Original Article
Acute lymphoblastic leukemia: Are Egyptian children adherent to maintenance therapy? ABSTRACT Background, Aims, Settings and Design: Poor adherence to oral maintenance chemotherapy can cause relapse of acute lymphoblastic leukemia (ALL). A multicenter study for the evaluation of adherence to oral 6‑mercaptopurine (6‑MP) maintenance chemotherapy for childhood ALL in Egypt to identify contributing factors and possible steps to promote adherence. Materials and Methods: The study included 129 children with ALL in complete remission receiving 6‑MP single daily oral dose in the evening. Evaluation was done through specific questionnaires for the patients as well as serum 6‑MP measurements. Results: Nonadherence was detected in around 56% by questionnaires and around 50% by serum 6‑MP level measurement. There was a highly significant correlation between nonadherence as found by the questionnaire and 6‑MP level (P ‑ 0.001). Nonadherence was significantly associated with low socioeconomic standard, noneducation and low educational level and large family size by both methods. High cost to come for follow‑up visits was significant by questionnaire but not by 6‑MP measurement. Adolescent age, the higher number of siblings, lack of written instructions, long time spent per visit, were all associated with higher rates of nonadherence, although none reached statistical significance. Conclusions: Nonadherence is a real problem in pediatric patients. Specific questionnaires can be an excellent reliable method for the routine follow‑up of these children, and drug level assay can be requested only for confirmation. This protocol is especially effective in developing countries where financial resources may be limited. Every effort should be made to uncover its true incidence, contributing factors, and best methods of intervention. KEY WORDS: 6‑mercaptopurine, acute lymphoblastic leukemia, adherence, questionnaire
INTRODUCTION Acute lymphoblastic leukemia (ALL) is the most common malignancy encountered at the pediatric age group, one in four cancerous children is affected with AL in the United States.[1] Although survival rates for childhood ALL have improved significantly over the past 50 years, so that the current 5‑year survival rate in developed countries exceeds 85%,[2] a substantial number of children and adolescents continue to relapse, greatly increasing the risk of mortality. Results of ALL treatment in developing countries have been inferior to those obtained in developed countries, even if the same protocols were used. Treatment nonadherence can be an important cause contributing to this substantial aggravation of the disease,[3] higher death rates and increased health care costs.[4] Our aim was, therefore, to evaluate the adherence and adherence to oral maintenance anti‑metabolite chemotherapy in leukemic children in Egypt, and 54
to identify underlying contributing factors and the possible steps to promote adherence. MATERIALS AND METHODS The current study was conducted on 129 children and adolescents on maintenance therapy for ALL attending the Pediatric Oncology Unit, Children Hospital during the period from January 2012 to March 2013. This study was approved by the Research and Ethical Committees of the previously mentioned hospitals. All recruited children received 6‑mercaptopurine (6‑MP) orally for at least 10 days (oral daily 6MP and oral weekly administration of methotrexate) according to the modified Children’s Cancer Group 1991 protocol.
Elhamy Rifky Abdel Khalek, Laila M. Sherif, Naglaa Mohamed Kamal1, Amal F. Gharib2, H. M. Shawky3 Departments of Pediatric Hematology and Oncology and 2 Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, 1Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, 3 Department of Pediatric Oncology, Banha Children Specialized Hospital, Banha, Egypt For correspondence: Dr. Naglaa Mohamed Kamal, Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt. E‑mail: nagla.kamal@ kasralainy.edu.eg
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.147698 PMID: ***
As required by this protocol of therapy, we did regular follow‑up visits on a weekly basis where laboratory follow‑up was done, and weekly medications were provided free of charge. The protocol was discussed with the patients and/or their parents and informed consent was obtained.
Quick Response Code:
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
Khalek, et al.: Adherence to maintenaence therapy of leukemia
At the same visit, adherence was assessed by a specific questionnaire for the patients or their caregivers and the serum 6‑MP level was measured by thin layer chromatography which is considered to be a simple, quick, and inexpensive procedure (Stoddard et al., 2007). The used questionnaire included the following Age at diagnosis and remission; family data: Total number, number of siblings, socioeconomic status, residence, cost to come to the hospital and time spent at each visit; feeding habits, leisure activities, and cultural activities; details about caregiver: Her/his education level, her/his knowledge about the illness and what will happen if the patient did not receive his maintenance therapy and if they received written instructions about maintenance therapy; maintenance medications given: Time, regularity, time, and number of occasions on which the patient did not receive the dose and what procedure has been adopted on such occasions. Statistical analysis Comparisons between groups were made with the use of Wilcoxon rank‑sum test, Kruskal–Wallis test, and Mann–Whitney for continuous variables. The significance of the correlation between two independent parameters was determined by the Spearman test. All statistical tests of significance were two‑tailed with a type I error. Analyses were performed using SAS statistical software (SAS Institute, Cary, NC, USA).
and among these negative results were obtained in 19%, very low levels (3 Caregiver Mother Father Other Educational level Not educated Low Moderate High Socioeconomic level Low Moderate High
Number
Percentage
4.9±3.12 1.5-15.3 5.9 5.03±3.24 1.6-16.1 6.0 71 58
~55 ~45
88 41
~73 ~27
114 11 4
~88 ~9 ~3
51 43 16 19
~40 ~33 ~12 ~15
41 88 0
~32 ~68 ~0.0
RESULTS
~Number is rounded up to full number. SD=Standard deviation
One hundred and twenty‑nine children on maintenance anti‑neoplastic therapy for ALL were included in the current study. The description of the patient population studied is shown in Table 1.
Table 2: Adherence and adherence to the drug by questionnaire with analysis of data
Nonadherence to medications was detected in 55.81% by questionnaires; ≥2 doses omitted. In 87.5%, this was within the last month. Mothers were the caregivers in 88% of patients. Around 94% of parents were well‑informed about the illness of their children and the consequence of stopping 6‑MP despite the fact that 50% did not receive written instructions for treatment. For 71% of the families a visit at their hospital caused moderate to the high cost to come to the hospital high, and 72% spent a moderate to long time at each visit [Table 2]. Forgetfulness was the main cause of nonadherence (47%) followed by refusal to take the drug, negligence, drug unavailability, and medical staff error [Table 3]. All patients were analyzed for serum 6‑MP as another way of evaluation of adherence. The median serum 6‑MP level in our series was found to be 9.3 ng. According to Lennard et al., the detected serum 6‑MP levels can be divided into four quartiles as shown in Table 4. About 50% of patients were in the 1st and 2nd quartiles with serum levels 1‑month
Number
Percentage
114 11 4
~88 ~9 ~3
65 64
~50 ~50
37 28 64
~29 ~21 ~50
36 32 61
~28 ~25 ~47
8 121
~6 ~94
54 81
~37 ~63
57 72
~44 ~56
63 9
~88 12
~Number is rounded up to full number. 6‑MP=6‑mercaptopurine
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Khalek, et al.: Adherence to maintenaence therapy of leukemia
Table 3: Causes of nonadherence in our patients according to the questionnaire Cause Forgotten Refusal of child to take 6‑MP Negligence Drug unavailability Medical stuff error
Number 34 18 8 9 3
Percentage ~47 ~25 ~11 ~13 ~4
~Number is rounded up to full number. 6‑MP=6‑mercaptopurine
Table 4: The detected serum 6‑MP levels can be divided into 4 quartiles Serum level The first quartile (≤4.5) The second quartile (4.51-9.3) The third quartile (9.31-13.9) The fourth quartile (13.91-22)
Number 41 24 28 36
Percentage ~31# ~19# ~22 ~28
Around 50% were noncompliant by 6‑MP level measurement, ~Number is rounded up to full number. 6‑MP=6‑mercaptopurine #
There was a highly significant correlation between nonadherence as found by the questionnaire and 6‑MP level (P ‑ 0.001). Nonadherence was highly significantly associated with low socioeconomic standard, noneducation and low educational level by both, the questionnaire and the 6‑MP level (P ‑ 0.001). Large families with five or more members showed a significant association with nonadherence by both the questionnaire and 6‑MP level with a P ‑ 0.02 and 0.04, respectively. Significant association with nonadherence was observed with those who needed more money to come for follow‑up visits by the questionnaire but not serum 6‑MP level with P ‑ 0.03 and 0.09, respectively.
Based on experience with other diseases, we know that children often fail to follow important diets or treatment schedules. It is, therefore, illogical to assume that just because they have a life‑threatening disease, young patients with leukemia will all reliably take pills every day without failure for 2 years when they (mostly) are in normal health.[19] Previous reports on children and adolescents with ALL, estimated nonadherence in 2-52% of cases.[16,18,20‑29] We assumed that doses of anti‑metabolites, frequency of their use, socioeconomic status, education, family size, and others can all be contributing factors for failure of maintenance treatment, reason why we conducted the current study to assess nonadherence in our cohort to the prescribed oral anti‑neoplastic maintenance therapy and to evaluate possible contributing factors. Adherence is a complex subject that plays an important part in clinical practice. It can be assessed through indirect methods (patient or parental reports, physician opinion, pill count, etc.) or direct methods (drug levels in biological samples). [30] In our cohort, we used both the indirect questionnaire method along with the direct measurement of serum 6‑MP levels. In our cohort, around 56% admitted that they have omitted more than 2 doses of 6‑MP and around 88% of the noncompliants stated that it was within the last 1 month. This could still be underestimated, given that self‑reports of nonadherence with medical prescriptions are generally more reliable than self‑reports of adherence. In addition, if either family or patient admits in an interview that the failure occurred, it is possible that the event might have been more frequent.[30]
DISCUSSION
The best data on nonadherence come from studies where drug or drug metabolite concentrations have been measured. In the current study, we used the questionnaire method, as a simple, cost‑effective, and easy to apply screening method while measuring serum 6‑MP level as a confirmatory objective method. Serum 6‑MP was measured in the morning after a supposed evening dose. This method detected nonadherence in around 50% of patients.
Treatment for childhood ALL requires a prolonged maintenance phase that relies on self‑ or parent‑administered daily oral anti‑metabolite chemotherapy given over a period of about 2 years.[5,6] Systemic exposure to 6‑MP, during the maintenance phase of therapy, is a critical component of curative regimens for ALL.[7‑9]
A study similar to ours was carried in South Africa measuring the urinary excretion of 6‑MP and showed that some patients had no trace of the drug.[11,27,28] They found wide variations in the levels of 6‑MP metabolites in their children studied. These studies and ours reveal that a substantial number of children with ALL fail, totally or intermittently, to take their oral 6‑MP.
When patients relapse, the maintenance component of treatment has probably failed for some reasons.[5] Potential determinants of adequate systemic 6‑MP exposure include pharmacogenetics,[8,10,11] bioavailability,[12‑15] and adherence to daily oral administration.[16‑18]
When adherence is assessed, and the patient is aware of monitoring, it seems that the outcome may be different as there will be a significant increase in their regularity of tablet taking. In our study, we eliminated this factor as the patients were informed about the protocol of the study and the consent
Adolescent age, those with more number of siblings, those who consumed more time in each visit and those who did not receive written instructions were all associated with higher rates of nonadherence, but none of them reached a statistically significant value [Table 5].
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Khalek, et al.: Adherence to maintenaence therapy of leukemia
Table 5: Relation between adherence and different studied parameters Data (number of patients)
According to the questionnaire Compliant n=57
Socioeconomic standard Low (41) Moderate (88) Educational level Not educated (51) Low (43) Moderate (16) High (19) Family number ≤5 (88) >5 (41) Number of sibling ≤3 (88) >3 (41) Cost to come to follow‑up visits Low (37) Moderate (28) High (64) Time spent in each visit Short (36) Moderate (32) Long (61) Received written instruct No (65) Yes (64)
Non n=72
χ2
n
%
n
%
7 50
17.1 56.8
34 38
82.9 43.2
17.91
15 11 13 18
29.4 25.6 81.3 94.7
36 32 3 1
70.6 74.4 18.7 5.3
45 12
51.1 29.3
43 29
44 13
50.0 31.7
23 11 23
According to the serum 6‑MP level P
Compliant n=64
Non n=65
χ2
P
n
%
n
%
0.001
6 58
14.6 65.9
35 30
85.4 34.1
29.42
0.001
39.15
0.001
22 12 12 18
43.1 27.9 75.0 94.7
29 31 4 1
56.9 72.1 25.0 5.3
28.56
0.001
48.9 70.7
5.42
0.02
49 15
55.7 36.6
39 26
44.3 63.4
4.08
0.04
44 28
50.0 68.3
3.79
0.051
47 17
53.4 41.5
41 24
46.6 58.5
1.60
0.21
62.2 39.3 35.9
14 17 41
37.8 60.7 64.1
6.89
0.03
24 12 28
64.9 42.9 43.8
13 16 36
35.1 57.1 56.2
4.83
0.09
20 15 22
55.6 46.9 36.1
16 17 39
44.4 53.1 63.9
3.61
0.16
24 14 26
66.7 43.8 42.6
12 18 35
33.3 56.2 57.4
5.82
0.054
27 30
41.5 46.9
38 34
58.5 53.1
0.37
0.54
30 34
46.2 53.1
35 30
53.8 46.9
0.63
0.43
6‑MP=6‑mercaptopurine
was signed along with the questionnaires asked and blood samples taken all in the same visit. We disclosed significant association between nonadherence and the low socioeconomic status, noneducation, low educational level, and large sized families of 5 or more which were in agreement with Richardson et al.[31] and Viana et al.,[32] respectively. Families with low cultural and socioeconomic conditions presumably have greater difficulty in understanding the disease and properly following medical instructions and prescriptions.[17] de Oliveira et al.[17] found a tendency for the monthly per capita income of the noncompliant group to be inferior to that of the compliant group, which was compatible with other authors’ findings.[16,22,23,29] Bonilla stated that therapeutic failures are significantly higher in places where poverty, malnutrition, barriers in communication between doctors and patients and low schooling levels prevail.[33] In our series, those with a higher number of siblings, those who spent more time in each visit and those who did not receive written instructions were all associated with higher rates of nonadherence, but none of them reached a statistically significant value, while those who needed high cost to come for follow‑up visits showed significant association with nonadherence by questionnaire but not by 6‑MP level measurement. In some countries, 25-45% of families fail to attend clinic at all during the maintenance phase of
treatment[34] and in other communities and ethnic groups, it is sometimes difficult to raise family awareness of the necessity of following the treatment in the maintenance phase, a time when children are apparently cured.[23,35] Lancaster et al. pointed‑out other contributing factors for nonadherence in his cohort of 496 children on maintenance 6‑MP for ALL, which were the adolescent age and the duration of treatment.[29] Nine patients of his series (2%) had undetectable levels of 6‑MP metabolites. Five of them were adolescents and had been receiving treatment for more than 1 year. We agree with him in this respect as most of the 21% of our patients having undetectable serum 6‑MP levels were near adolescence but this didn’t reach statistical significance. This was in agreement with other studies which showed higher nonadherence rates in adolescents.[20,21,24] The biopsychosocial model of adherence suggests that adherence in adolescents may be affected by an individual’s subjective assessment of his or her illness and its treatment. Finally, we conclude that the nonadherence to oral maintenance anti‑metabolite chemotherapy is a real problem in pediatric cancer patient. Careful medical history including specific questionnaires can be a very reliable method for the routine follow‑up of these children, and drug level assay can be requested only for confirmation. This protocol is especially effective in developing countries where financial resources may be limited.
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Khalek, et al.: Adherence to maintenaence therapy of leukemia
Every effort should be made to eliminate possible contributing factors by: (1) Implementing proper education plans (oral and written) for the patients and their families about the disease, its treatment, and necessity for adherence to maintenance therapy to avoid relapse which is more difficult to treat than the primary disease; (2) decreasing the number of follow‑up visits and the time spent in each visit; and by (3) establishing a good relationship between the parents and the health care team. Further studies in this critical area are highly needed to uncover its true incidence, contributing factors, and best methods of interventions. REFERENCES 1. Horner MJ, Ries LA, Krapcho M, Neyman N, Aminou R, Howlader N, et al., editors. SEER Cancer Statistics Review, 1976-2006, Based on November 2008 SEER Data Submission. Bethesda, MD: National Cancer Institute; 2009. 2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277‑300. 3. Davies HA, Lilleyman JS. Compliance with oral chemotherapy in childhood lymphoblastic leukaemia. Cancer Treat Rev 1995;21:93‑103. 4. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487‑97. 5. Gale RP, Butturini A. Maintenance chemotherapy and cure of childhood acute lymphoblastic leukaemia. Lancet 1991;338:1315‑8. 6. Stanulla M, Schrappe M. Treatment of childhood acute lymphoblastic leukemia. Semin Hematol 2009;46:52‑63. 7. Koren G, Ferrazini G, Sulh H, Langevin AM, Kapelushnik J, Klein J, et al. Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children. N Engl J Med 1990;323:17‑21. 8. Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE. Prognostic importance of 6‑mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 1999;93:2817‑23. 9. Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med 1998;339:605‑15. 10. Aplenc R, Lange B. Pharmacogenetic determinants of outcome in acute lymphoblastic leukaemia. Br J Haematol 2004;125:421‑34. 11. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6‑mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 1990;336:225‑9. 12. de Lemos ML, Hamata L, Jennings S, Leduc T. Interaction between mercaptopurine and milk. J Oncol Pharm Pract 2007;13:237‑40. 13. Rivard GE, Lin KT, Leclerc JM, David M. Milk could decrease the bioavailability of 6‑mercaptopurine. Am J Pediatr Hematol Oncol 1989;11:402‑6. 14. Schmidt LE, Dalhoff K. Food‑drug interactions. Drugs 2002;62:1481‑502. 15. Sofianou‑Katsoulis A, Khakoo G, Kaczmarski R. Reduction in bioavailability of 6‑mercaptopurine on simultaneous administration with cow’s milk. Pediatr Hematol Oncol 2006;23:485‑7. 16. Lennard L, Welch J, lilleyman JS. Intracellular metabolites of mercaptopurine in children with all: A possible factor of non adherence? Br J Cancer 1995;75:1004‑6. 17. de Oliveira BM, Viana MB, Zani CL, Romanha AJ. Clinical and
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laboratory evaluation of compliance in acute lymphoblastic leukaemia. Arch Dis Child 2004;89:785‑8. 18. Lau RC, Matsui D, Greenberg M, Koren G. Electronic measurement of compliance with mercaptopurine in pediatric patients with acute lymphoblastic leukemia. Med Pediatr Oncol 1998;30:85‑90. 19. Tebbi CK. Treatment compliance in childhood and adolescence. Cancer 1993;71 10 Suppl: 3441‑9. 20. Smith SD, Rosen D, Trueworthy RC, Lowman JT. A reliable method for evaluating drug compliance in children with cancer. Cancer 1979;43:169‑73. 21. Lansky SB, Smith SD, Cairns NU, Cairns GF Jr. Psychological correlates of compliance. Am J Pediatr Hematol Oncol 1983;5:87‑92. 22. Tebbi CK, Cummings KM, Zevon MA, Smith L, Richards M, Mallon J. Compliance of pediatric and adolescent cancer patients. Cancer 1986;58:1179‑84. 23. MacDougall LG, Wilson TD, Cohn R, Shuenyane EN, McElligott SE. Compliance with chemotherapy in childhood leukaemia in Africa. S Afr Med J 1989;75:481‑4. 24. Festa RS, Tamaroff MH, Chasalow F, Lanzkowsky P. Therapeutic adherence to oral medication regimens by adolescents with cancer. I. Laboratory assessment. J Pediatr 1992;120:807‑11. 25. Snodgrass W, Smith S, Trueworthy R, Vats P, Klopovich P, Kisker S. Pediatric clinical pharmacology of 6-mercaptopurine: lack of compliance as a factor in leukemia relapse. Proc Am Soc Clin Oncol. 1984;3:204. 26. Azeemuddin S, Israili ZH, Bharmal FM. Rapid method for evaluating compliance of 6‑mercaptopurine therapy in children with leukemia. J Chromatogr 1988;430:163‑9. 27. Macdougall LG, McElligott SE, Ross E, Greeff MC, Poole JE. Pattern of 6‑mercaptopurine urinary excretion in children with acute lymphoblastic leukemia: Urinary assays as a measure of drug compliance. Ther Drug Monit 1992;14:371‑5. 28. Davies HA, Lennard L, Lilleyman JS. Variable mercaptopurine metabolism in children with leukaemia: A problem of non‑compliance? BMJ 1993;306:1239‑40. 29. Lancaster D, Lennard L, Lilleyman JS. Profile of non‑compliance in lymphoblastic leukaemia. Arch Dis Child 1997;76:365‑6. 30. Wright EC. Non‑compliance – or how many aunts has Matilda? Lancet 1993;342:909‑13. 31. Richardson JL, Marks G, Levine A. The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. J Clin Oncol 1988;6:1746‑52. 32. Viana MB, Fernandes RA, de Oliveira BM, Murao M, de Andrade Paes C, Duarte AA. Nutritional and socio‑economic status in the prognosis of childhood acute lymphoblastic leukemia. Haematologica 2001;86:113‑20. 33. Bonilla M, Moreno N, Marina N, deReyes G, Shurtleff SA, Downing JR, et al. Acute lymphoblastic leukemia in a developing country: Preliminary results of a nonrandomized clinical trial in El Salvador. J Pediatr Hematol Oncol 2000;22:495‑501. 34. Hicsönmez G, Ozsoylu S, Yetgin S, Zamani V, Gurgey A. Poor prognosis of childhood acute lymphoblastic leukaemia. Br Med J (Clin Res Ed) 1983;286:1437. 35. Lilleyman JS, Lennard L. Non‑compliance with oral chemotherapy in childhood leukaemia. BMJ 1996;313:1219‑20. Cite this article as: Khalek ER, Sherif LM, Kamal NM, Gharib AF, Shawky HM. Acute lymphoblastic leukemia: Are Egyptian children adherent to maintenance therapy?. J Can Res Ther 2015;11:54-8. Source of Support: Nil, Conflict of Interest: None declared.
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
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Acute lymphoblastic leukemia: Are Egyptian children adherent to maintenance therapy? ABSTRACT Background, Aims, Settings and Design: Poor adherence to oral maintenance chemotherapy can cause relapse of acute lymphoblastic leukemia (ALL). A multicenter study for the evaluation of adherence to oral 6‑mercaptopurine (6‑MP) maintenance chemotherapy for childhood ALL in Egypt to identify contributing factors and possible steps to promote adherence. Materials and Methods: The study included 129 children with ALL in complete remission receiving 6‑MP single daily oral dose in the evening. Evaluation was done through specific questionnaires for the patients as well as serum 6‑MP measurements. Results: Nonadherence was detected in around 56% by questionnaires and around 50% by serum 6‑MP level measurement. There was a highly significant correlation between nonadherence as found by the questionnaire and 6‑MP level (P ‑ 0.001). Nonadherence was significantly associated with low socioeconomic standard, noneducation and low educational level and large family size by both methods. High cost to come for follow‑up visits was significant by questionnaire but not by 6‑MP measurement. Adolescent age, the higher number of siblings, lack of written instructions, long time spent per visit, were all associated with higher rates of nonadherence, although none reached statistical significance. Conclusions: Nonadherence is a real problem in pediatric patients. Specific questionnaires can be an excellent reliable method for the routine follow‑up of these children, and drug level assay can be requested only for confirmation. This protocol is especially effective in developing countries where financial resources may be limited. Every effort should be made to uncover its true incidence, contributing factors, and best methods of intervention. KEY WORDS: 6‑mercaptopurine, acute lymphoblastic leukemia, adherence, questionnaire
INTRODUCTION Acute lymphoblastic leukemia (ALL) is the most common malignancy encountered at the pediatric age group, one in four cancerous children is affected with AL in the United States.[1] Although survival rates for childhood ALL have improved significantly over the past 50 years, so that the current 5‑year survival rate in developed countries exceeds 85%,[2] a substantial number of children and adolescents continue to relapse, greatly increasing the risk of mortality. Results of ALL treatment in developing countries have been inferior to those obtained in developed countries, even if the same protocols were used. Treatment nonadherence can be an important cause contributing to this substantial aggravation of the disease,[3] higher death rates and increased health care costs.[4] Our aim was, therefore, to evaluate the adherence and adherence to oral maintenance anti‑metabolite chemotherapy in leukemic children in Egypt, and 54
to identify underlying contributing factors and the possible steps to promote adherence. MATERIALS AND METHODS The current study was conducted on 129 children and adolescents on maintenance therapy for ALL attending the Pediatric Oncology Unit, Children Hospital during the period from January 2012 to March 2013. This study was approved by the Research and Ethical Committees of the previously mentioned hospitals. All recruited children received 6‑mercaptopurine (6‑MP) orally for at least 10 days (oral daily 6MP and oral weekly administration of methotrexate) according to the modified Children’s Cancer Group 1991 protocol.
Elhamy Rifky Abdel Khalek, Laila M. Sherif, Naglaa Mohamed Kamal1, Amal F. Gharib2, H. M. Shawky3 Departments of Pediatric Hematology and Oncology and 2 Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, 1Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, 3 Department of Pediatric Oncology, Banha Children Specialized Hospital, Banha, Egypt For correspondence: Dr. Naglaa Mohamed Kamal, Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt. E‑mail: nagla.kamal@ kasralainy.edu.eg
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.147698 PMID: ***
As required by this protocol of therapy, we did regular follow‑up visits on a weekly basis where laboratory follow‑up was done, and weekly medications were provided free of charge. The protocol was discussed with the patients and/or their parents and informed consent was obtained.
Quick Response Code:
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
Khalek, et al.: Adherence to maintenaence therapy of leukemia
At the same visit, adherence was assessed by a specific questionnaire for the patients or their caregivers and the serum 6‑MP level was measured by thin layer chromatography which is considered to be a simple, quick, and inexpensive procedure (Stoddard et al., 2007). The used questionnaire included the following Age at diagnosis and remission; family data: Total number, number of siblings, socioeconomic status, residence, cost to come to the hospital and time spent at each visit; feeding habits, leisure activities, and cultural activities; details about caregiver: Her/his education level, her/his knowledge about the illness and what will happen if the patient did not receive his maintenance therapy and if they received written instructions about maintenance therapy; maintenance medications given: Time, regularity, time, and number of occasions on which the patient did not receive the dose and what procedure has been adopted on such occasions. Statistical analysis Comparisons between groups were made with the use of Wilcoxon rank‑sum test, Kruskal–Wallis test, and Mann–Whitney for continuous variables. The significance of the correlation between two independent parameters was determined by the Spearman test. All statistical tests of significance were two‑tailed with a type I error. Analyses were performed using SAS statistical software (SAS Institute, Cary, NC, USA).
and among these negative results were obtained in 19%, very low levels (3 Caregiver Mother Father Other Educational level Not educated Low Moderate High Socioeconomic level Low Moderate High
Number
Percentage
4.9±3.12 1.5-15.3 5.9 5.03±3.24 1.6-16.1 6.0 71 58
~55 ~45
88 41
~73 ~27
114 11 4
~88 ~9 ~3
51 43 16 19
~40 ~33 ~12 ~15
41 88 0
~32 ~68 ~0.0
RESULTS
~Number is rounded up to full number. SD=Standard deviation
One hundred and twenty‑nine children on maintenance anti‑neoplastic therapy for ALL were included in the current study. The description of the patient population studied is shown in Table 1.
Table 2: Adherence and adherence to the drug by questionnaire with analysis of data
Nonadherence to medications was detected in 55.81% by questionnaires; ≥2 doses omitted. In 87.5%, this was within the last month. Mothers were the caregivers in 88% of patients. Around 94% of parents were well‑informed about the illness of their children and the consequence of stopping 6‑MP despite the fact that 50% did not receive written instructions for treatment. For 71% of the families a visit at their hospital caused moderate to the high cost to come to the hospital high, and 72% spent a moderate to long time at each visit [Table 2]. Forgetfulness was the main cause of nonadherence (47%) followed by refusal to take the drug, negligence, drug unavailability, and medical staff error [Table 3]. All patients were analyzed for serum 6‑MP as another way of evaluation of adherence. The median serum 6‑MP level in our series was found to be 9.3 ng. According to Lennard et al., the detected serum 6‑MP levels can be divided into four quartiles as shown in Table 4. About 50% of patients were in the 1st and 2nd quartiles with serum levels 1‑month
Number
Percentage
114 11 4
~88 ~9 ~3
65 64
~50 ~50
37 28 64
~29 ~21 ~50
36 32 61
~28 ~25 ~47
8 121
~6 ~94
54 81
~37 ~63
57 72
~44 ~56
63 9
~88 12
~Number is rounded up to full number. 6‑MP=6‑mercaptopurine
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Khalek, et al.: Adherence to maintenaence therapy of leukemia
Table 3: Causes of nonadherence in our patients according to the questionnaire Cause Forgotten Refusal of child to take 6‑MP Negligence Drug unavailability Medical stuff error
Number 34 18 8 9 3
Percentage ~47 ~25 ~11 ~13 ~4
~Number is rounded up to full number. 6‑MP=6‑mercaptopurine
Table 4: The detected serum 6‑MP levels can be divided into 4 quartiles Serum level The first quartile (≤4.5) The second quartile (4.51-9.3) The third quartile (9.31-13.9) The fourth quartile (13.91-22)
Number 41 24 28 36
Percentage ~31# ~19# ~22 ~28
Around 50% were noncompliant by 6‑MP level measurement, ~Number is rounded up to full number. 6‑MP=6‑mercaptopurine #
There was a highly significant correlation between nonadherence as found by the questionnaire and 6‑MP level (P ‑ 0.001). Nonadherence was highly significantly associated with low socioeconomic standard, noneducation and low educational level by both, the questionnaire and the 6‑MP level (P ‑ 0.001). Large families with five or more members showed a significant association with nonadherence by both the questionnaire and 6‑MP level with a P ‑ 0.02 and 0.04, respectively. Significant association with nonadherence was observed with those who needed more money to come for follow‑up visits by the questionnaire but not serum 6‑MP level with P ‑ 0.03 and 0.09, respectively.
Based on experience with other diseases, we know that children often fail to follow important diets or treatment schedules. It is, therefore, illogical to assume that just because they have a life‑threatening disease, young patients with leukemia will all reliably take pills every day without failure for 2 years when they (mostly) are in normal health.[19] Previous reports on children and adolescents with ALL, estimated nonadherence in 2-52% of cases.[16,18,20‑29] We assumed that doses of anti‑metabolites, frequency of their use, socioeconomic status, education, family size, and others can all be contributing factors for failure of maintenance treatment, reason why we conducted the current study to assess nonadherence in our cohort to the prescribed oral anti‑neoplastic maintenance therapy and to evaluate possible contributing factors. Adherence is a complex subject that plays an important part in clinical practice. It can be assessed through indirect methods (patient or parental reports, physician opinion, pill count, etc.) or direct methods (drug levels in biological samples). [30] In our cohort, we used both the indirect questionnaire method along with the direct measurement of serum 6‑MP levels. In our cohort, around 56% admitted that they have omitted more than 2 doses of 6‑MP and around 88% of the noncompliants stated that it was within the last 1 month. This could still be underestimated, given that self‑reports of nonadherence with medical prescriptions are generally more reliable than self‑reports of adherence. In addition, if either family or patient admits in an interview that the failure occurred, it is possible that the event might have been more frequent.[30]
DISCUSSION
The best data on nonadherence come from studies where drug or drug metabolite concentrations have been measured. In the current study, we used the questionnaire method, as a simple, cost‑effective, and easy to apply screening method while measuring serum 6‑MP level as a confirmatory objective method. Serum 6‑MP was measured in the morning after a supposed evening dose. This method detected nonadherence in around 50% of patients.
Treatment for childhood ALL requires a prolonged maintenance phase that relies on self‑ or parent‑administered daily oral anti‑metabolite chemotherapy given over a period of about 2 years.[5,6] Systemic exposure to 6‑MP, during the maintenance phase of therapy, is a critical component of curative regimens for ALL.[7‑9]
A study similar to ours was carried in South Africa measuring the urinary excretion of 6‑MP and showed that some patients had no trace of the drug.[11,27,28] They found wide variations in the levels of 6‑MP metabolites in their children studied. These studies and ours reveal that a substantial number of children with ALL fail, totally or intermittently, to take their oral 6‑MP.
When patients relapse, the maintenance component of treatment has probably failed for some reasons.[5] Potential determinants of adequate systemic 6‑MP exposure include pharmacogenetics,[8,10,11] bioavailability,[12‑15] and adherence to daily oral administration.[16‑18]
When adherence is assessed, and the patient is aware of monitoring, it seems that the outcome may be different as there will be a significant increase in their regularity of tablet taking. In our study, we eliminated this factor as the patients were informed about the protocol of the study and the consent
Adolescent age, those with more number of siblings, those who consumed more time in each visit and those who did not receive written instructions were all associated with higher rates of nonadherence, but none of them reached a statistically significant value [Table 5].
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Khalek, et al.: Adherence to maintenaence therapy of leukemia
Table 5: Relation between adherence and different studied parameters Data (number of patients)
According to the questionnaire Compliant n=57
Socioeconomic standard Low (41) Moderate (88) Educational level Not educated (51) Low (43) Moderate (16) High (19) Family number ≤5 (88) >5 (41) Number of sibling ≤3 (88) >3 (41) Cost to come to follow‑up visits Low (37) Moderate (28) High (64) Time spent in each visit Short (36) Moderate (32) Long (61) Received written instruct No (65) Yes (64)
Non n=72
χ2
n
%
n
%
7 50
17.1 56.8
34 38
82.9 43.2
17.91
15 11 13 18
29.4 25.6 81.3 94.7
36 32 3 1
70.6 74.4 18.7 5.3
45 12
51.1 29.3
43 29
44 13
50.0 31.7
23 11 23
According to the serum 6‑MP level P
Compliant n=64
Non n=65
χ2
P
n
%
n
%
0.001
6 58
14.6 65.9
35 30
85.4 34.1
29.42
0.001
39.15
0.001
22 12 12 18
43.1 27.9 75.0 94.7
29 31 4 1
56.9 72.1 25.0 5.3
28.56
0.001
48.9 70.7
5.42
0.02
49 15
55.7 36.6
39 26
44.3 63.4
4.08
0.04
44 28
50.0 68.3
3.79
0.051
47 17
53.4 41.5
41 24
46.6 58.5
1.60
0.21
62.2 39.3 35.9
14 17 41
37.8 60.7 64.1
6.89
0.03
24 12 28
64.9 42.9 43.8
13 16 36
35.1 57.1 56.2
4.83
0.09
20 15 22
55.6 46.9 36.1
16 17 39
44.4 53.1 63.9
3.61
0.16
24 14 26
66.7 43.8 42.6
12 18 35
33.3 56.2 57.4
5.82
0.054
27 30
41.5 46.9
38 34
58.5 53.1
0.37
0.54
30 34
46.2 53.1
35 30
53.8 46.9
0.63
0.43
6‑MP=6‑mercaptopurine
was signed along with the questionnaires asked and blood samples taken all in the same visit. We disclosed significant association between nonadherence and the low socioeconomic status, noneducation, low educational level, and large sized families of 5 or more which were in agreement with Richardson et al.[31] and Viana et al.,[32] respectively. Families with low cultural and socioeconomic conditions presumably have greater difficulty in understanding the disease and properly following medical instructions and prescriptions.[17] de Oliveira et al.[17] found a tendency for the monthly per capita income of the noncompliant group to be inferior to that of the compliant group, which was compatible with other authors’ findings.[16,22,23,29] Bonilla stated that therapeutic failures are significantly higher in places where poverty, malnutrition, barriers in communication between doctors and patients and low schooling levels prevail.[33] In our series, those with a higher number of siblings, those who spent more time in each visit and those who did not receive written instructions were all associated with higher rates of nonadherence, but none of them reached a statistically significant value, while those who needed high cost to come for follow‑up visits showed significant association with nonadherence by questionnaire but not by 6‑MP level measurement. In some countries, 25-45% of families fail to attend clinic at all during the maintenance phase of
treatment[34] and in other communities and ethnic groups, it is sometimes difficult to raise family awareness of the necessity of following the treatment in the maintenance phase, a time when children are apparently cured.[23,35] Lancaster et al. pointed‑out other contributing factors for nonadherence in his cohort of 496 children on maintenance 6‑MP for ALL, which were the adolescent age and the duration of treatment.[29] Nine patients of his series (2%) had undetectable levels of 6‑MP metabolites. Five of them were adolescents and had been receiving treatment for more than 1 year. We agree with him in this respect as most of the 21% of our patients having undetectable serum 6‑MP levels were near adolescence but this didn’t reach statistical significance. This was in agreement with other studies which showed higher nonadherence rates in adolescents.[20,21,24] The biopsychosocial model of adherence suggests that adherence in adolescents may be affected by an individual’s subjective assessment of his or her illness and its treatment. Finally, we conclude that the nonadherence to oral maintenance anti‑metabolite chemotherapy is a real problem in pediatric cancer patient. Careful medical history including specific questionnaires can be a very reliable method for the routine follow‑up of these children, and drug level assay can be requested only for confirmation. This protocol is especially effective in developing countries where financial resources may be limited.
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Khalek, et al.: Adherence to maintenaence therapy of leukemia
Every effort should be made to eliminate possible contributing factors by: (1) Implementing proper education plans (oral and written) for the patients and their families about the disease, its treatment, and necessity for adherence to maintenance therapy to avoid relapse which is more difficult to treat than the primary disease; (2) decreasing the number of follow‑up visits and the time spent in each visit; and by (3) establishing a good relationship between the parents and the health care team. Further studies in this critical area are highly needed to uncover its true incidence, contributing factors, and best methods of interventions. REFERENCES 1. Horner MJ, Ries LA, Krapcho M, Neyman N, Aminou R, Howlader N, et al., editors. SEER Cancer Statistics Review, 1976-2006, Based on November 2008 SEER Data Submission. Bethesda, MD: National Cancer Institute; 2009. 2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277‑300. 3. Davies HA, Lilleyman JS. Compliance with oral chemotherapy in childhood lymphoblastic leukaemia. Cancer Treat Rev 1995;21:93‑103. 4. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487‑97. 5. Gale RP, Butturini A. Maintenance chemotherapy and cure of childhood acute lymphoblastic leukaemia. Lancet 1991;338:1315‑8. 6. Stanulla M, Schrappe M. Treatment of childhood acute lymphoblastic leukemia. Semin Hematol 2009;46:52‑63. 7. Koren G, Ferrazini G, Sulh H, Langevin AM, Kapelushnik J, Klein J, et al. Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children. N Engl J Med 1990;323:17‑21. 8. Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE. Prognostic importance of 6‑mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 1999;93:2817‑23. 9. Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med 1998;339:605‑15. 10. Aplenc R, Lange B. Pharmacogenetic determinants of outcome in acute lymphoblastic leukaemia. Br J Haematol 2004;125:421‑34. 11. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6‑mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 1990;336:225‑9. 12. de Lemos ML, Hamata L, Jennings S, Leduc T. Interaction between mercaptopurine and milk. J Oncol Pharm Pract 2007;13:237‑40. 13. Rivard GE, Lin KT, Leclerc JM, David M. Milk could decrease the bioavailability of 6‑mercaptopurine. Am J Pediatr Hematol Oncol 1989;11:402‑6. 14. Schmidt LE, Dalhoff K. Food‑drug interactions. Drugs 2002;62:1481‑502. 15. Sofianou‑Katsoulis A, Khakoo G, Kaczmarski R. Reduction in bioavailability of 6‑mercaptopurine on simultaneous administration with cow’s milk. Pediatr Hematol Oncol 2006;23:485‑7. 16. Lennard L, Welch J, lilleyman JS. Intracellular metabolites of mercaptopurine in children with all: A possible factor of non adherence? Br J Cancer 1995;75:1004‑6. 17. de Oliveira BM, Viana MB, Zani CL, Romanha AJ. Clinical and
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laboratory evaluation of compliance in acute lymphoblastic leukaemia. Arch Dis Child 2004;89:785‑8. 18. Lau RC, Matsui D, Greenberg M, Koren G. Electronic measurement of compliance with mercaptopurine in pediatric patients with acute lymphoblastic leukemia. Med Pediatr Oncol 1998;30:85‑90. 19. Tebbi CK. Treatment compliance in childhood and adolescence. Cancer 1993;71 10 Suppl: 3441‑9. 20. Smith SD, Rosen D, Trueworthy RC, Lowman JT. A reliable method for evaluating drug compliance in children with cancer. Cancer 1979;43:169‑73. 21. Lansky SB, Smith SD, Cairns NU, Cairns GF Jr. Psychological correlates of compliance. Am J Pediatr Hematol Oncol 1983;5:87‑92. 22. Tebbi CK, Cummings KM, Zevon MA, Smith L, Richards M, Mallon J. Compliance of pediatric and adolescent cancer patients. Cancer 1986;58:1179‑84. 23. MacDougall LG, Wilson TD, Cohn R, Shuenyane EN, McElligott SE. Compliance with chemotherapy in childhood leukaemia in Africa. S Afr Med J 1989;75:481‑4. 24. Festa RS, Tamaroff MH, Chasalow F, Lanzkowsky P. Therapeutic adherence to oral medication regimens by adolescents with cancer. I. Laboratory assessment. J Pediatr 1992;120:807‑11. 25. Snodgrass W, Smith S, Trueworthy R, Vats P, Klopovich P, Kisker S. Pediatric clinical pharmacology of 6-mercaptopurine: lack of compliance as a factor in leukemia relapse. Proc Am Soc Clin Oncol. 1984;3:204. 26. Azeemuddin S, Israili ZH, Bharmal FM. Rapid method for evaluating compliance of 6‑mercaptopurine therapy in children with leukemia. J Chromatogr 1988;430:163‑9. 27. Macdougall LG, McElligott SE, Ross E, Greeff MC, Poole JE. Pattern of 6‑mercaptopurine urinary excretion in children with acute lymphoblastic leukemia: Urinary assays as a measure of drug compliance. Ther Drug Monit 1992;14:371‑5. 28. Davies HA, Lennard L, Lilleyman JS. Variable mercaptopurine metabolism in children with leukaemia: A problem of non‑compliance? BMJ 1993;306:1239‑40. 29. Lancaster D, Lennard L, Lilleyman JS. Profile of non‑compliance in lymphoblastic leukaemia. Arch Dis Child 1997;76:365‑6. 30. Wright EC. Non‑compliance – or how many aunts has Matilda? Lancet 1993;342:909‑13. 31. Richardson JL, Marks G, Levine A. The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. J Clin Oncol 1988;6:1746‑52. 32. Viana MB, Fernandes RA, de Oliveira BM, Murao M, de Andrade Paes C, Duarte AA. Nutritional and socio‑economic status in the prognosis of childhood acute lymphoblastic leukemia. Haematologica 2001;86:113‑20. 33. Bonilla M, Moreno N, Marina N, deReyes G, Shurtleff SA, Downing JR, et al. Acute lymphoblastic leukemia in a developing country: Preliminary results of a nonrandomized clinical trial in El Salvador. J Pediatr Hematol Oncol 2000;22:495‑501. 34. Hicsönmez G, Ozsoylu S, Yetgin S, Zamani V, Gurgey A. Poor prognosis of childhood acute lymphoblastic leukaemia. Br Med J (Clin Res Ed) 1983;286:1437. 35. Lilleyman JS, Lennard L. Non‑compliance with oral chemotherapy in childhood leukaemia. BMJ 1996;313:1219‑20. Cite this article as: Khalek ER, Sherif LM, Kamal NM, Gharib AF, Shawky HM. Acute lymphoblastic leukemia: Are Egyptian children adherent to maintenance therapy?. J Can Res Ther 2015;11:54-8. Source of Support: Nil, Conflict of Interest: None declared.
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
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