction phase showed leukemic blasts (M1 BM at ITR diagnosis); this patient was considered resistant. No major toxicities or deaths were observed during the induction. Of the 48 patients achieving remission, one is still on treatment, 19 are off therapy in continuous CR, 26 have had a second relapse, and two underwent BMT while on treatment. One of the two transplanted patients subsequently presented a testicular relapse. Two patients did not receive testicular irradiation; of these one had a combined relapse (testis plus bone marrow) 35 months after ITR. No major toxicities or deaths in second CR were observed. Of the 23 patients who relapsed in the first year off-therapy, a routine testicular biopsy at treatment discontinuation was performed and positive in five, negative in 13, and not done in five. Of the five patients with an occult ITR, one was resistant and the other four subsequently experienced a BM relapse at 4, 8, 11, and 28 months, respectively, after ITR. Corresponding numbers for second relapses in the other two groups were five of 13 patients in those with a negative biopsy-two of eight with ITR in the first 6 months (both BM), and three of five with ITR in the second 6 months (one BM, one CNS, and one mediastinal)-and four of five (all BM, in one combined BM plus eye) in those who did not undergo this procedure (all with ITR in the first 6 months). One boy of the last group had a negative testicular biopsy 6 months before therapy discontinuation. He experienced the ITR 3
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UDERZO ET AL
months after treatment withdrawal and subsequently had a second relapse in the BM. The median time of observation after ITR for patients still in second CR was 51 months (range, 11 to 96). The 4-year estimates (±95% confidence level [CL]) of survival and DFS are 67.7% (53.6% to 81.8%) and 41% (26.3% to 55.9%), respectively. Patients presenting an ITR while on first treatment showed the poorest outcome (Fig 1). The Kaplan-Meier estimate of DFS at 36 months (± 95% CL) is 20% (0% to 40%), 47.6% (26% to 69.2%) and 100%, respectively, for patients who had an ITR during first treatment (16 cases), within the first year after treatment withdrawal (22 cases), and after I or more years off therapy (10 cases) (X2 = 13.4667; TP = .001). Distribution of relapses by site and time from ITR is shown in Table 1. In 81% of the cases, the second relapse involved the BM. Two patients had a second ITR. Sixteen relapses (61.5%) occurred during the first 18 months after ITR. DFS and BM DFI are shown in Fig 2. The Kaplan-Meier estimate of the probability of having a second recurrence involving the BM at 3 years is 68.2% for the patients who had an ITR on therapy, 46.6% for those with an ITR in the first off-therapy year, and 0% for those in whom it occurred later (x2 = 10.5396; P = .005). Given the same length of first remission, both
the initial prognostic risk group, determined according to the Rome Workshop criteria,to and the type of treatment received (standard v more aggressive) did not influence the outcome after ITR. On the other hand, only nine of 38 (23.7%) patients at standard versus seven out of 11 (63.6%) at high initial prognostic risk developed ITR while on initial therapy. DISCUSSION In this study, 49 consecutive children with ALL in first ITR were treated according to the same therapeutic protocol. Although 57% of the children relapsed off therapy, in 46% of them, the recurrence occurred in the first 6 months. Thirty-four ITR (69.4%) were observed on therapy or within the first 6 months of treatment withdrawal. Patients with higher initial prognostic risk showed an earlier pattern of testicular relapse, 64% of high-risk patients relapsing while on treatment. On the other hand, no testicular recurrence was seen during the first 12 months of CR and only one within the first 18 months. In our study, the length of first remission, as reported by others, 9 and the time from treatment withdrawal heavily influence the prognosis: the three-year DFS rate was 20%, 48%, and 100%, respectively, in patients relapsing on therapy, during, and after the first year off therapy. Morphologic and functional studies have dem(8)
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675
TREATMENT OF ISOLATED TESTICULAR RELAPSE IN ALL Table 1. Second Relapses by Site and Time From Second CR in Children With First Isolated Testicular ALL Relapse Time From Second CR (Month)
Patients at interval start Site BM CNS Testis BM + testis BM + eye Mediastinum Total
0-5
6-11
12-17
18-23
24-35
36+
48
44
34
29
28
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7 1 8
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1
5
onstrated that the testis can act as a functional "sanctuary" of leukemic clones13 because of local factors such as a relatively lower concentration of immunoglobulins,1 4 hypothermia, 15 and a lower concentration of antitumoral drugs in the interstitium or in the seminiferous tubuli,1"'1316 possibly secondary to the expression of P-glycoprotein in capillary endothelium.' 7 The adoption of more aggressive front-line protocols and, more specifically, the introduction of intermediate- or highdose MTX has led to a marked decrease of testicular recurrences, 5 6' '18 presumably because of the high gradient reached by this drug at the blood-gonad barrier level.19 In our series, the role of functional sanctuary played by the testis seems especially relevant in patients experiencing a "late" ITR (at least 6 months after treatment discontinuation), while, on the contrary, the outcome of those with an "early" ITR suggests that, in this case, testicular
1
Total
19 2 2 1 1 1 26
relapse could represent the first signal of a disseminated systemic disease, partially controlled by front-line treatment. In fact, the probability of a subsequent relapse involving the BM was significantly higher in patients with an early ITR than in those with a late ITR (4-year estimate of BM relapse rate probability, 69% v 7%). Of the 33 patients with an early ITR achieving second remission, 20 have already had a BM relapse, whereas in three, a second recurrence was again testicular (in one case after BMT) and in one meningeal. On the other hand, none of the 10 patients who had an ITR after the first year off therapy had a further relapse in a median follow-up of 50 months. Thus, in this series, only patients with a late ITR seem to have a truly local disease and, possibly, the expectation of a long-term second remission. Patients presenting an asymptomatic occult
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DFS and BM DFI after first isolated testicular relapse in childhood ALL.
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5
676
UDERZO ET AL
infiltrate at treatment withdrawal shared, in this series, the same unfavorable prognosis as those with overt early testicular disease. The presence of 22 children with testicular relapse after a negative testicular biopsy (in 13 cases within 1 year) deserves a specific comment. If light microscopy is of little help in identifying focal infiltrates, 20,21 a more sensitive technique like electron microscopy 22 can also yield false negative results.23,24 Alternative methods such as immunohistochemical studies with terminal deoxyribonucleotidyl transferase are not always specific enough and are frequently difficult to perform. 25 Thus, at present, conventional techniques to detect minimal residual disease in the testis do not offer adequate sensitivity and reproducibility. A longer follow-up is needed to evaluate fully
any difference in prognosis between different categories of patients with ITR. As demonstrated in the case of CNS relapses, 26 extramedullary events can lead to late second recurrences and to an extremely poor long-term prognosis. Although front-line prophylaxis will presumably decrease the occurrence of testicular relapse, a better understanding of its biology is needed to identify optimal second-line treatment strategies. If our observations are confirmed, a different therapeutic approach should be adopted according to time of relapse. In our opinion, whereas in late ITR conventional treatment, as in protocol REC80-ITR, could presumably be adequate, in early events the treatment strategy should be the same as in overt systemic disease, that is, very intensive systemic chemotherapy or BMT.
APPENDIX Institutions participating in the study (and number of cases) include the following: Clinica Pediatrica III, Bologna (G. Paolucci) (one); Clinica Pediatrica, Brescia (A.G. Ugazio) (three); Clinica Pediatrica, Catania (A. Russo) (two); Clinica Pediatrica III, Firenze (C. Guazzelli) (three); Istituto G. Gaslini, Genova (L. Massimo) (five); Clinica Pediatrica Milano, Monza (G. Masera) (eight); Clinica Pediatrica, Modena (F. Massolo) (one); Clinica Pediatrica, Napoli (S. Cutillo) (three); Clinica Pediatrica, Padova (P. Pasut) (three); Clinica Pediatrica, Parma (F. Casa) (one); Clinica Pediatrica, Pavia (G.R. Burgio) (five); Clinica Pediatrica, Pisa (P. Macchia) (two); Clinica Pediatrica,Roma (G. Digilio) (three); Ospedale Bambino Geso, Roma (D. Rosati) (three); Clinica Pediatrica III, Torino (E. Madon) (five); Clinica Pediatrica, Trieste (P. Tamaro) (one).
REFERENCES 1. Bowman WP, Aur RJA, Ustu OH, et al: Isolated testicular relapse in acute lymphocytic leukemia of childhood: Categories and influence on survival. J Clin Oncol 2:924-929, 1984 2. Uderzo C, Adamoli L, Locasciulli A, et al: Testicular relapse in childhood acute lymphoblastic leukemia: Diagnosis, prognosis and treatment. Riv Ital Ped (IJP) 10:226-228, 1984 3. Lampert F, Henze G, Langermann H-J, et al: Acute lymphoblastic leukemia: Current status of therapy in children-Recent results. Cancer Res 93:159-181, 1984 4. Land VJ, Berry DH, Herson J, et al: Long-term survival in childhood acute leukemia: "Late" relapses. Med Pediatr Oncol 7:19-24, 1979 5. Brecher ML, Weinberg V, Boyett JM, et al: Intermediate dose methotrexate in childhood acute lymphoblastic leukemia resulting in decreased incidence of testicular relapse. Cancer 58:1024-1028, 1986 6. Moe PJ, Seip M, Finne PH, et al: Intermediate dose methotrexate in childhood acute lymphocytic leukemia. Eur Paediatr Haematol Oncol 1:113-118, 1984 7. MRC Working Party on leukemia in childhood: Testicular disease in Acute Lymphoblastic Leukemia in childhood. Br Med J 1:334-338, 1978 8. Riehm H, Feickert H-J, Lampert F: Acute lymphoblastic leukemia in Voute PA, Barrett A, Bloom HJG, et al (eds):
Cancer in Children: Clinical Management. New York, NY, Springer-Verlag, 1986, pp 98-116 9. Bleyer WA, Sather H, Hammond GD: Prognosis and treatment after relapse of acute lymphoblastic leukemia and non-Hodgkin's lymphoma: 1985. A report from the Children Cancer Study Group, Cancer 58:590-594, 1986 10. Mastrangelo R, Poplack D, Bleyer A, et al: Report and recommendations of the Rome Workshop concerning poorprognosis acute lymphoblastic leukemia in children: Biologic bases for staging, stratification and treatment. Med Pediatr Oncol 14:191-194, 1986 11. Wollner N, Excelby PR, Lieberman PH: NonHodgkin's lymphoma in children. A progress report on the original patients treated with LSA2-L2 protocol. Cancer 44:1990-1991, 1979 12. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Stat Assoc 53:457-481, 1958 13. Hoots WK, Nelson JA: Are testes a pharmacologic sanctuary for leukemia? Am Soc Clin Oncol Proc 2:68, 1983 (abstr) 14. Withmore WF, Gittes RF: Studies on the prostate and testis as immunologically privileged sites. Cancer Treat Rep 61:217-222, 1977 15. Van Eys J, Sullivan MP: Testicular leukemia and temperature. Lancet 2:256-257, 1976
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TREATMENT OF ISOLATED TESTICULAR RELAPSE IN ALL 16. Kay HEM: Annotation. Testicular infiltration in acute lymphoblastic leukemia. Br J Haematol 53:537-542, 1983 17. Cordon-Cardo C, O'Brien JP, Casals D, et al: Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86:695-698, 1989 18. Pui C-H, Dahl GV, Bowman WP, et al: Effective testicular biopsy during chemotherapy for childhood leukaemia is of no clinical value. Lancet 2:410-412, 1985 19. Riccardi R, Vigersky RA, Barnes S, et al: MTX levels in the interstitial space and seminiferous tubule of rat testis. Cancer Res 42:1617-1619, 1982 20. Askin FB, Land VS, Sullivan MP, et al: Occult testicular leukemia: Testicular biopsy at three years continuous remission of childhood leukemia. Cancer 47:470-475, 1981 21. Hudson MM, Frankel LS, Mullins J, et al: Diagnostic value of surgical testicular biopsy after therapy for acute lymphoblastic leukemia. J Pediatr 107:50-53, 1985
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22. Masera G, Uderzo C, Marzorati R, et al: Diagnosis of testicular Leukemia. J Pediatr 101:314-316, 1982 23. Palmer N, Prince F, Newton W, et al: Morphologic findings in occult testicular relapse in childhood acute lymphoblastic leukemia. XIV Meeting of the International Society of Pediatric Oncology (SIOP), Board of SIOP, Berne, 1982, p 67 (abstr) 24. Miller DR: Childhood acute lymphoblastic leukemiaL: 2. Strategies and innovations for producing more cures. Am J Pediatr Hematol Oncol 10:174-179, 1988 25. Thomas JA, Janossy G, Eden OB, et al: Nuclear terminal deoxynucleotidyl transferase in leukaemic infiltrates of testicular tissue. Br J Cancer 45:709-717, 1982 26. Ortega JA, Nesbit ME, Sather HN, et al: Long-term evaluation of a CNS prophylaxis trial-treatment. Comparisons and outcome after CNS relapse in childhood ALL: A report from the Children Cancer Study Group. J Clin Oncol 5:1646-1654, 1987
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THE TESTES are one of the most common extramedullary sites of relapse in childhood acute lymphoblastic leukemia (ALL). The reported incidence of isolated testicular relapse (ITR) varies from 3% to 16% in patients on therapy and from 7% to 40% in those off thera-
off-therapy year showed the poorest outcome. The DFS at 3 years was 20%, 47.6%, and 100%, respectively, for children who had an ITR on treatment (n = 16), within the first year of treatment withdrawal (n = 22), or later (n = 10) (P = .001). Pa-
tients with an asymptomatic occult testicular infiltrate at treatment discontinuation had a very unfavorable prognosis. Eighty-one percent of second relapses involved the bone marrow. In our experience, children presenting an early ITR (ie, within 6 months of treatment withdrawal) need a very aggressive treatment because of the high probability of an underlying systemic disease. On the other hand, patients with a late ITR seem to have a truly local recurrence and can apparently be cured by standard protocols, as shown in protocol REC80-ITR. J Clin Oncol 8:672-677. © 1990 by American Society of Clinical Oncology.
In 1980, the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) started a multicenter study, AIEOP REC80-ITR, based on the treatment of first isolated testicular relapse in childhood ALL. The results of this study are the subject of this report.
py.1-4 In recent years, the increasing intensity of
front-line therapies has apparently reduced these figures.5,6 ITR is usually a relatively late relapse, presenting mainly in the first year following treatment withdrawal.7' Its prognosis is definitely better in patients relapsing off therapy. 1,9
From the ClinicaPediatricaUniversithdi Milano, Monza; Clinica Pediatrica,Padova, Clinica Pediatrica,Pavia; Clinica Pediatrica,Brescia; Istituto G. Gaslini, Genova; Clinica PediatricaIII, Torino; Clinica Pediatrica,Napoli; Clinica PediatricaIII, Firenze; OspedaleBambino Gesfi, Roma; and the Clinica Pediatrica,Roma, Italy. Submitted December 5, 1988; accepted November 9, 1989. Address reprintrequests to Cornelio Uderzo, MD, Clinica Pediatrica,Nuovo Ospedale San Gerardo,via Donizetti 106, 20052 Monza, MI Italy. © 1990 by American Society of ClinicalOncology. 0732-183X/90/0804-0004$3.00/0
672
PATIENTS AND METHODS Patients From May 1980 to April 1987 all 49 children followed in the 19 participating institutions who had a histologically confirmed isolated testicular and first ALL relapse were enrolled in this study. Median age at first ALL diagnosis was 5 years 7 months (range, 5 months to 10 years 11 months); 89.8% of the patients were between 1 and 9 years, and 10.2% less than 1 or more than 10 years old. Initial WBC count was above 50 x 109/L in 15% of the cases. Since the first leukemia diagnosis was made between 1974 and 1984, some other data such as immunophenotype and French-American-British (FAB) morphology at diagnosis are not available for all the children. According to the criteria proposed at the Rome Workshop'0 38 (77.6%) patients were at standard and 11 (22.4%) at high initial prognostic risk. Previous treatment was not uniform. Thirty-five patients were treated with multidrug regimens for standard-risk leukemia, including a two-(vincristine [VCR] plus prednisone [PRD]) or three-drug (plus asparaginase [L-asp]) induction,
Journalof ClinicalOncology, Vol 8, No 4 (April), 1990: pp 672-677
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TREATMENT OF ISOLATED TESTICULAR RELAPSE IN ALL prophylaxis to the CNS with intrathecal methotrexate (MTX) plus cranial radiation, followed in the majority of the cases by a consolidation phase (cytarabine [ARA-C], thioguanine, and daunomycin [daunorubicin]) and a classic mercaptopurine plus MTX maintenance, and in 15 cases with pulses of VCR plus PRD. The remaining 14 patients were treated with more aggressive protocols, with anthracyclines and cyclophosphamide. None of the front-line protocols adopted required a testicular biopsy at the time of treatment withdrawal. That notwithstanding, of the 33 of 49 patients who continued treatment until the time the initial therapy was to be discontinued, 27 underwent this procedure. The diagnosis of ITR was made on an open-wedge testicular biopsy, bilateral in 37 cases. At the same time, a bone marrow (BM) aspirate and a CSF sample were examined and found negative in all the cases. Clinical remission (CR) of overt ITR was evaluated at the end of the induction (chemotherapy plus local radiation) and was defined as the return of testicular size to normal in a well boy with normal counts and no other signs or symptoms of disease. Remission was evaluated with a second testicular biopsy in only two patients.
Treatment The REC80-ITR therapeutic protocol consisted of: induction chemotherapy, VCR 1.5 mg/sqm intravenously (IV), ARA-C 150 mg/m2 IV push and 300 mg/sqm IV in 24 hours, MTX 150 mg/m2 IV over 4 hours on days 1 and 15, and L-asp 5,000 IU/m 2 intramuscularly (IM) on days 2 to 4 and 16 to 18; radiotherapy, bilateral testicular irradiation, starting from the first day of the induction (dose, 20 Gy in 10 fractions); CNS prophylaxis, intrathecal administrations of MTX (standard dose per age) plus ARA-C (30 mg/m2) once a week for the first month and then every 6 weeks until treatment withdrawal; maintenance chemotherapy, multidrug rotating regimen according to LSA2-L2 protocol maintenance" for 30 months.
Evaluation and StatisticalMethods The Kaplan-Meier method and log-rank tests 12 were used respectively to estimate and compare survival, disease-free survival (DFS), and disease-free interval (DFI) curves. Time on study or time to terminal event were calculated from the date of testicular relapse. Terminal events considered were for survival, death; for DFS, death in second CR and second relapse; for BM DFI, second relapse involving the BM. Patients who underwent BM transplantation (BMT) in second CR were censored from the analysis at the time of BMT. All analyses are based on follow-up to April 30, 1988.
RESULTS In 16 of 49 patients (32.7%), ITR presented during treatment, in five (10.2%) at therapy suspension (occult infiltrate at routine testicular biopsy), and in 28 (57.1%) after treatment with-, drawal (13 of these in the first 6 months, five in 6
673
to 11 months, and ten 1 or more years after therapy suspension). In 22 of 28 patients who were off therapy when ITR occurred, a routine testicular biopsy was performed at therapy suspension and was negative. In eight of these patients, ITR was observed within 6 months from treatment withdrawal, in five of these patients it was observed in the following 6 months, and in the remaining nine, thereafter. Thus, if only the 43 patients assessable for testicular biopsy at treatment withdrawal are considered, the proportion of boys with an occult infiltrate-all from the standard initial prognostic risk group-is 11.6%. All the patients completed the induction phase of protocol REC80-ITR. In one patient with an occult testicular infiltrate, the routine BM performed at the end of REC80-ITR induction phase showed leukemic blasts (M1 BM at ITR diagnosis); this patient was considered resistant. No major toxicities or deaths were observed during the induction. Of the 48 patients achieving remission, one is still on treatment, 19 are off therapy in continuous CR, 26 have had a second relapse, and two underwent BMT while on treatment. One of the two transplanted patients subsequently presented a testicular relapse. Two patients did not receive testicular irradiation; of these one had a combined relapse (testis plus bone marrow) 35 months after ITR. No major toxicities or deaths in second CR were observed. Of the 23 patients who relapsed in the first year off-therapy, a routine testicular biopsy at treatment discontinuation was performed and positive in five, negative in 13, and not done in five. Of the five patients with an occult ITR, one was resistant and the other four subsequently experienced a BM relapse at 4, 8, 11, and 28 months, respectively, after ITR. Corresponding numbers for second relapses in the other two groups were five of 13 patients in those with a negative biopsy-two of eight with ITR in the first 6 months (both BM), and three of five with ITR in the second 6 months (one BM, one CNS, and one mediastinal)-and four of five (all BM, in one combined BM plus eye) in those who did not undergo this procedure (all with ITR in the first 6 months). One boy of the last group had a negative testicular biopsy 6 months before therapy discontinuation. He experienced the ITR 3
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674
UDERZO ET AL
months after treatment withdrawal and subsequently had a second relapse in the BM. The median time of observation after ITR for patients still in second CR was 51 months (range, 11 to 96). The 4-year estimates (±95% confidence level [CL]) of survival and DFS are 67.7% (53.6% to 81.8%) and 41% (26.3% to 55.9%), respectively. Patients presenting an ITR while on first treatment showed the poorest outcome (Fig 1). The Kaplan-Meier estimate of DFS at 36 months (± 95% CL) is 20% (0% to 40%), 47.6% (26% to 69.2%) and 100%, respectively, for patients who had an ITR during first treatment (16 cases), within the first year after treatment withdrawal (22 cases), and after I or more years off therapy (10 cases) (X2 = 13.4667; TP = .001). Distribution of relapses by site and time from ITR is shown in Table 1. In 81% of the cases, the second relapse involved the BM. Two patients had a second ITR. Sixteen relapses (61.5%) occurred during the first 18 months after ITR. DFS and BM DFI are shown in Fig 2. The Kaplan-Meier estimate of the probability of having a second recurrence involving the BM at 3 years is 68.2% for the patients who had an ITR on therapy, 46.6% for those with an ITR in the first off-therapy year, and 0% for those in whom it occurred later (x2 = 10.5396; P = .005). Given the same length of first remission, both
the initial prognostic risk group, determined according to the Rome Workshop criteria,to and the type of treatment received (standard v more aggressive) did not influence the outcome after ITR. On the other hand, only nine of 38 (23.7%) patients at standard versus seven out of 11 (63.6%) at high initial prognostic risk developed ITR while on initial therapy. DISCUSSION In this study, 49 consecutive children with ALL in first ITR were treated according to the same therapeutic protocol. Although 57% of the children relapsed off therapy, in 46% of them, the recurrence occurred in the first 6 months. Thirty-four ITR (69.4%) were observed on therapy or within the first 6 months of treatment withdrawal. Patients with higher initial prognostic risk showed an earlier pattern of testicular relapse, 64% of high-risk patients relapsing while on treatment. On the other hand, no testicular recurrence was seen during the first 12 months of CR and only one within the first 18 months. In our study, the length of first remission, as reported by others, 9 and the time from treatment withdrawal heavily influence the prognosis: the three-year DFS rate was 20%, 48%, and 100%, respectively, in patients relapsing on therapy, during, and after the first year off therapy. Morphologic and functional studies have dem(8)
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DFS after first isolated testicular relapse in childhood ALL, by time to first relapse.
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675
TREATMENT OF ISOLATED TESTICULAR RELAPSE IN ALL Table 1. Second Relapses by Site and Time From Second CR in Children With First Isolated Testicular ALL Relapse Time From Second CR (Month)
Patients at interval start Site BM CNS Testis BM + testis BM + eye Mediastinum Total
0-5
6-11
12-17
18-23
24-35
36+
48
44
34
29
28
19
2 1 3
7 1 8
3 1 1
-
4 1 1 6
3 3
1
5
onstrated that the testis can act as a functional "sanctuary" of leukemic clones13 because of local factors such as a relatively lower concentration of immunoglobulins,1 4 hypothermia, 15 and a lower concentration of antitumoral drugs in the interstitium or in the seminiferous tubuli,1"'1316 possibly secondary to the expression of P-glycoprotein in capillary endothelium.' 7 The adoption of more aggressive front-line protocols and, more specifically, the introduction of intermediate- or highdose MTX has led to a marked decrease of testicular recurrences, 5 6' '18 presumably because of the high gradient reached by this drug at the blood-gonad barrier level.19 In our series, the role of functional sanctuary played by the testis seems especially relevant in patients experiencing a "late" ITR (at least 6 months after treatment discontinuation), while, on the contrary, the outcome of those with an "early" ITR suggests that, in this case, testicular
1
Total
19 2 2 1 1 1 26
relapse could represent the first signal of a disseminated systemic disease, partially controlled by front-line treatment. In fact, the probability of a subsequent relapse involving the BM was significantly higher in patients with an early ITR than in those with a late ITR (4-year estimate of BM relapse rate probability, 69% v 7%). Of the 33 patients with an early ITR achieving second remission, 20 have already had a BM relapse, whereas in three, a second recurrence was again testicular (in one case after BMT) and in one meningeal. On the other hand, none of the 10 patients who had an ITR after the first year off therapy had a further relapse in a median follow-up of 50 months. Thus, in this series, only patients with a late ITR seem to have a truly local disease and, possibly, the expectation of a long-term second remission. Patients presenting an asymptomatic occult
100-
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3 TESTICULAR
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DFS and BM DFI after first isolated testicular relapse in childhood ALL.
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5
676
UDERZO ET AL
infiltrate at treatment withdrawal shared, in this series, the same unfavorable prognosis as those with overt early testicular disease. The presence of 22 children with testicular relapse after a negative testicular biopsy (in 13 cases within 1 year) deserves a specific comment. If light microscopy is of little help in identifying focal infiltrates, 20,21 a more sensitive technique like electron microscopy 22 can also yield false negative results.23,24 Alternative methods such as immunohistochemical studies with terminal deoxyribonucleotidyl transferase are not always specific enough and are frequently difficult to perform. 25 Thus, at present, conventional techniques to detect minimal residual disease in the testis do not offer adequate sensitivity and reproducibility. A longer follow-up is needed to evaluate fully
any difference in prognosis between different categories of patients with ITR. As demonstrated in the case of CNS relapses, 26 extramedullary events can lead to late second recurrences and to an extremely poor long-term prognosis. Although front-line prophylaxis will presumably decrease the occurrence of testicular relapse, a better understanding of its biology is needed to identify optimal second-line treatment strategies. If our observations are confirmed, a different therapeutic approach should be adopted according to time of relapse. In our opinion, whereas in late ITR conventional treatment, as in protocol REC80-ITR, could presumably be adequate, in early events the treatment strategy should be the same as in overt systemic disease, that is, very intensive systemic chemotherapy or BMT.
APPENDIX Institutions participating in the study (and number of cases) include the following: Clinica Pediatrica III, Bologna (G. Paolucci) (one); Clinica Pediatrica, Brescia (A.G. Ugazio) (three); Clinica Pediatrica, Catania (A. Russo) (two); Clinica Pediatrica III, Firenze (C. Guazzelli) (three); Istituto G. Gaslini, Genova (L. Massimo) (five); Clinica Pediatrica Milano, Monza (G. Masera) (eight); Clinica Pediatrica, Modena (F. Massolo) (one); Clinica Pediatrica, Napoli (S. Cutillo) (three); Clinica Pediatrica, Padova (P. Pasut) (three); Clinica Pediatrica, Parma (F. Casa) (one); Clinica Pediatrica, Pavia (G.R. Burgio) (five); Clinica Pediatrica, Pisa (P. Macchia) (two); Clinica Pediatrica,Roma (G. Digilio) (three); Ospedale Bambino Geso, Roma (D. Rosati) (three); Clinica Pediatrica III, Torino (E. Madon) (five); Clinica Pediatrica, Trieste (P. Tamaro) (one).
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TREATMENT OF ISOLATED TESTICULAR RELAPSE IN ALL 16. Kay HEM: Annotation. Testicular infiltration in acute lymphoblastic leukemia. Br J Haematol 53:537-542, 1983 17. Cordon-Cardo C, O'Brien JP, Casals D, et al: Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86:695-698, 1989 18. Pui C-H, Dahl GV, Bowman WP, et al: Effective testicular biopsy during chemotherapy for childhood leukaemia is of no clinical value. Lancet 2:410-412, 1985 19. Riccardi R, Vigersky RA, Barnes S, et al: MTX levels in the interstitial space and seminiferous tubule of rat testis. Cancer Res 42:1617-1619, 1982 20. Askin FB, Land VS, Sullivan MP, et al: Occult testicular leukemia: Testicular biopsy at three years continuous remission of childhood leukemia. Cancer 47:470-475, 1981 21. Hudson MM, Frankel LS, Mullins J, et al: Diagnostic value of surgical testicular biopsy after therapy for acute lymphoblastic leukemia. J Pediatr 107:50-53, 1985
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22. Masera G, Uderzo C, Marzorati R, et al: Diagnosis of testicular Leukemia. J Pediatr 101:314-316, 1982 23. Palmer N, Prince F, Newton W, et al: Morphologic findings in occult testicular relapse in childhood acute lymphoblastic leukemia. XIV Meeting of the International Society of Pediatric Oncology (SIOP), Board of SIOP, Berne, 1982, p 67 (abstr) 24. Miller DR: Childhood acute lymphoblastic leukemiaL: 2. Strategies and innovations for producing more cures. Am J Pediatr Hematol Oncol 10:174-179, 1988 25. Thomas JA, Janossy G, Eden OB, et al: Nuclear terminal deoxynucleotidyl transferase in leukaemic infiltrates of testicular tissue. Br J Cancer 45:709-717, 1982 26. Ortega JA, Nesbit ME, Sather HN, et al: Long-term evaluation of a CNS prophylaxis trial-treatment. Comparisons and outcome after CNS relapse in childhood ALL: A report from the Children Cancer Study Group. J Clin Oncol 5:1646-1654, 1987
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