Int J Hematol (2010) 91:850–854 DOI 10.1007/s12185-010-0594-9
ORIGINAL ARTICLE
Late effects in survivors of childhood acute lymphoblastic leukemia: a study from Thai Pediatric Oncology Group Samart Pakakasama • Gavivann Veerakul • Darin Sosothikul • Su-on Chainansamit • Vichai Laosombat • Pattra Thanarattanakorn • Rachata Lumkul • Surapon Wiangnon Somporn Wangruangsathit • Nattee Narkbunnam • Somjai Kanjanapongkul
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Received: 28 December 2009 / Revised: 25 April 2010 / Accepted: 26 April 2010 / Published online: 20 May 2010 Ó The Japanese Society of Hematology 2010
Abstract Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk of long-term late effects. Therefore, systematic screenings of the late complications are essential. The objective of this study was to determine the prevalence of late effects of Thai children and adolescents after completion of ALL therapy. We performed a cross-sectional study for evaluation of the late effects in ALL survivors who came for follow-up at 10 pediatric oncology centers in Thailand. We evaluated the treatmentrelated late complications of children and adolescents who had finished ALL treatment for at least 2 years. Demographic data, treatment modalities, and late effects were recorded and analyzed. There were 258 survivors with a median age of 12.2 years (range 3.6–23.3 years). The median follow-up time was 7.2 years (range 2–17.5 years). Forty-seven percent (122 cases) suffered from at least one late effect. Overweight/obesity was the most common late
effect. Radiation of central nervous system was a significant risk factor for overweight/obesity (OR 1.97, 95% CI 1.02–3.81) and educational problems (OR 4.3, 95% CI 1.32–14.02). Our data have demonstrated a significant prevalence of late effects after childhood ALL therapy. A long-term follow-up program for survivors of childhood cancer is therefore needed in our country.
S. Pakakasama (&) Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Road, Rajthevi, Bangkok 10400, Thailand e-mail:
[email protected]
P. Thanarattanakorn Faculty of Medicine, Chiangmai University, Chiangmai, Thailand
G. Veerakul N. Narkbunnam Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand D. Sosothikul Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand S. Chainansamit Khon Kaen Hospital, Khon Kaen, Thailand V. Laosombat Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
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Keywords Acute lymphoblastic leukemia ALL Late effects Survivors Thai
1 Introduction Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. With advances in treatment of children with ALL, long-term survival rate has
R. Lumkul Phramongkutklao Hospital, Bangkok, Thailand S. Wiangnon Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand S. Wangruangsathit Buddhachinaraj Hospital, Phitsanulok, Thailand S. Kanjanapongkul Queen Sirikit National Institute of Child Health, Bangkok, Thailand
Late effects in childhood ALL survivors
continuously improved over the years to [80% based on data of large comprehensive studies [1]. A number of ALL survivors are now increasing each year. Several studies have clearly identified cancer-related late effects in these survivors [2–4]. The late effects after ALL therapy occur in all organs including neurocognitive and psychosocial functions. Furthermore, adult survivors of childhood ALL are at higher risk for mortality and morbidity when compared with their siblings [5]. The adult survivors also report the excess rate of chronic health conditions in which their accumulative incidences are up to 73.4% at 30 years after the cancer diagnosis [6]. The long-term late effects program for follow-up of cancer survivors is essential for early detection and treatment of morbidity and prevention or minimizing mortality [7]. However, systemic screenings for organ dysfunctions have not been established for individuals receiving cancer therapy during childhood in Thailand. Therefore, Thai Pediatric Oncology Group (ThaiPOG) performed this study to determine the prevalence of the late complications after the completion of childhood ALL treatment for at least 2 years.
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Completed physical examination was performed in survivors at Hematology-Oncology clinics of their follow-up centers. The medical records were reviewed. We modified the long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers of Children’s Oncology Group as a tool for investigating the chemotherapy, radiation, and treatment-related complications [11]. Demographic data included age at diagnosis, sex, type of ALL, age at completion of therapy, and age at study. The types of chemotherapy and CNS prophylaxis were recorded. Physicians, then, further evaluated the at-risk late effects in each survivor depending on which chemotherapeutic agents and radiation fields were employed. In depth evaluations would be expected to identify the severity of organ dysfunctions in patients suffering from late complications. Univariate analysis was performed to assess the relationship between the selected late effects (overweight/ obesity, short stature, and educational problems) and CNS irradiation. Then, the estimate odds ratio (OR) with 95% confidence interval (95% CI) was determined.
3 Results 2 Materials and methods We performed a multi-center cross-sectional study in children and adolescents who were diagnosed with ALL and completed their therapy for at least 2 years. There were 10 centers under Thai Pediatric Oncology Group (ThaiPOG) that participated in this study. The study protocol was approved by each institutional ethics committee. The incidence of childhood ALL in our country during 1995–1997 and 2003–2005 were 26.8 and 29.3 per million [8]. Approximately 360 children have been diagnosed with ALL each year (G. Veerakul et al., The incidence of childhood cancers in Thailand from 2003–2005: a report from Thai-POG registry, unpublished). The diagnosis of ALL was based on bone marrow or peripheral blood cells analysis. Lymphoblasts were identified by using comprehensive methods including cell morphology, cytochemistry, flow cytometry, and cytogenetics. The subjects received treatment per individual institutional protocols. Nine institutes used modified CCG105 and CCG-106 protocols and one used St Jude total XIII A and B protocols [9, 10]. Multi-chemotherapeutic agents were mainly used for ALL therapy. Each protocol was composed of induction, consolidation, and maintenance phases. Central nervous system (CNS) prophylaxis included intrathecal chemotherapy with or without cranial irradiation. The dose of cranial irradiation was 18 Gy. For patients with CNS disease at diagnosis, cranio-spinal irradiation (CSI) was applied in some protocols. The 5-year event-free survival and overall survival rate of 50 and 66% after ALL therapy in Thailand was reported [9].
There were 258 survivors (128 males and 130 females) who were diagnosed with ALL participated in this study. The characteristics of these survivors are shown in Table 1. The median age at diagnosis was 3.8 years (range 0–14.4 years). The median age at study was 12.2 years (range 3.6–23.2 years). They were followed up with a median time of 7.2 years (range 2–17.5 years). The diagnoses were composed of precursor B ALL 121 (46.9%), T ALL 14 (5.4%), mature B ALL 3 (1.2%), and ALL NOS (not otherwise specified) 120 cases (46.5%). During the treatment periods, 91 cases (35.3%) received chemotherapeutic drugs without irradiation. The common drugs consisted of vincristine, prednisolone, L-asparaginase, doxorubicin, cyclophosphamide, cytosine arabinoside, mercaptopurine, thioguanine, and dexamethasone. Apart from chemotherapy, more than half of them received irradiation at some parts of the treatment protocols. Cranial irradiation was employed in 143 cases (55.4%). Three cases (1.2%) had CSI, whereas two cases (0.8%) had cranial and testicular irradiation. Nineteen cases (7.4%) received total body irradiation as a part of the preparative regimen for stem cell transplantation. The long-term side effects of 14 systems were evaluated. One hundred and twenty-two survivors (47.3%) were found to have at least one late effect. Two or more organ dysfunctions were identified in 32 (12.4%) cases. The adverse endocrine complications were the most common late sequelae found in this study (Table 2). Over 50% of survivors with endocrine late effects suffered from
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Table 1 Characteristics of ALL survivors Characteristics
Table 3 Endocrine and metabolic complications Number (%) (n = 258)
Complications
Number (%) (n = 64)
Male
128 (49.6)
Obesity (BW [120% of weight for height)
28 (43.8)
Female
130 (50.4)
Overweight (BW 110–120% of weight for height)
15 (23.4)
Short stature (height \3rd percentile)
13 (20.3)
Gender
Age at diagnosis (years)
Underweight (BW \3rd percentile)
7 (10.9)
90 (34.9)
Delayed puberty
6 (9.4)
26 (10.1)
Hyperthyroidism
2 (3.1)
0–4
1 (0.4)
Hypothyroidism Dyslipidemia
1 (1.6) 2 (3.1)
5–9
26 (10.1)
Type 2 diabetes mellitus
2 (3.1)
10–14 15–19
149 (57.7) 78 (30.2)
Type 1 diabetes mellitus
1 (1.6)
Insulin resistance
1 (1.6)
20–24
4 (1.6)
Adrenal insufficiency
1 (1.6)
Growth hormone deficiency
1 (1.6)
0–4 5–9 10–14
142 (55)
Age at study (years)
Treatment era 1990–1994
25 (9.7)
1995–1999
93 (36)
2000–2004
139 (53.9)
2005–2009
1 (0.4)
Table 4 Effect of CNS irradiation on common late effects Late effects
Chemotherapy Anthracyclines
211 (81.8)
Alkylating agents
211 (81.8)
Both anthracyclines and alkylating agents 181 (70.2) Radiation therapy Cranial irradiation Craniospinal irradiation Cranial and testicular irradiation Total body irradiation Bone marrow transplant
143 (55.4) 3 (1.2) 2 (0.8) 19 (7.4) 19 (7.4)
Table 2 Late effects of ALL survivors stratified by organ system Late effects
Number (%) (n = 258)
Endocrine/metabolic
64 (24.8)
Psychosocial
28 (10.9)
Cardiovascular
9 (3.5)
Dental
5 (1.9)
Nervous system
4 (1.5)
Dermatologic
2 (0.8)
Immune
2 (0.8)
Pain
2 (0.8)
Auditory
2 (0.8)
Gastrointestinal/hepatic
1 (0.4)
Ocular Musculoskeletal
1 (0.4) 1 (0.4)
Pulmonary
0
Urinary
0
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CNS irradiation
OR (95% CI)
Exposure No exposure (n = 148) (n = 91) Obesity/overweight
32
10
1.97 (1.02–3.81)
Short stature 10 Educational problems 21
2 3
3.07 (0.69–13.72) 4.3 (1.32–14.02)
Excluded patients receiving total body irradiation
overweight/obesity (Table 3). Other common endocrine complications included short stature, underweight, and delayed puberty, respectively. Patients exposed to the CNS irradiation had significantly increased risk of overweight/ obesity with an OR of 1.97 (95% CI 1.02–3.81). Almost all survivors with short stature received cranial or craniospinal radiation during the ALL treatment. However, radiation exposure did not significantly increase the risk of short stature (OR 3.07, 95% CI 0.69–13.72) (Table 4). The other common late effects in ALL patients were the complications of psychosocial, cardiovascular, dental, and nervous systems, respectively (Table 2). Educational problems were reported in 26 cases. CNS irradiation was the significant risk factor for educational problems with an OR of 4.3 (95% CI 1.32–14.02) (Table 4). Pulmonary and urinary dysfunctions were unlikely to be the late complications.
4 Discussion This is the first multi-center study of late effects in children who experienced ALL therapy in Thailand. In our country,
Late effects in childhood ALL survivors
pediatric oncologists continue to take care of children and adolescents after the completion of cancer therapy. However, we still lack a continuing care program for childhood cancer survivors during adulthood. Therefore, our study was performed to explore the prevalence of late effects, mainly in childhood and adolescents. Our data showed that almost half of the survivors (47.3%) developed at least one treatment-related complication. Oeffinger et al. [6] reported that adult survivors had increased risk of chronic conditions with an OR of 3.3 when compared with their siblings, and the prevalence of at least one long-term morbidity was 62.3% after the treatment of childhood cancer. Therefore, some late effects may occur early after the treatment while some may appear later. The higher prevalence of late complications in adult survivors might be the accumulation of these medical conditions since childhood and adolescents. These data emphasize the need for regular screening program starting since childhood through adulthood after the treatment of pediatric malignancies. Defective physical growth, disturbed neurocognitive function, emotional difficulties, cardiac abnormalities, hypertension, osteoporosis/osteopenia, fractures, and second neoplasms were the common late effects of 324 acute leukemia survivors [2]. Overweight/obesity was the most common late complication (16.7%) reported from our multi-centers. From a national health examination survey in Thailand, the prevalence of obesity in children aged 6–12 years was 6.7% [12]. Therefore, the prevalence of this condition was higher in Thai children who had survived from ALL. The prevalence of obesity after completion of ALL therapy ranged from 11 to 56% [13]. Exposure of CNS irradiation was the risk factor for overweight/ obesity in Thai childhood cancer survivors. The risk factors for overweight/obesity in ALL survivors have been studied in several settings. Oeffinger et al. [14] demonstrated that cranial irradiation C20 Gy significantly increases the risk of this complication. Female with younger age at diagnosis (0–4 years) and received radiation dose C20 Gy was the greatest risk group of ALL survivors suffering from overweight/obesity (OR 3.81). Sklar et al. [15] showed that body mass index of patients receiving cranial irradiation is increased starting from diagnosis to the end of therapy. The change in BMI was greater in patients receiving higher dose of cranial irradiation (24 Gy) when compared with the lower dose (18 Gy). Other risk factors for overweight/ obesity in ALL survivors included young age at diagnosis (\6 years), overweight/obesity at diagnosis, and maternal obesity [16, 17]. Growth failure or short stature was significantly detected in ALL survivors [2]. Children with ALL received cranial irradiation were at risk to have decreased final height [18, 19]. Five percent of our survivors had
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short stature. However, CNS irradiation was not a statistically significant risk factor of short stature in this study. Thus, a further follow-up study of these survivors may demonstrate the impact of ALL treatment on final height in adulthood. Psychosocial issue was the second most common late effect of our survivors for which educational problems was the major concern. Treatment modalities of childhood ALL consisting of cranial irradiation, high dose intravenous methotrexate (MTX), and intrathecal MTX are associated with neurocognitive impairment [20]. CNS prophylaxis with cranial irradiation is a significant risk for deficits in intellectual and cognitive performances compared to without cranial irradiation [21]. Thus, our results rendered support to the significant adverse effect of CNS irradiation on the neurocognitive impairment in these patients. Therefore, neurocognitive evaluation should be regularly monitored in post-therapy of childhood ALL, so that early intervention may be given to the needed child. Our study has used the modified COG-LTFU guidelines for identifying the late effects of organ systems according to individual’s specific treatment-related exposure [11, 22]. The guidelines are appropriate for asymptomatic survivors after the completion of childhood cancer for 2 or more years [22]. We found that these recommendations were useful and practical for the screening of late effects at the clinics. The guidelines for long-term follow-up in this group of patients should be used continually in adult survivors program, because most of these late effects do appear in adulthood [23]. A limitation of this study is the shorter follow-up period compared to some studies [5, 14, 24]. Therefore, prevalence of some late complications such as short stature and secondary malignancy may not be well presented. The median time to develop some secondary cancers including basal-cell carcinoma, meningioma, and soft-tissue sarcoma is more than 10 years [24]. Thus, an extended long-term follow-up study of our survivors should be performed. In conclusion, our study has demonstrated a significant prevalence of late effects in survivors of childhood ALL therapy. Overweight/obesity was the most common long-term complication for which CNS irradiation was the risk factor. It is recommended that follow-up guidelines of childhood cancer survivors should be implemented in our country. Acknowledgments This study was supported by National Research Council of Thailand, Clinical Research Collaboration Network (CRCN), and the Thai Society of Hematology. We thank Director of CRCN, Professor Piyatat Tatsanavivat. We would like to thank Ms Sommaphun Tabjareon who served as a project coordinator and analyzed the data. We also wish to thank Professor Amnuay Thithapandha for his help with English editing of this manuscript.
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