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The effect of scheduling in children undergoing prophylactic cranial irradiation for acute lymphoblastic leukaemia
56
Radiotherapy and Oncology, 22 (1991) 56-59 © 1991 Elsevier Science Publishers B.V. All rights reserved 0167-8140/91/$03.50
RADION 00876
The effect of scheduling in children undergoing prophylactic cranial irradiation for acute lymphoblastic leukaemia Shaun A. Costello, Richard D. Jones and A n n Barrett Department of Radiation Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow, U.K. (Received 13 November 1990, revision received 4 June 1991, accepted 17 June 1991)
Key words: Acute lymphatic leukaemia; CNS leukaemia; Cranial irradiation
Summary Control of central nervous system (CNS) disease and overall survival have been analysed in a group of 829 children with leukaemia entered into the UKALL VIII trial to determine whether scheduling of the cranial irradiation is of prognostic significance. We show that short gaps in treatment do not influence prognosis and that current radiotherapy practice need not be modified.
Introduction Acute lymphoblastic leukaemia (ALL) constitutes 75 ~o of childhood leukaemias, making it the most common malignancy of childhood, occurring in 3.5 per 100 000 live births in the U.K. [1 ]. With the advent of effective chemotherapy it became clear that apart from the marrow the central nervous system (CNS) was the major site of relapse [2]. This is because the brain is a so-called sanctuary site into which chemotherapy penetrates poorly. Treatment of the CNS shortly after diagnosis when the patient is in systemic remission can reduce the relapse rate from up to 56~o to 10-35~o [3,17]. Since the early report of Pinkel that craniospinai irradiation reduced the relapse rate, irradiation has played a part in most protocols [ 5 ], although the recognition of serious late effects, such as hormonal deficiencies [6] and intellectual impairment [7] has led to a search for alternative approaches to the problem. There are four methods of CNS treatment in clinical use;
(1) intrathecal methotrexate plus other intrathecal agents
(2) high dose systemic methotrexate (3) cranial irradiation plus intrathecal methotrexate (4) craniospinal irradiation. Craniospinal radiation has been abandoned in current trials (UKALL XI) because of unacceptable effects on the spinal epiphyses and bone marrow, cranial radiation has however been retained for high risk groups and those with meningeal involvement at presentation. Low and normal risk groups receive intrathecal chemotherapy with or without high dose methotrexate. Among the recognized prognostic factors in childhood ALL which include presenting WBC and age [ 9], control of CN S disease by radiation may be significant. Low doses (500-1200 cGy) are insufficient to prevent relapse [5,10]. High doses (2500-2900 cGy) [ 11 ] and large dose/fraction [ 12] may increase the complication rate. There is considerable interest in the influence of the scheduling of radiation on the control of other tumour types. Breaks in radiation therapy have been shown to be detrimental to tumour control in the treatment of other tumours such as laryngeal carcinoma [ 13 14]. We have analysed data from the UKALL VIII trial to see if gaps in cranial irradiation adversely affected the
Address for correspondence: Shaun A. Costello, Registrar in Radiation Oncology, Beatson Oncology Centre, Western Infirmary, Dumbarton Rd., Glasgow Gll 6NT, U.K.
57 rate of CNS relapse in this group of patients with acute lymphoblastic leukaemia.
TABLE 1 Group
Treatment time (days)
Elapsed time (days)
Total No.
Relapses No.
Relapse rate
A B C D E
12 14 16 > 16 Variable
11 13 15 > 15 Variable
255 223 128 42 106
16 6 5 6 8
7.11 2.69 3.91 14.29 7.50
Method
The U K A L L VIII trial was a multicentre trial comparing two different regimes of chemotherapy (vincristine, prednisolone, asparaginase + daunorubicin) to determine the role of daunorubicin in the remission induction of childhood ALL. The trial closed in December 1984 after 4 years, with a minimum follow-up time of 46 months and a maximum of 98 months. All children aged 0-14 presenting with ALL including those with CNS leukaemia (25 or 3~o ) were entered, a total of 829 children in all. CNS treatment was given to all children entered, although there was discretion to delay it up to age two years in the younger children because of fear of side effects such as intellectual impairment and pituitary dysfunction. Cranial radiotherapy was given during the fifth and sixth weeks of treatment starting any day except Friday. Each child received 1800 cGy in 10 fractions plus intrathecal methotrexate over 12-14 days by a standard technique except for those who had CNS involvement at presentation. These patients received 2400 cGy in 12 fractions over 14-16 days to craniospinal fields [15-17]. A perspex beam directing shell was produced for most patients to allow accurate reproduction of the treatment position and shielding on each day of treatment. Sensitive structures such as the anterior orbit and nasopharynx were shielded to prevent cataract formation and mucositis whilst including all the meninges. Two opposing lateral fields were used. For this analysis, patients were divided into five groups ( A - E ) depending on how irradiation was actually given (see Table I). All groups received 1800 cGy in l0 fractions except for Group E where dose, fractionation and scheduling varied from patient to patient. Many of this group were treated with orthovoltage and a modified prescription instead ofmegavoltage radiation although this was a deviation from the protocol. Others received non-protocol regimes because of local practice or because it was felt that the patient would not tolerate conventional fractionation. Many children (except those with overt CNS involvement) received their radiation over 14 days as a consequence of starting treatment mid week because of the practice of not working over weekends. Others received their radiation over 15-16 days because of servicing requirements of the treatment machine, tran sport difficulties or public holidays. A few of this group were too sick to have treatment
Groups A, B and C who all received a standard treatment differing only in the overall time of delivery of radiation were analysed by obtaining the chi-square coefficient. No significant difference was found between tham (p = 0.05). Group D was composed of patients whose treatment was very prolonged. The relapse rate was significantly higher in this group, p < 0.05. Group E has a relapse rate which is not significantly (p > 0.05) different from those of groups A B C . It is unsafe to draw any conclusion from this because of the heterogeneity of the group.
either because of disease or of chemotherapy, but unless their problems were of a transient nature most will have received their treatment in > 16 days. The groups were first analysed together by obtaining the Pearson chi-square coefficient and then the presenting white cell count (WBC) and age of each individual patient was analysed by group in order to exclude any between group variation of these major prognostic factors. Results
The overall results for the U K A L L VIII trial were initially reported as showing a reduced relapse rate in the arm containing daunorubicin [ 17] but more recent data show no significant difference. It is therefore possible to combine both arms for this analysis. Of the 829 patients entered into the study, 764 records were available for evaluation. 8 0 ~ of patients had their treatment completed within 16 days with an overall CNS relapse rate of 4.4~o. This compares well with other studies. Ten children had CNS involvement at presentation of which three suffered isolated CNS relapse. These have been excluded from further analysis. In order to exclude any uneven distribution of poor prognostic factors, the principal prognostic factors of each group, age under two and presenting peripheral WBC, was assessed using a Kruskal-Wallis test which showed no significant difference in distribution of age under two or presenting WBC between groups (p > 0.05). It was up to the discretion of each institution whether the patients presenting at under 2 years had their cranial
58 TABLE II Group
Total < 2
Relapses
Relapse rate
A B C D E
]9
15 10 6 7
2 0 0 2 3
9.5% 0% 0% 25% 30~o
prophylaxis delayed until they were 2 years old (Table II). This was a group with few relapses making subgroup analysis unreliable. The overall relapse rate for these patients in Groups A, B and C was 5.5~o and not dissimilar from that of the main group.
Discussion When a course of treatment is given for a tumour, there is sound radiobiological evidence that gaps in treatment are deleterious to the aim of tumour control [ 18]. These gaps can be intentional or unintentional. Intentional gaps come about as a result of the treatment regimen (although regimens featuring gaps are now less common) or due to local practice (e.g. not working at weekends). Unintentional gaps are brought about by poor patient treatment tolerance (e.g. severe mucosal reactions), machine breakdown or service time and transportation difficulties. Tumour growth is well known to follow a Gompertzian pattern in vitro, which has several important implications for the treatment of cancer. As the tumour shrinks the rate of division increases, because the tumour is no longer restricted by lack of nutrients and growth factors, recruitment from the cells in Go phase occurs and there may be an overall shortening of the cell cycle time. Thus some of the control obtained by irradiation may be lost if gaps are left in treatment [ 18 ]. There is some clinical evidence for this in solid tumours. A radical treatment for laryngeal 20 1B 16 14 ~2 /
10
/
/
/
P
/
8
/
6
/
Conclusions The purpose of this study was to determine whether or not gaps in the delivery of prophylactic cranial radiation to children with ALL had any effect on the meningeal relapse rate. This study has revealed no evidence that this is so, except where treatment is very prolonged and no change in current radiotherapy scheduling is required. Continuity of treatment is important and gaps should be avoided if at all possible.
/
4 o
2 C
carcinoma of 6000 cGy to the 95 % isodose line is often associated with a severe mucosal reaction which may in some cases prove to be the dose limiting factor. In an attempt to avoid this problem, regimens have been devised to incorporate a gap to allow the acutely reacting mucosal tissues to recover. Unfortunately although these regimens were accompanied with a much reduced early morbidity as a result of treatment, the rate of turnout recurrence was also higher as was the late morbidity [13 14]. These observations may not be relevant to childhood ALL where the turnout is not in solid phase and in the CNS exists either in suspension or as meningeal deposits of only a few microns. Thus it is neither starved of nutrients or of growth factors and tends to grow in an exponential fashion rather than a Gompertzian fashion until the patient is treated or dies. There is good in vivo evidence for this in animals from the classic work of Skipper in 1964 in which he showed that a single leukaemic cell transplanted into a susceptible host would multiply in an exponential fashion until the host succumbed [19]. It is probable therefore that in the case of childhood leukaemia, little significant increase in doubling time will occur with treatment. This suggestion is borne out by the results for Groups A, B and C suggesting little or no significant effect of scheduling on relapse rate. This is consonant with the results of treatment of Hodgkin's disease where gaps do not seem to affect relapse rate and may in fact improve patient tolerance [20]. The increased relapse rate seen in Group D reflects the type of patients within it. Group D contains a large proportion of patients who were infected or otherwise ill from their disease. Because of these poor prognostic features, it is not surprising that they did not do well.
i
12 DAYS
~
Acknowledgements
°
i
L
14 DAYS
Relapse
16DAYS
t
> 16 DAYS
r o t e */o
Fig. 1. Relapse rate according to schedule of fractionation.
We acknowledge the help of Professor Tim McElwain of the MRC steering committee, and should like to thank Sue Richards of the Oxford Clinical Trials Unit
59 and all members of the MRC leukaemia working party for permission to study data from UKALL VIII, and Diane Henderson of the Royal Hospital for Sick Chil-
dren Glasgow and Jim Paul of the Beatson Oncology Centre, Glasgow, for help in acquiring and processing the data.
References 1 Riehm, M., Feickert, H. J. and Lampert, F. Acute lymphoblastic leukaemia. In: Cancer in children UICC, pp. 101-118. Editors: P. A. Voute, A. Barrett andSpringer H. J. G. Bloom. Springer-Verlag, Berlin, 1986. 2 Pinkel, D. Patterns of failure in acute lymphocytic leukaemia. Cancer Treat. Symp. 2: 259-266, 1983. 3 Krepler, P., Kummer, M. and Pawlowsky, J. Prevention of meningeal leukaemia and relases by cranial irradiation and intrathecal MTX in A.L.L. Acta Neuropath. (Berlin) Suppl. VI: 241-245, 1975. 4 Reinartz, G., Kogelnik, H.D. and Krepler, P. Preventative cranial irradiation in the treatment of A.L.L. in children. Radiol. Clin. 47: 380-389, 1978. 5 Pinkel, D., Simone, J., Hustu, H. O. and Aur, R. J.A. Nine years experience with "total therapy" of childhood A.LL. Paediatrics 50: 246-251, 1972. 6 Mauras, N., Sabio, H. and Rogal, A.D. Neuroendocrine function in survivors of childhood A.L.L. and N.H.L. A study of pulsatile growth hormone and gonadotropin secretions. Am. J. Paediatr. Haematol./Oncol. 10: 9-17, 1988. 7 Fogarty, K., Volonino, V. and Caul, J. Learing disabilities following C.N.S. irradiation. Clin. Paediatr. 27: 524-528, 1988. 8 Freeman, A. I., Weinburg, V. and Brecher, M.L. Comparison of intermediate dose methotrexate with cranial irradiation for the post induction treatment of A.L.L. in children. N. Engl. J. Med. 308: 477-484, 1983. 9 Pluss, H.J. Prognostic factor analysis in A.L.L. of childhood. Helv. Paediat. Acta. 42: 197-247, 1987. 10 Hustu, O., Aur, R. and Verzosa, M. Prevention ofC.N.S, leukaemia by irradiation. Cancer 32: 585-597, 1973. 11 Chessels, J.M. Cranial irradiation in childhood lymphoblastic leukaemia time for reappraisal. Br. Med. J. 291: 680-687, 1985.
12 Duffner, P.K. and Cohen, M.E. The long term effects of cranial irradiation on the C.N.S. Cancer 56: 1841-1846, 1985. 13 Overgaard, J., Hjelm-Hansen, M. and Vendelbo, L. Comparison of conventional and split course radiotherapy as primary treatment in carcinoma of the larynx (Abstract). Estro 5th Annual Meeting, 1986, Baden-Baden, F.R.G. 14 Robertson, A.G., Robertson, C., Boyle, P. and Symonds, R.P. The effect of varying dose schedules on response of glottic carcinoma of larynx. BJC 61: 160-161, 1990. 15 Hardisty, R. M., Eden, O. B. and Lilleyman, J.S. Ukall viii trial protocol 1982 (revised) M.R.C. Working party on leukaemia in childhood. 16 Lilleyman, J. S. and Eden O.E. United Kingdom Medical Research Council Acute Lymphoblastic Leukaemia (UKALL) Trials i-viii: clinical features and results of treatment in four groups of children with adverse prognostic features. Med. Paediatr. Oncol. 14: 182-186, 1986. 17 Eden, O. B., Lilleyman, M. P. and Shaw, P.M. Medical Research Council Childhood Leukaemia Trial viii compared with Trials ii-vii: lessons for future management. In: Haemotology and Blood Transfusion 1987, 30 acute leukaemias. Editors: T. Buchner, G. ScheUong and W. Hiddemann. Springer-Verlag, Berlin and Heidelburg, 1987. 18 Thames. H.D. and Hendry, J.H. Proliferative response to radiation injury. In: Fractionation in radiotherapy, pp. 100-136. Taylor and Francis, London, 1987. 19 Skipper, H. E., Sehabel, F. M. and Wilcox, W.S. Experimental evaluation of potential anticancer agents xiii. On the criteria and kinetics associated with curability of experimental leukaemia. Cancer Chemother. Rep. 35:1-111, 1964. 20 Johnson, R. E., Ruhl, U. and Johnson, S.K. Split course radiotherapy of Hodgkins disease. Cancer 37: 1713-1717~ 1976.
Radiotherapy and Oncology, 22 (1991) 56-59 © 1991 Elsevier Science Publishers B.V. All rights reserved 0167-8140/91/$03.50
RADION 00876
The effect of scheduling in children undergoing prophylactic cranial irradiation for acute lymphoblastic leukaemia Shaun A. Costello, Richard D. Jones and A n n Barrett Department of Radiation Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow, U.K. (Received 13 November 1990, revision received 4 June 1991, accepted 17 June 1991)
Key words: Acute lymphatic leukaemia; CNS leukaemia; Cranial irradiation
Summary Control of central nervous system (CNS) disease and overall survival have been analysed in a group of 829 children with leukaemia entered into the UKALL VIII trial to determine whether scheduling of the cranial irradiation is of prognostic significance. We show that short gaps in treatment do not influence prognosis and that current radiotherapy practice need not be modified.
Introduction Acute lymphoblastic leukaemia (ALL) constitutes 75 ~o of childhood leukaemias, making it the most common malignancy of childhood, occurring in 3.5 per 100 000 live births in the U.K. [1 ]. With the advent of effective chemotherapy it became clear that apart from the marrow the central nervous system (CNS) was the major site of relapse [2]. This is because the brain is a so-called sanctuary site into which chemotherapy penetrates poorly. Treatment of the CNS shortly after diagnosis when the patient is in systemic remission can reduce the relapse rate from up to 56~o to 10-35~o [3,17]. Since the early report of Pinkel that craniospinai irradiation reduced the relapse rate, irradiation has played a part in most protocols [ 5 ], although the recognition of serious late effects, such as hormonal deficiencies [6] and intellectual impairment [7] has led to a search for alternative approaches to the problem. There are four methods of CNS treatment in clinical use;
(1) intrathecal methotrexate plus other intrathecal agents
(2) high dose systemic methotrexate (3) cranial irradiation plus intrathecal methotrexate (4) craniospinal irradiation. Craniospinal radiation has been abandoned in current trials (UKALL XI) because of unacceptable effects on the spinal epiphyses and bone marrow, cranial radiation has however been retained for high risk groups and those with meningeal involvement at presentation. Low and normal risk groups receive intrathecal chemotherapy with or without high dose methotrexate. Among the recognized prognostic factors in childhood ALL which include presenting WBC and age [ 9], control of CN S disease by radiation may be significant. Low doses (500-1200 cGy) are insufficient to prevent relapse [5,10]. High doses (2500-2900 cGy) [ 11 ] and large dose/fraction [ 12] may increase the complication rate. There is considerable interest in the influence of the scheduling of radiation on the control of other tumour types. Breaks in radiation therapy have been shown to be detrimental to tumour control in the treatment of other tumours such as laryngeal carcinoma [ 13 14]. We have analysed data from the UKALL VIII trial to see if gaps in cranial irradiation adversely affected the
Address for correspondence: Shaun A. Costello, Registrar in Radiation Oncology, Beatson Oncology Centre, Western Infirmary, Dumbarton Rd., Glasgow Gll 6NT, U.K.
57 rate of CNS relapse in this group of patients with acute lymphoblastic leukaemia.
TABLE 1 Group
Treatment time (days)
Elapsed time (days)
Total No.
Relapses No.
Relapse rate
A B C D E
12 14 16 > 16 Variable
11 13 15 > 15 Variable
255 223 128 42 106
16 6 5 6 8
7.11 2.69 3.91 14.29 7.50
Method
The U K A L L VIII trial was a multicentre trial comparing two different regimes of chemotherapy (vincristine, prednisolone, asparaginase + daunorubicin) to determine the role of daunorubicin in the remission induction of childhood ALL. The trial closed in December 1984 after 4 years, with a minimum follow-up time of 46 months and a maximum of 98 months. All children aged 0-14 presenting with ALL including those with CNS leukaemia (25 or 3~o ) were entered, a total of 829 children in all. CNS treatment was given to all children entered, although there was discretion to delay it up to age two years in the younger children because of fear of side effects such as intellectual impairment and pituitary dysfunction. Cranial radiotherapy was given during the fifth and sixth weeks of treatment starting any day except Friday. Each child received 1800 cGy in 10 fractions plus intrathecal methotrexate over 12-14 days by a standard technique except for those who had CNS involvement at presentation. These patients received 2400 cGy in 12 fractions over 14-16 days to craniospinal fields [15-17]. A perspex beam directing shell was produced for most patients to allow accurate reproduction of the treatment position and shielding on each day of treatment. Sensitive structures such as the anterior orbit and nasopharynx were shielded to prevent cataract formation and mucositis whilst including all the meninges. Two opposing lateral fields were used. For this analysis, patients were divided into five groups ( A - E ) depending on how irradiation was actually given (see Table I). All groups received 1800 cGy in l0 fractions except for Group E where dose, fractionation and scheduling varied from patient to patient. Many of this group were treated with orthovoltage and a modified prescription instead ofmegavoltage radiation although this was a deviation from the protocol. Others received non-protocol regimes because of local practice or because it was felt that the patient would not tolerate conventional fractionation. Many children (except those with overt CNS involvement) received their radiation over 14 days as a consequence of starting treatment mid week because of the practice of not working over weekends. Others received their radiation over 15-16 days because of servicing requirements of the treatment machine, tran sport difficulties or public holidays. A few of this group were too sick to have treatment
Groups A, B and C who all received a standard treatment differing only in the overall time of delivery of radiation were analysed by obtaining the chi-square coefficient. No significant difference was found between tham (p = 0.05). Group D was composed of patients whose treatment was very prolonged. The relapse rate was significantly higher in this group, p < 0.05. Group E has a relapse rate which is not significantly (p > 0.05) different from those of groups A B C . It is unsafe to draw any conclusion from this because of the heterogeneity of the group.
either because of disease or of chemotherapy, but unless their problems were of a transient nature most will have received their treatment in > 16 days. The groups were first analysed together by obtaining the Pearson chi-square coefficient and then the presenting white cell count (WBC) and age of each individual patient was analysed by group in order to exclude any between group variation of these major prognostic factors. Results
The overall results for the U K A L L VIII trial were initially reported as showing a reduced relapse rate in the arm containing daunorubicin [ 17] but more recent data show no significant difference. It is therefore possible to combine both arms for this analysis. Of the 829 patients entered into the study, 764 records were available for evaluation. 8 0 ~ of patients had their treatment completed within 16 days with an overall CNS relapse rate of 4.4~o. This compares well with other studies. Ten children had CNS involvement at presentation of which three suffered isolated CNS relapse. These have been excluded from further analysis. In order to exclude any uneven distribution of poor prognostic factors, the principal prognostic factors of each group, age under two and presenting peripheral WBC, was assessed using a Kruskal-Wallis test which showed no significant difference in distribution of age under two or presenting WBC between groups (p > 0.05). It was up to the discretion of each institution whether the patients presenting at under 2 years had their cranial
58 TABLE II Group
Total < 2
Relapses
Relapse rate
A B C D E
]9
15 10 6 7
2 0 0 2 3
9.5% 0% 0% 25% 30~o
prophylaxis delayed until they were 2 years old (Table II). This was a group with few relapses making subgroup analysis unreliable. The overall relapse rate for these patients in Groups A, B and C was 5.5~o and not dissimilar from that of the main group.
Discussion When a course of treatment is given for a tumour, there is sound radiobiological evidence that gaps in treatment are deleterious to the aim of tumour control [ 18]. These gaps can be intentional or unintentional. Intentional gaps come about as a result of the treatment regimen (although regimens featuring gaps are now less common) or due to local practice (e.g. not working at weekends). Unintentional gaps are brought about by poor patient treatment tolerance (e.g. severe mucosal reactions), machine breakdown or service time and transportation difficulties. Tumour growth is well known to follow a Gompertzian pattern in vitro, which has several important implications for the treatment of cancer. As the tumour shrinks the rate of division increases, because the tumour is no longer restricted by lack of nutrients and growth factors, recruitment from the cells in Go phase occurs and there may be an overall shortening of the cell cycle time. Thus some of the control obtained by irradiation may be lost if gaps are left in treatment [ 18 ]. There is some clinical evidence for this in solid tumours. A radical treatment for laryngeal 20 1B 16 14 ~2 /
10
/
/
/
P
/
8
/
6
/
Conclusions The purpose of this study was to determine whether or not gaps in the delivery of prophylactic cranial radiation to children with ALL had any effect on the meningeal relapse rate. This study has revealed no evidence that this is so, except where treatment is very prolonged and no change in current radiotherapy scheduling is required. Continuity of treatment is important and gaps should be avoided if at all possible.
/
4 o
2 C
carcinoma of 6000 cGy to the 95 % isodose line is often associated with a severe mucosal reaction which may in some cases prove to be the dose limiting factor. In an attempt to avoid this problem, regimens have been devised to incorporate a gap to allow the acutely reacting mucosal tissues to recover. Unfortunately although these regimens were accompanied with a much reduced early morbidity as a result of treatment, the rate of turnout recurrence was also higher as was the late morbidity [13 14]. These observations may not be relevant to childhood ALL where the turnout is not in solid phase and in the CNS exists either in suspension or as meningeal deposits of only a few microns. Thus it is neither starved of nutrients or of growth factors and tends to grow in an exponential fashion rather than a Gompertzian fashion until the patient is treated or dies. There is good in vivo evidence for this in animals from the classic work of Skipper in 1964 in which he showed that a single leukaemic cell transplanted into a susceptible host would multiply in an exponential fashion until the host succumbed [19]. It is probable therefore that in the case of childhood leukaemia, little significant increase in doubling time will occur with treatment. This suggestion is borne out by the results for Groups A, B and C suggesting little or no significant effect of scheduling on relapse rate. This is consonant with the results of treatment of Hodgkin's disease where gaps do not seem to affect relapse rate and may in fact improve patient tolerance [20]. The increased relapse rate seen in Group D reflects the type of patients within it. Group D contains a large proportion of patients who were infected or otherwise ill from their disease. Because of these poor prognostic features, it is not surprising that they did not do well.
i
12 DAYS
~
Acknowledgements
°
i
L
14 DAYS
Relapse
16DAYS
t
> 16 DAYS
r o t e */o
Fig. 1. Relapse rate according to schedule of fractionation.
We acknowledge the help of Professor Tim McElwain of the MRC steering committee, and should like to thank Sue Richards of the Oxford Clinical Trials Unit
59 and all members of the MRC leukaemia working party for permission to study data from UKALL VIII, and Diane Henderson of the Royal Hospital for Sick Chil-
dren Glasgow and Jim Paul of the Beatson Oncology Centre, Glasgow, for help in acquiring and processing the data.
References 1 Riehm, M., Feickert, H. J. and Lampert, F. Acute lymphoblastic leukaemia. In: Cancer in children UICC, pp. 101-118. Editors: P. A. Voute, A. Barrett andSpringer H. J. G. Bloom. Springer-Verlag, Berlin, 1986. 2 Pinkel, D. Patterns of failure in acute lymphocytic leukaemia. Cancer Treat. Symp. 2: 259-266, 1983. 3 Krepler, P., Kummer, M. and Pawlowsky, J. Prevention of meningeal leukaemia and relases by cranial irradiation and intrathecal MTX in A.L.L. Acta Neuropath. (Berlin) Suppl. VI: 241-245, 1975. 4 Reinartz, G., Kogelnik, H.D. and Krepler, P. Preventative cranial irradiation in the treatment of A.L.L. in children. Radiol. Clin. 47: 380-389, 1978. 5 Pinkel, D., Simone, J., Hustu, H. O. and Aur, R. J.A. Nine years experience with "total therapy" of childhood A.LL. Paediatrics 50: 246-251, 1972. 6 Mauras, N., Sabio, H. and Rogal, A.D. Neuroendocrine function in survivors of childhood A.L.L. and N.H.L. A study of pulsatile growth hormone and gonadotropin secretions. Am. J. Paediatr. Haematol./Oncol. 10: 9-17, 1988. 7 Fogarty, K., Volonino, V. and Caul, J. Learing disabilities following C.N.S. irradiation. Clin. Paediatr. 27: 524-528, 1988. 8 Freeman, A. I., Weinburg, V. and Brecher, M.L. Comparison of intermediate dose methotrexate with cranial irradiation for the post induction treatment of A.L.L. in children. N. Engl. J. Med. 308: 477-484, 1983. 9 Pluss, H.J. Prognostic factor analysis in A.L.L. of childhood. Helv. Paediat. Acta. 42: 197-247, 1987. 10 Hustu, O., Aur, R. and Verzosa, M. Prevention ofC.N.S, leukaemia by irradiation. Cancer 32: 585-597, 1973. 11 Chessels, J.M. Cranial irradiation in childhood lymphoblastic leukaemia time for reappraisal. Br. Med. J. 291: 680-687, 1985.
12 Duffner, P.K. and Cohen, M.E. The long term effects of cranial irradiation on the C.N.S. Cancer 56: 1841-1846, 1985. 13 Overgaard, J., Hjelm-Hansen, M. and Vendelbo, L. Comparison of conventional and split course radiotherapy as primary treatment in carcinoma of the larynx (Abstract). Estro 5th Annual Meeting, 1986, Baden-Baden, F.R.G. 14 Robertson, A.G., Robertson, C., Boyle, P. and Symonds, R.P. The effect of varying dose schedules on response of glottic carcinoma of larynx. BJC 61: 160-161, 1990. 15 Hardisty, R. M., Eden, O. B. and Lilleyman, J.S. Ukall viii trial protocol 1982 (revised) M.R.C. Working party on leukaemia in childhood. 16 Lilleyman, J. S. and Eden O.E. United Kingdom Medical Research Council Acute Lymphoblastic Leukaemia (UKALL) Trials i-viii: clinical features and results of treatment in four groups of children with adverse prognostic features. Med. Paediatr. Oncol. 14: 182-186, 1986. 17 Eden, O. B., Lilleyman, M. P. and Shaw, P.M. Medical Research Council Childhood Leukaemia Trial viii compared with Trials ii-vii: lessons for future management. In: Haemotology and Blood Transfusion 1987, 30 acute leukaemias. Editors: T. Buchner, G. ScheUong and W. Hiddemann. Springer-Verlag, Berlin and Heidelburg, 1987. 18 Thames. H.D. and Hendry, J.H. Proliferative response to radiation injury. In: Fractionation in radiotherapy, pp. 100-136. Taylor and Francis, London, 1987. 19 Skipper, H. E., Sehabel, F. M. and Wilcox, W.S. Experimental evaluation of potential anticancer agents xiii. On the criteria and kinetics associated with curability of experimental leukaemia. Cancer Chemother. Rep. 35:1-111, 1964. 20 Johnson, R. E., Ruhl, U. and Johnson, S.K. Split course radiotherapy of Hodgkins disease. Cancer 37: 1713-1717~ 1976.