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Outcomes of a Randomized Trial of Hyperfractionated Cranial Radiation Therapy for Treatment of High-Risk Acute Lymphoblastic Leukemia: Therapeutic Efficacy and Neurotoxicity

From the Division of Psychology, Department of Psychiatry, and Divisions of Hematology and Oncology, Department of Medicine, Children's Hospital; Departments of Psychiatry and Pediatrics, Harvard Medical School; Departments of Pediatric Oncology and Biostatistical Science, Dana-Farber Cancer Institute; Department of Biostatistics, Harvard School of Public Health; Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA; Department of Pediatrics, Golisano Children's Hospital at Strong, University of Rochester Medical Center, Rochester, NY; Interamerican University, San Juan, Puerto Rico; Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Ontario; and Departments of Pediatric Hematology/Oncology, Division of Hematology/Oncology, Hopital Sainte Justine, Montreal, Quebec, Canada

Address reprint requests to Deborah P. Waber, PhD, Department of Psychiatry, Children's Hospital, 300 Longwood Ave, Boston, MA 02115; e-mail: deborah.waber{at}childrens.harvard.edu

	ABSTRACT

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PURPOSE: We evaluated 8-year survival and late neuropsychologic toxicity in children with acute lymphoblastic leukemia treated in a randomized clinical trial to test whether hyperfractionated (twice daily) cranial radiation therapy (CRT) can reduce incidence and severity of late toxicities associated with 18 Gy of CRT.

PATIENTS AND METHODS: Between 1987 and 1995, 369 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for high-risk acute lymphoblastic leukemia were randomly assigned to conventionally fractionated CRT (CFX) or hyperfractionated CRT (HFX) to a total dose of 18 Gy. Neuropsychologic testing was completed for 125 of 287 children in continuous complete remission. Event-free and overall survival, as well as neuropsychologic function, were compared for the two arms of the protocol.

RESULTS: Eight-year event-free survival (± SE) was 80% ± 3% for children randomly assigned to CFX and 72% ± 3% for HFX (P = .06). Overall survival was 85% ± 3% for CFX and 78% ± 3% for HFX (P = .06). CNS relapses occurred in 2.8% of patients receiving CFX and 2.7% receiving HFX (P = .99). Cognitive function for both groups was solidly in the average range, with no group differences in intelligence, academic achievement, visuospatial reasoning, or verbal learning. Children on the HFX arm exhibited a modest advantage for visual memory (P < .05).

CONCLUSION: HFX provides no benefit in terms of cognitive late effects and may compromise antileukemic efficacy. HFX should not be substituted for conventionally dosed CRT in children who require radiation therapy for treatment of acute lymphoblastic leukemia.

	INTRODUCTION

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Although cranial radiation therapy (CRT) is highly effective in preventing CNS relapse among children with acute lymphoblastic leukemia, there have been continuing concerns about the potential for late effects, especially those affecting cognition and growth.^1,2 Some investigators have reported that children treated with prophylactic CRT with an 18-Gy dose demonstrate increased risk for diminished intelligence quotient (IQ) and other cognitive sequelae, but this is not a consistent finding.^3-9 Young age at treatment⁷ and female sex¹⁰ have also been cited as risk factors for cognitive sequelae of CNS prophylaxis, more consistently with higher doses of CRT.¹¹ Further, chemotherapeutic agents, specifically methotrexate¹² and possibly corticosteroids,¹³ have been implicated in cognitive late effects. Concerns about late effects of CRT in particular have led to considerable caution in its application.

In an effort to diminish the potential risk for late effects associated with CRT without compromising efficacy, Dana-Farber Cancer Institute (DFCI) Acute Lymphoblastic Leukemia Consortium protocols 87-01¹⁴ and 91-01¹⁵ implemented a randomized clinical trial to test whether hyperfractionated (twice daily) CRT (HFX) reduced the incidence and severity of late toxicities in children receiving 18 Gy of CRT. We hypothesized that proliferating leukemia cells would be more sensitive to a low-dose of radiation than the more slowly proliferating neuronal cells.^16,17 Thus HFX, in which lower doses of radiation are delivered twice daily to the same total dose, might result in less toxicity and equal efficacy in the prevention of CNS leukemia.

The two toxicity end points of the study were linear growth and neuropsychologic function. We have previously reported that there was no difference in linear growth in patients who received HFX compared with conventionally fractionated (once daily) CRT (CFX).¹⁸ We report here the survival rate (with 8.2 years median follow-up) and late neuropsychologic toxicity (measured at a median of 7.6 years postdiagnosis) of children with high-risk acute lymphoblastic leukemia who participated in this randomization.

	PATIENTS AND METHODS

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Treatment Protocols
Patients were treated on one of two previously reported protocols, DFCI Acute Lymphoblastic Leukemia Consortium Protocol 87-01¹⁴ or 91-01.¹⁵ Both included six-drug induction therapy with doxorubicin, asparaginase, methotrexate, vincristine, prednisone, and intrathecal cytarabine. Both protocols included post-remission consolidation with weekly high-dose asparaginase for all risk groups and doxorubicin for high-risk patients. Children were considered high-risk if they presented with any of the following characteristics: age less than 2 years or greater than 9 years, presenting leukocyte count greater than 20,000/µL, T-cell immunophenotype, an anterior mediastinal mass, or CNS leukemia. All other children were classified as standard risk.

High-risk patients on both protocols were eligible for the radiation randomization, to receive either CFX or HFX to a total dose of 18 Gy, always in combination with intrathecal methotrexate and cytarabine. CFX consisted of 18 Gy delivered in 10 1.8-Gy fractions, one fraction per day over 12 to 14 days. HFX consisted of 18 Gy delivered in 20 0.9-Gy fractions, with a minimum of 6 hours between the twice-daily treatments, over 12 to 14 days. Port and simulation films from all sites were centrally reviewed at the DFCI. Intrathecal therapy dose was based on patient age (< 1 year, methotrexate 6 mg, cytarabine 15 mg; 1 to 1.99 years, methotrexate 8 mg, cytarabine 20 mg; 2 to 3 years, methotrexate 10 mg, cytarabine 30 mg; > 3 years, methotrexate12 mg, cytarabine 40 mg) and was administered every 18 weeks after the completion of initial intensive CNS therapy, which consisted of four therapeutic lumbar punctures over a 2-week period concurrent with CRT. Patients diagnosed with acute lymphoblastic leukemia in infancy had cranial radiation delayed until they reached 12 months of age. High-risk patients with CNS leukemia at diagnosis received a higher dose of CRT (19.8 Gy) and were excluded from the randomization.

Patient Population
Between November 1987 and December 1995, 746 children diagnosed with acute lymphoblastic leukemia were eligible and treated on DFCI Acute Lymphoblastic Leukemia Consortium protocols 87-01 and 91-01, both of which were approved by the investigational review boards at the DFCI and collaborating sites. Of these, 467 children met criteria for high-risk disease, 369 of whom participated in the radiation randomization (CFX, n = 180; HFX, n = 189). Evaluation of treatment efficacy was based on the 369 high-risk patients who participated in the radiation randomization. Human investigations were performed after approval by local human investigation committees and in accordance with an assurance filed with and approved by the United States Department of Health and Human Services.

Eighty-two of the 369 randomly assigned high-risk patients were not eligible for neuropsychologic testing (58 patients died; 20 patients experienced relapse; three patients had strokes; one patient was not eligible for other cause). Of the remaining 287 children, 135 families consented to testing. One hundred fifty-two children were not tested for the following reasons: 77 did not respond or refused to participate; 11 were lost to follow-up; 19 lived too far away; 34 could not be contacted for logistical reasons; and 11 miscellaneous other reasons. Of the 135 who were tested, nine were excluded from the analysis because of problems that existed before the diagnosis of acute lymphoblastic leukemia that could have compromised neuropsychologic function: six patients had preexisting developmental delays, and three patients had medical or neurologic problems. One additional child was excluded because of chronic marijuana use. Thus evaluation of neuropsychologic outcomes is based on the 125 children who were evaluated and met eligibility criteria for neuropsychologic testing. Comparison of eligible patients who were tested with those who were not tested revealed no differences in sex, CRT randomization, methotrexate dose, or native language. Children who were not tested were older at diagnosis (P < .001) and were more likely to have been treated on protocol 87-01 than 91-01 (P < .01).

An intent-to-treat analysis was conducted. For efficacy analyses, 46 (12%) of 369 randomly assigned high-risk patients did not receive the intended therapy. Of the 125 patients who were evaluated for late neuropsychologic outcomes, 10 patients did not receive the intended therapy. Nine of these patients had been randomly assigned to the HFX arm. Thus 92% of children whose data were analyzed for neuropsychologic outcomes received the intended therapy, but those who did not were more likely to have been randomly assigned to the HFX arm of the study (P < .01).

Neuropsychologic Testing
Neuropsychologic testing was performed at a median of 7.6 years after diagnosis of acute lymphoblastic leukemia (range, 6.5 to 10.4 years). We used a relatively brief neuropsychologic test battery to enhance reliability and comparability of data across the various institutions and to encourage compliance. This approach also facilitated testing for a study group in which a substantial portion of the children did not speak English.

Table 1 lists the neuropsychologic battery. It included five representative subtests of the age-appropriate Wechsler IQ test: Vocabulary, Digit Span, Picture Arrangement, and Block Design. Two of these, the vocabulary and block design, permit estimation of full-scale IQ; the correlation of this dyad with full-scale IQ is 0.9.²⁴ For the children from Puerto Rico and Quebec, whose primary language was Spanish and French respectively, the most recent edition of the Wechsler Scale in that language was used.

New learning was assessed using the visual and verbal learning subtests from the Wide Range Assessment of Memory and Learning. Because the norms for this test only go up to 17 years, the 17-year norms were used for the few individuals who were older. For children who did not speak English, the verbal learning subtest was translated to French or Spanish.

To assess academic achievement, standardized measures of single-word reading, reading comprehension, calculation, and spelling were administered. Because of uncertainties about the comparability of measures across languages, however, results are reported here for English-speaking children only. On the basis of our prior work,²⁶ we speculated that tasks sensitive to general cognitive function and integration, specifically IQ and performance on the Rey-Osterrieth Complex Figure Test, might be more sensitive to sparing.

Statistical Methods
Overall survival (OS) was defined as the time from initiation of treatment to death from any cause; event-free survival (EFS) was defined as the time from diagnosis to the first outcome event (induction death, induction failure, remission death, or disease recurrence, whichever occurred first). Induction failure and induction death were considered events at time zero. OS and EFS were estimated using the Kaplan-Meier method,²⁷ and SEs for the 8-year estimates were calculated using Greenwood's formula.²⁸

Two-tailed t tests and Fisher's exact tests were used to compare children on the two arms of the protocol in terms of various characteristics that might affect their cognitive performance and to evaluate differences in neuropsychologic test scores between these groups. There was no correction for multiple comparisons. With the present sample size, the study had 80% power to detect an effect size of 0.51 using a two-sided t test assuming a 5% significance level.

	RESULTS

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Overall Survival and Event-Free Survival
Efficacy data are presented in Figs 1 and 2. The median follow-up for the 369 high-risk patients participating in this randomization was 8.2 years, based on a reverse censoring method.²⁹ The 8-year EFS (± SE) for patients randomly assigned to CFX was 80% ± 3% compared with 72% ± 3% for HFX-randomly assigned patients (P = .06). The 8-year OS for CFX-randomly assigned patients was 85% ± 3% compared with 78% ± 3% for HFX randomized patients (P = .06).

View larger version (19K): [in this window] [in a new window]   Fig 1. Event-free survival (EFS) for all patients randomly assigned to conventional versus hyperfractionated cranial radiation therapy. EFS rates (± SE) are at 8 years.

View larger version (19K): [in this window] [in a new window]   Fig 2. Overall survival (OS) for all patients randomly assigned to conventional versus hyperfractionated cranial radiation therapy. OS rates (± SE) are at 8 years.

Relapses involving the CNS occurred in five (2.8%) of the patients on the CFX arm and five (2.7%) of the patients on the HFX arm (P = .99), including isolated CNS relapses in three patients (1.7%) receiving CFX and one patient (0.5%) receiving HFX (P = .36). The remission death rate, moreover, was equivalent in the two groups, with five (2.8%) such deaths in each arm (P = .99). Thus the observed difference in EFS between the two treatment groups was due primarily to fewer bone marrow relapses on the CFX arm (16 [8.9%]) compared with the HFX arm (32 [17.0%]).

Neuropsychologic Function
Table 2 displays patient characteristics according to the CRT randomization. There were no significant differences between the groups for any of the variables, including age at diagnosis, age at evaluation, sex, protocol, methotrexate randomization, or parent education. There was, however, a marginal (P = .06) difference in native language; French-speaking children were more likely to be on the HFX arm of the protocol than the CFX arm. The median elapsed time from diagnosis to neuropsychologic evaluation for all the children in the sample was 7.6 years, with a range of 6.5 to 10.4 years.

	DISCUSSION

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This randomized trial was conducted to determine whether HFX might reduce late effects without compromising efficacy. We found virtually no evidence that HFX resulted in cognitive sparing in high-risk children with acute lymphoblastic leukemia. Although there was no significant difference in CNS relapse rates between HFX and CFX, there was a trend toward inferior EFS and OS in patients randomly assigned to the hyperfractionated arm as a result of higher rates of marrow relapse. At this time, we do not have an explanation for this unexpected finding.

This report is based on children with high-risk acute lymphoblastic leukemia only. In a previous report,¹⁵ we reported differences in EFS for children in the high-risk but not the standard-risk group. A recent update of outcomes for the standard-risk children still documented no significant difference (P = .90).

In terms of late neuropsychologic effects, there were no group differences for IQ, academic achievement, visuospatial function, or verbal learning when comparing HFX and CFX. Children on the hyperfractionation arm demonstrated better visual memory, but the effect size was relatively modest.

Review of the group means for the various tests indicates that despite the fact that these children were all treated with CRT, as a group they were functioning solidly within the average range expected for age based on published norms for the tests. This is consistent with our previously published report that children who received 18 Gy did not demonstrate significant neurocognitive deficits.³⁰ Similarly, we have also observed no significant difference in growth outcomes in irradiated and nonirradiated patients.¹⁸ Other investigators,^7,31 however, have reported late neurocognitive effects associated with 18 Gy, raising questions about these results. One potential source of the discrepancy is variation in the chemotherapy component of the protocol, because these agents seem to act synergistically with CRT to cause late neurotoxic effects.

In any event, given that radiation-related neurocognitive impairments were apparently minimal in our sample, there might have been little advantage to a dose strategy intended to spare function. At a higher dose, such as 24 Gy, where cognitive late effects are known to be more prominent, or in a setting where MTX doses were greater, the hyperfractionation strategy might have resulted in sparing of function. Alternatively, there may indeed have been some degree of impairment referable to CRT, but the hyperfractionation strategy might not have been effective in preventing it.

Although 92% of patients received the intended therapy, the majority of patients who did not were randomly assigned to the hyperfractionation arm of the protocol. However, results for neuropsychologic outcomes were not different when analyses were performed based on actual treatment received (data not shown). The fact that most of the children who were not treated as intended were on the hyperfractionation arm may reflect the practical difficulty for families of complying with a regimen of twice-daily radiation therapy.

In conclusion, our data bear relevance to current therapies by helping to delineate risks associated with CRT in different therapeutic contexts as well as contributing to the body of knowledge on effects of CRT. The findings suggest that HFX provides no benefit in terms of cognitive late effects, and may even compromise efficacy. The data also suggest that the impact of the 18-Gy dose on cognitive function is relatively modest. We conclude that HFX should not be substituted for CFX in children with acute lymphoblastic leukemia receiving 18 Gy of CRT.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by grant Nos. CA 68484 and CA06516 from the National Cancer Institute, the Michael J. Garil Fund for Leukemia Research, and in part by Mental Retardation Center grant P30-HD18655.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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1. Waber DP, Tarbell NJ: Toxicity of CNS prophylaxis for childhood leukemia. Oncology 11:259-264, 1997[Medline]

2. Ochs J, Mulhern RK: Late effects of antileukemic treatment. Pediatr Clin North Am 35:815-833, 1988[Medline]

3. Langer T, Martus P, Ottensmeier H, et al: CNS late-effects after ALL therapy in childhood: Part III. Neuropsychological performance in long-term survivors of childhood ALL: Impairments of concentration, attention, and memory. Med Pediatr Oncol 38:320-328, 2002[CrossRef][Medline]

4. Waber DP, Tarbell NJ, Fairclough D, et al: Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: Cranial radiation requires an accomplice. J Clin Oncol 13:2490-2496, 1995[Abstract]

5. Mulhern RK, Wasserman AL, Fairclough D, et al: Memory function in disease-free survivors of childhood acute lymphoblastic leukemia given CNS prophylaxis with or without 1,800 cGy cranial irradiation. J Clin Oncol 6:315-320, 1988[Abstract]

6. Ochs J Mulhern RK, Fairclough D, et al: Comparison of neuropsychologic functioning and clinical indicators of neurotoxicity in long-term survivors of childhood leukemia given cranial radiation or parenteral methotrexate: A prospective study. J Clin Oncol 9:145-151, 1991[Abstract/Free Full Text]

7. Jankovic M, Brouwers P, Valsecchi MG, et al: Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. Lancet 344:224-227, 1994[CrossRef][Medline]

8. MacLean WE Jr, Noll RB, Stehbens JA, et al: Neuropsychological effects of cranial irradiation in young children with acute lymphoblastic leukemia 9 months after diagnosis. Arch Neurol 52:156-160, 1995[Abstract/Free Full Text]

9. Raymond-Speden E, Tripp G, Lawrence B, et al: Intellectual, neuropsychological, and academic functioning in long-term survivors of leukemia. J Pediatr Psychol 25:59-68, 2000[Abstract/Free Full Text]

10. Iuvone L, Mariotti P, Colosimo C, et al: Long-term cognitive outcome, brain computed tomography scan, and magnetic resonance imaging in children cured for acute lymphoblastic leukemia. Cancer 95:2562-2570, 2002[CrossRef][Medline]

11. Waber DP, Urion DK, Tarbell NJ, et al: Late effects of central nervous system treatment of acute lymphoblastic leukemia in childhood are sex-dependent. Dev Med Child Neurol 32:238-248, 1990[Medline]

12. Moleski M: Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol 15:603-630, 2000[CrossRef][Medline]

13. Waber DP, Carpentieri SC, Klar N, et al: Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol 22:206-213, 2000[CrossRef][Medline]

14. LeClerc JM, Billett AL, Gelber RD, et al: Treatment of childhood acute lymphoblastic leukemia: Results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol 20:237-246, 2002[Abstract/Free Full Text]

15. Silverman LB, Gelber RD, Dalton VK, et al: Improved outcome for children with acute lymphoblastic leukemia: Results of Dana-Farber Consortium Protocol 91-01. Blood 97:1211-1218, 2001[Abstract/Free Full Text]

16. O'Donoghue JA, Wheldon TE, Gregor A: The implications of in-vitro radiation-survival curves for the optimal scheduling of total-body irradiation with bone marrow rescue in the treatment of leukaemia. Br J Radiol 60:279-283, 1987[Abstract/Free Full Text]

17. Withers HR, Peters LJ, Thames HD, et al: Hyperfractionation. Int J Radiat Oncol Biol Phys 8:1807-1809, 1982[Medline]

18. Dalton VK, Rue M, Silverman LB, et al: Height and weight in children treated for acute lymphoblastic leukemia: Relationship to central nervous system treatment. J Clin Oncol 21:2953-2960, 2003[Abstract/Free Full Text]

19. Wechsler D: Wechsler Intelligence Scale for Children (ed 3). New York, NY, Psychological Corporation, 1991

20. Wechsler D: Wechsler Adult Intelligence Scale: Revised. New York, NY, Psychological Corporation, 1981

21. Bernstein JH, Waber D: Developmental Scoring System for the Rey-Osterrieth Complex Figure. Odessa, FL, Psychological Assessment Resources, 1996

22. Sheslow D, Adams W: Wide Range Assessment of Memory and Learning. Wilmington, Delaware, Wide Range Inc, 1990

23. Woodcock RW, Johnson MB: Woodcock-Johnson Tests of Achievement—Revised. Itasca, IL, Riverside Publishing, 1989

24. Sattler J: Assessment of Children. San Diego, CA, Jerome Sattler, 1988

25. Waber DP, Bernstein JH: Performance of learning-disabled and non-learning-disabled children on the Rey-Osterrieth Complex Figure: Validation of the developmental scoring system. Dev Neuropsychol 11:237-252, 1994

26. Waber DP, Mullenix PJ: Acute lymphoblastic leukemia, in Yeates KO, Ris MD, Taylor HG (eds): Pediatric Neuropsychology: Research, Theory, and Practice. New York, NY, Guilford, 2000, pp 300-319

27. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:448-457, 1958[CrossRef]

28. Greenwood M: The natural duration of cancer: Reports on Public Health and Medical Subjects. London, United Kingdom, His Majesty's Stationery Office, 1926, pp 1-26

29. Shuster JJ: Median follow-up in clinical trials. J Clin Oncol 9:191-192, 1989

30. Waber DP, Shapiro BL, Carpentieri SC, et al: Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk acute lymphoblastic leukemia: A 7-year follow-up study of the Dana-Farber Cancer Institute Consortium Protocol 87-01. Cancer 92:15-22, 2001[CrossRef][Medline]

31. Anderson VA, Godber T, Smibert E, et al: Cognitive and academic outcome following cranial irradiation and chemotherapy in children: A longitudinal study. Br J Cancer 82:255-262, 2000[CrossRef][Medline]

Submitted October 24, 2003; accepted April 12, 2004.

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