British Journal of Haematology, 1990, 75, 496-498
Testicular irradiation in childhood lymphoblastic leukaemia 0 . B. EDEN,*J. S . L I L L E Y M A N t A N D S . RICHARDS$on behalf of the Medical Research Council Working Party on Leukaemia in Childhoods *Department of Haematology, Royal Hospital for Sick Children, Edinburgh, tDepartnient of Haematology, Shefield Children’s Hospital, and $Clinical Trials Service Unit, Oxford
Received 29 November 1989; accepted for publication 5 April 1990
Summary. The effect of randomly allocated testicular irradiation on the subsequent incidence of testicular infiltration and disease-free survival was assessed in two Medical Research Council Childhood Leukaemia Trials. UKALL VI and UKALL VII. None of the 83 boys who actually received testicular radiotherapy subsequently developed gonadal disease, whereas 18 of the 163 who were not irradiated did. Despite this there is no apparent difference in disease-free survival for
those randomized to receive testicular irradiation compared to those who were not, after a minimum of 8 years follow up. Although prophylactic testicular irradiation appears to prevent subsequent gonadal relapse there is no evidence that it improves overall prognosis when adequate systemic chemotherapy is used. As it has considerable long-term side effects it cannot be recommended as routine therapy.
An apparently increasing incidence of overt testicular relapse in boys with acute lymphoblastic leukaemia (ALL) observed in the first three Medical Research Council (MRC) ALL Trials (Eden et al, 1978) and the poor prognosis for the patients in that series even for those with apparently ‘isolated’ relapse (Eden et al, 1983) led to a protocol requirement for testicular biopsy prior to cessation of therapy in order to detect minimal disease. However, there were major difficulties in obtaining adequate specimens, and a histologically false negative rate of 7% (Eden, 1982).Use of the nuclear terminal deoxynucleotidy1 transferase stain to try to improve detection rates proved inconclusive (Thomas et al, 1982). Consequently, two trials incorporating randomized ‘prophylactic’ irradiation were initiated. The aim was to treat minimal disease early in therapy rather than to await detection of disease by biopsy or overt swelling. This paper reports the results of the total MRC experience with such ‘prophylactic’ irradiation given in the context of randomized controlled trials.
central nervous system (CNS) therapy in two sequential MRC Trials, UKALL VI and UKALL VII. Entry to UKALL VI was open to ALL patients of any age with an initial white cell count greater than 20 x 10”l between 1978 and 1980. There was a randomization between two induction regimens, both containing vincristine and prednisolone in standard dose but one (arm A) contained two pulses thereafter of cyclophosphamide, cytosine arabinoside and prednisolone with late asparaginase and adriamycin whilst the other schedule (arm B) included asparaginase and three moderate dose infusions of intravenous methotrexate (500 mg/m2). Cranial and testicular irradiation were given between weeks 11 and 13. Randomization to receive testicular irradiation or not was performed at diagnosis. Some trial participants did not wish to randomize their patients for testicular irradiation and elected to treat all boys from their centre in the same way, choosing irradiation or not. The total dose to the scrotum and inguinal canals was 1200 cGray in six fractions. Continuing therapy was with daily 6-mercaptopurine interrupted by pulses of prednisolone and vincristine, and 5 d of methotrexate every 4 weeks. Subcutaneous cytosine arabinoside was given twice every 12-week cycle. Of 18 7 boys entered into UKALL VI. 73 were randomized, 36 to receive testicular irradiation and 3 7 not. One randomized patient failed to remit. In total, 59 boys actually received irradiation in the trial (randomized plus physician’s choice). UKALL VII was for ‘standard’ risk ALL defined as children aged less than 14 years with an initial white cell count below 2 0 x 109/1(T and B cell leukaemia excluded) and ran from March 1979 to March 1980. The drugs, doses and routes of therapy used in this trial have previously been reported
PATIENTS AND METHODS Randomized testicular irradiation was given concurrent with
5 Members: R. M. Hardisty. C. C. Bailey, F. Barbor, N. D. Barnes, C. Barton, S. Cartwright. A. W. Craft, J. C. M. Chessells. R. Collins, S. I. Dempsey, J. H. Durrant, 0. B. Eden, P. Emerson, D. I. K. Evans, J. J. Fennelly. D. A. G. Galton. I. M. Hann, F. G. H. Hill, J. Kernahan, J. S. Lilleyman. T. J. McElwain. J. R. Mann, J. Martin, P. H. Morris Jones, A. Oakhill, J. Peto, J. K. H. Rees. M. Radford. S. Richards, R. F. Stevens, G. P. Summerfield and E. Thompson. Correspondence: Dr 0. B. Eden, Department of Haematology, Royal Hospital for Sick Children, 1 7 Millerfield Place, Edinburgh EH9 1LF.
496
Childhood ALL: Testicular Irradiation Table 11. Testicular irradiation actually given for testicular relapse (as first event)
Table I. Testicular irradiation (allocated): testicular relapses (as first event) ~
49 7
~~
Trial
R/T
No R/T
P values
Trial
R/T
No R/T
VI VII
0/36* 2/22*
3/37 4/21
0.04 0.2
VI VII
0159 0124
13/120 6118
Total
2/58
7/58
0.06
*One patient in both VI and VII failed to remit following randomization to testicular irradiation (R/T).
Table 111. Testicular irradiation allocated: all relapses/death
(Lilleymanet al, 198 5). Randomization for testicular irradiation made at diagnosis was again at the participating physician's discretion. Dosage here was 1800 cGray in nine fractions over 21 d to the testes only (not including the spermatic cords) between weeks 8 and 11.Twenty-two boys were randomized to gonadal irradiation and 21 to none. Twenty-four actually received radiotherapy and 1 8 did not. One boy failed to remit. Treatments were compared by the logrank method of analysis of time to first event (Peto et a!, 1977). All P values given are one-tailed. The end points used were (1)any relapse or death (DFS) and (2) isolated testicular relapse. For the latter, a testicular relapse was counted as isolated only if it was more than 30 d before any other relapse and times were censored at a first relapse of any other type: non-remitters were excluded. In the analysis of DFS, non-remitters were counted as having an event on day 1. In order to avoid biases due to differences in centre or patient selection the analyses were done for randomized treatment, whether or not this was actually given.
R/T
No R/T
P values
VI VII
23/36* 11/22*
27/37 8/21
0.2 0.8
Total
34/58
35/58
0.4
*Includes the two patients who failed to remit.
significant difference between the allocated treatment groups. It was clear from data files that some participants had problems with this randomization. Five patients (two in VI; three in VII) allocated to receive radiotherapy did not actually receive it (two relapsed in the testes in UKALL VII), five (one in VI; four in VII) were allocated no radiotherapy but were irradiated and three (one in VI; two in VII) randomized not to receive radiotherapy had non-protocol treatment. If these protocol deviants were excluded, then there was a significant difference between treatments ( P = 0.002). Table I1 shows the data by actual treatment given in both trials. No patient who actually received testicular irradiation in either trial subsequently relapsed in the testes.
KESULTS
Table I shows the data for both trials by allocation of irradiation and subsequent testicular relapse. There was no
0
Trial
I
I
I
I
I
I
I
I
I
L
I
2
3
4
5
6
7
8
9
10
T i m e 10 relapse or death (years)
Fig 1. UKALL VI and VII disease-free survival curve by allocation of testicular irradiation. -, irradiation.
Testicular irradiation: - - -, no testicular
498
0. B. Eden, 1. S. Lilleyman and S. Richards
Table I11 shows the data for all relapses and/or death for those randomized. There was no significant difference between treatments whether or not the protocol deviants were excluded. Fig 1 shows the disease-free survival curves for those randomized to testicular irradiation or not, with a minimum follow up time of 8 years from the last patient entry. There was no difference in terms of overall event-free survival between those irradiated and those not. In this series salvage chemotherapy was no more successful in the non-irradiated than in the irradiated patients for relapses at any site. DISCUSSION For some time it has been suggested that the widely experienced difference in survival for childhood leukaemia between boys and girls could be attributed to gonadal relapse and that a blood-testis (or blood-interstitium) barrier akin to the blood-brain barrier might explain why disease appears difficult to eradicate in this site. This was the rationale for use of testicular irradiation in the trials described which have now been followed to maturity. Our results indicate that testicular irradiation in dosages of 1200-1 800 cGray, given early in therapy, can prevent overt testicular relapse. However, in our patients, although testicular relapse was prevented there was no overall benefit for disease-free survival in these trials, even after an extended period of follow up. The simultaneously observed apparent benefit of intramuscular methotrexate over the oral route in UKALL VII (Lilleyman et al, 1985), implies that a strategy of more effective ‘total body’ chemotherapy rather than concentrating on local treatment to ‘sanctuary sites’ may be the best approach. Although not advocating i.m. methotrexate, which may be associated with neurotoxicity when given over a protracted period, it must be admitted that more intensive or effectivechemotherapy may eradicate all sites of disease including ‘sanctuaries’. In the more myelosuppressive MRC UKALL VIII-which includes all prognostic groups-the overt testicular relapse rate is under 7% (Eden, 1990)and an overall improvement in survival compared with previous trials has been noted (Peto et al, 1986). Others have found that systemic chemotherapy alone can apparently remove the sex differenceand reduce sanctuary site relapses (Lampert et a!, 1984). From histological studies (Eden, 1982) and the results of these more enthusiastic chemotherapy regimens there is little evidence to support the idea of the testis being a true sanctuary site. Rather, testicular infiltration appears to be a flag of persistent leukaemia heralding haematological relapse unless treated very aggressively. Aggressive retreatment has been reported to be capable of salvaging a much larger proportion of those with isolated testicular relapse occurring off treatment than in the MRC series (Tiedemann et al, 1982). Our failure to show any beneficial effect in terms of diseasefree survival for those irradiated accords with the experience
of the Children’s Cancer Study Group following sanctuary therapy (Nesbit et al, 1982). Nor is the treatment without problems. Irradiation in dosages of 1200-1800 cGray is very likely to cause infertility and may damage Leydig cell function (Shalet et al, 1977). In view of these risks and in the absence of any benefit in survival we feel that it is no longer appropriate to use testicular irradiation as part of therapy for childhood lymphoblastic leukaemia.
ACKNOWLEDGMENTS The authors most gratefully acknowledge members of the MRC Working Party for permission to publish data on their patients and Miss R. Brown for her typing. Further details of protocols VI and VII can be obtained from the authors.
REFERENCES Eden. O.B. (1982) Extramedullary leukaemia. Paediatric Haenlatofogy and Oncology (ed. by M. Willoughby and S. Siegel), pp. 47-79. Butterworth International Medical Reviews. Eden, O.B. (1990) Analysis of UKALL VIII. (Personal communication). Eden. O.B.,Hardisty, R.M., Innes,E.M.,Kay.H.E.M.&Peto,J. (1978) Testicular disease in acute lymphoblastic leukaemia in childhood. Report on behalf of the Medical Research Council’sWorking Party on Leukaemia in Childhood. British Medical Journal, i, 334-338. Eden, O.B.. Rankin. A., Kay, H.E.M. & Chessells, J. (1983) Isolated testicular relapse in acute lymphoblastic leukaemia in childhood. Archives of Diseases in Childhood, 58, 128-1 32. Lampert, F., Henze. G., Langermann, H.J.. Schellong, G., Gadner, H. & Riehm. H.J. (1984) Acute lymphoblastic leukaemia: current status of therapy in children. Recent Results in Cancer Research, pp. 159-1 8 1. Springer Verlag, New York. Lilleyman. J.S., Richards, S. & Rankin. A. (1985) Medical Research Council Leukaemia Trial UKALL VII. A report to the Council by the Working Party on leukaemia in childhood. Archives of Diseases in Childhood. 60, 1050-1054. Nesbit, M.E., Sather. H. & Robison. L.L. (1982) Sanctuary therapy: a randomised trial of 724 children with previously untreated acute lymphoblastic leukaemia. Cancer Research, 42, 674-680. Peto. J., Eden, O.B., Lilleyman. J.S. & Richards, S.M. (1986) Improvement in treatment for children with acute lymphoblastic leukaemia. Lancet, i, 408-411. Peto, R., Pike, M.C., Armitage, P., etal (1977)Design and analysis of randomised clinical trials requiring prolonged observation of each patient. 11. British Journal of Cancer, 3 5 , 1-39. Shalet, S.M.. Beardwell. D.G.. Turomey, J.A., et al (1977) Endocrine function followingthe treatment of acute leukaemia in childhood. Journal of Pediatrics, 90, 920-923. Thomas, J.A., Janossy, G., Eden, O.B. & Bollum, FJ. (1982) Nuclear terminal deoxynucleotidyl transferase in leukaemic infiltrates of testicular tissue. British Journal of Cancer, 45, 709-71 7. Tiedemann, K., Chessells, J.M. & Sandland, R.M. (1982) Isolated testicular relapse in boys with acute lymphoblastic leukaemia: treatment andoutcome. British Medical Journal,285,1614-1616.
Testicular irradiation in childhood lymphoblastic leukaemia 0 . B. EDEN,*J. S . L I L L E Y M A N t A N D S . RICHARDS$on behalf of the Medical Research Council Working Party on Leukaemia in Childhoods *Department of Haematology, Royal Hospital for Sick Children, Edinburgh, tDepartnient of Haematology, Shefield Children’s Hospital, and $Clinical Trials Service Unit, Oxford
Received 29 November 1989; accepted for publication 5 April 1990
Summary. The effect of randomly allocated testicular irradiation on the subsequent incidence of testicular infiltration and disease-free survival was assessed in two Medical Research Council Childhood Leukaemia Trials. UKALL VI and UKALL VII. None of the 83 boys who actually received testicular radiotherapy subsequently developed gonadal disease, whereas 18 of the 163 who were not irradiated did. Despite this there is no apparent difference in disease-free survival for
those randomized to receive testicular irradiation compared to those who were not, after a minimum of 8 years follow up. Although prophylactic testicular irradiation appears to prevent subsequent gonadal relapse there is no evidence that it improves overall prognosis when adequate systemic chemotherapy is used. As it has considerable long-term side effects it cannot be recommended as routine therapy.
An apparently increasing incidence of overt testicular relapse in boys with acute lymphoblastic leukaemia (ALL) observed in the first three Medical Research Council (MRC) ALL Trials (Eden et al, 1978) and the poor prognosis for the patients in that series even for those with apparently ‘isolated’ relapse (Eden et al, 1983) led to a protocol requirement for testicular biopsy prior to cessation of therapy in order to detect minimal disease. However, there were major difficulties in obtaining adequate specimens, and a histologically false negative rate of 7% (Eden, 1982).Use of the nuclear terminal deoxynucleotidy1 transferase stain to try to improve detection rates proved inconclusive (Thomas et al, 1982). Consequently, two trials incorporating randomized ‘prophylactic’ irradiation were initiated. The aim was to treat minimal disease early in therapy rather than to await detection of disease by biopsy or overt swelling. This paper reports the results of the total MRC experience with such ‘prophylactic’ irradiation given in the context of randomized controlled trials.
central nervous system (CNS) therapy in two sequential MRC Trials, UKALL VI and UKALL VII. Entry to UKALL VI was open to ALL patients of any age with an initial white cell count greater than 20 x 10”l between 1978 and 1980. There was a randomization between two induction regimens, both containing vincristine and prednisolone in standard dose but one (arm A) contained two pulses thereafter of cyclophosphamide, cytosine arabinoside and prednisolone with late asparaginase and adriamycin whilst the other schedule (arm B) included asparaginase and three moderate dose infusions of intravenous methotrexate (500 mg/m2). Cranial and testicular irradiation were given between weeks 11 and 13. Randomization to receive testicular irradiation or not was performed at diagnosis. Some trial participants did not wish to randomize their patients for testicular irradiation and elected to treat all boys from their centre in the same way, choosing irradiation or not. The total dose to the scrotum and inguinal canals was 1200 cGray in six fractions. Continuing therapy was with daily 6-mercaptopurine interrupted by pulses of prednisolone and vincristine, and 5 d of methotrexate every 4 weeks. Subcutaneous cytosine arabinoside was given twice every 12-week cycle. Of 18 7 boys entered into UKALL VI. 73 were randomized, 36 to receive testicular irradiation and 3 7 not. One randomized patient failed to remit. In total, 59 boys actually received irradiation in the trial (randomized plus physician’s choice). UKALL VII was for ‘standard’ risk ALL defined as children aged less than 14 years with an initial white cell count below 2 0 x 109/1(T and B cell leukaemia excluded) and ran from March 1979 to March 1980. The drugs, doses and routes of therapy used in this trial have previously been reported
PATIENTS AND METHODS Randomized testicular irradiation was given concurrent with
5 Members: R. M. Hardisty. C. C. Bailey, F. Barbor, N. D. Barnes, C. Barton, S. Cartwright. A. W. Craft, J. C. M. Chessells. R. Collins, S. I. Dempsey, J. H. Durrant, 0. B. Eden, P. Emerson, D. I. K. Evans, J. J. Fennelly. D. A. G. Galton. I. M. Hann, F. G. H. Hill, J. Kernahan, J. S. Lilleyman. T. J. McElwain. J. R. Mann, J. Martin, P. H. Morris Jones, A. Oakhill, J. Peto, J. K. H. Rees. M. Radford. S. Richards, R. F. Stevens, G. P. Summerfield and E. Thompson. Correspondence: Dr 0. B. Eden, Department of Haematology, Royal Hospital for Sick Children, 1 7 Millerfield Place, Edinburgh EH9 1LF.
496
Childhood ALL: Testicular Irradiation Table 11. Testicular irradiation actually given for testicular relapse (as first event)
Table I. Testicular irradiation (allocated): testicular relapses (as first event) ~
49 7
~~
Trial
R/T
No R/T
P values
Trial
R/T
No R/T
VI VII
0/36* 2/22*
3/37 4/21
0.04 0.2
VI VII
0159 0124
13/120 6118
Total
2/58
7/58
0.06
*One patient in both VI and VII failed to remit following randomization to testicular irradiation (R/T).
Table 111. Testicular irradiation allocated: all relapses/death
(Lilleymanet al, 198 5). Randomization for testicular irradiation made at diagnosis was again at the participating physician's discretion. Dosage here was 1800 cGray in nine fractions over 21 d to the testes only (not including the spermatic cords) between weeks 8 and 11.Twenty-two boys were randomized to gonadal irradiation and 21 to none. Twenty-four actually received radiotherapy and 1 8 did not. One boy failed to remit. Treatments were compared by the logrank method of analysis of time to first event (Peto et a!, 1977). All P values given are one-tailed. The end points used were (1)any relapse or death (DFS) and (2) isolated testicular relapse. For the latter, a testicular relapse was counted as isolated only if it was more than 30 d before any other relapse and times were censored at a first relapse of any other type: non-remitters were excluded. In the analysis of DFS, non-remitters were counted as having an event on day 1. In order to avoid biases due to differences in centre or patient selection the analyses were done for randomized treatment, whether or not this was actually given.
R/T
No R/T
P values
VI VII
23/36* 11/22*
27/37 8/21
0.2 0.8
Total
34/58
35/58
0.4
*Includes the two patients who failed to remit.
significant difference between the allocated treatment groups. It was clear from data files that some participants had problems with this randomization. Five patients (two in VI; three in VII) allocated to receive radiotherapy did not actually receive it (two relapsed in the testes in UKALL VII), five (one in VI; four in VII) were allocated no radiotherapy but were irradiated and three (one in VI; two in VII) randomized not to receive radiotherapy had non-protocol treatment. If these protocol deviants were excluded, then there was a significant difference between treatments ( P = 0.002). Table I1 shows the data by actual treatment given in both trials. No patient who actually received testicular irradiation in either trial subsequently relapsed in the testes.
KESULTS
Table I shows the data for both trials by allocation of irradiation and subsequent testicular relapse. There was no
0
Trial
I
I
I
I
I
I
I
I
I
L
I
2
3
4
5
6
7
8
9
10
T i m e 10 relapse or death (years)
Fig 1. UKALL VI and VII disease-free survival curve by allocation of testicular irradiation. -, irradiation.
Testicular irradiation: - - -, no testicular
498
0. B. Eden, 1. S. Lilleyman and S. Richards
Table I11 shows the data for all relapses and/or death for those randomized. There was no significant difference between treatments whether or not the protocol deviants were excluded. Fig 1 shows the disease-free survival curves for those randomized to testicular irradiation or not, with a minimum follow up time of 8 years from the last patient entry. There was no difference in terms of overall event-free survival between those irradiated and those not. In this series salvage chemotherapy was no more successful in the non-irradiated than in the irradiated patients for relapses at any site. DISCUSSION For some time it has been suggested that the widely experienced difference in survival for childhood leukaemia between boys and girls could be attributed to gonadal relapse and that a blood-testis (or blood-interstitium) barrier akin to the blood-brain barrier might explain why disease appears difficult to eradicate in this site. This was the rationale for use of testicular irradiation in the trials described which have now been followed to maturity. Our results indicate that testicular irradiation in dosages of 1200-1 800 cGray, given early in therapy, can prevent overt testicular relapse. However, in our patients, although testicular relapse was prevented there was no overall benefit for disease-free survival in these trials, even after an extended period of follow up. The simultaneously observed apparent benefit of intramuscular methotrexate over the oral route in UKALL VII (Lilleyman et al, 1985), implies that a strategy of more effective ‘total body’ chemotherapy rather than concentrating on local treatment to ‘sanctuary sites’ may be the best approach. Although not advocating i.m. methotrexate, which may be associated with neurotoxicity when given over a protracted period, it must be admitted that more intensive or effectivechemotherapy may eradicate all sites of disease including ‘sanctuaries’. In the more myelosuppressive MRC UKALL VIII-which includes all prognostic groups-the overt testicular relapse rate is under 7% (Eden, 1990)and an overall improvement in survival compared with previous trials has been noted (Peto et al, 1986). Others have found that systemic chemotherapy alone can apparently remove the sex differenceand reduce sanctuary site relapses (Lampert et a!, 1984). From histological studies (Eden, 1982) and the results of these more enthusiastic chemotherapy regimens there is little evidence to support the idea of the testis being a true sanctuary site. Rather, testicular infiltration appears to be a flag of persistent leukaemia heralding haematological relapse unless treated very aggressively. Aggressive retreatment has been reported to be capable of salvaging a much larger proportion of those with isolated testicular relapse occurring off treatment than in the MRC series (Tiedemann et al, 1982). Our failure to show any beneficial effect in terms of diseasefree survival for those irradiated accords with the experience
of the Children’s Cancer Study Group following sanctuary therapy (Nesbit et al, 1982). Nor is the treatment without problems. Irradiation in dosages of 1200-1800 cGray is very likely to cause infertility and may damage Leydig cell function (Shalet et al, 1977). In view of these risks and in the absence of any benefit in survival we feel that it is no longer appropriate to use testicular irradiation as part of therapy for childhood lymphoblastic leukaemia.
ACKNOWLEDGMENTS The authors most gratefully acknowledge members of the MRC Working Party for permission to publish data on their patients and Miss R. Brown for her typing. Further details of protocols VI and VII can be obtained from the authors.
REFERENCES Eden. O.B. (1982) Extramedullary leukaemia. Paediatric Haenlatofogy and Oncology (ed. by M. Willoughby and S. Siegel), pp. 47-79. Butterworth International Medical Reviews. Eden, O.B. (1990) Analysis of UKALL VIII. (Personal communication). Eden. O.B.,Hardisty, R.M., Innes,E.M.,Kay.H.E.M.&Peto,J. (1978) Testicular disease in acute lymphoblastic leukaemia in childhood. Report on behalf of the Medical Research Council’sWorking Party on Leukaemia in Childhood. British Medical Journal, i, 334-338. Eden, O.B.. Rankin. A., Kay, H.E.M. & Chessells, J. (1983) Isolated testicular relapse in acute lymphoblastic leukaemia in childhood. Archives of Diseases in Childhood, 58, 128-1 32. Lampert, F., Henze. G., Langermann, H.J.. Schellong, G., Gadner, H. & Riehm. H.J. (1984) Acute lymphoblastic leukaemia: current status of therapy in children. Recent Results in Cancer Research, pp. 159-1 8 1. Springer Verlag, New York. Lilleyman. J.S., Richards, S. & Rankin. A. (1985) Medical Research Council Leukaemia Trial UKALL VII. A report to the Council by the Working Party on leukaemia in childhood. Archives of Diseases in Childhood. 60, 1050-1054. Nesbit, M.E., Sather. H. & Robison. L.L. (1982) Sanctuary therapy: a randomised trial of 724 children with previously untreated acute lymphoblastic leukaemia. Cancer Research, 42, 674-680. Peto. J., Eden, O.B., Lilleyman. J.S. & Richards, S.M. (1986) Improvement in treatment for children with acute lymphoblastic leukaemia. Lancet, i, 408-411. Peto, R., Pike, M.C., Armitage, P., etal (1977)Design and analysis of randomised clinical trials requiring prolonged observation of each patient. 11. British Journal of Cancer, 3 5 , 1-39. Shalet, S.M.. Beardwell. D.G.. Turomey, J.A., et al (1977) Endocrine function followingthe treatment of acute leukaemia in childhood. Journal of Pediatrics, 90, 920-923. Thomas, J.A., Janossy, G., Eden, O.B. & Bollum, FJ. (1982) Nuclear terminal deoxynucleotidyl transferase in leukaemic infiltrates of testicular tissue. British Journal of Cancer, 45, 709-71 7. Tiedemann, K., Chessells, J.M. & Sandland, R.M. (1982) Isolated testicular relapse in boys with acute lymphoblastic leukaemia: treatment andoutcome. British Medical Journal,285,1614-1616.
