The adolescents and young adults population (AYA) has

Transcription

1 ORIGINAL ARTICLE Survival Analysis After Diagnosis With Malignancy of Egyptian Adolescent Patients: A Single-center Experience Azza A. G. Tantawy, MD,* Nayera H. K. El Sherif, MD,* Fatma S. E. Ebeid, MD,* and Eman D. El-Desouky, MScw Background: Adolescents with malignancy represent a unique population in oncology, receiving care in pediatric or adult oncology institutions. Previously, adolescents and young adults (AYAs) had good survival rates; yet in the last few decades, AYAs have shown inferior survival rates compared with children due to the increasingly reported AYA-specific malignancies with poor survival rates. This study evaluates the clinicoepidemiological aspects of adolescent cancer diagnosed in a Pediatric Oncology Unit over a 10-year period, the associated risk factors, and the survival rate. Methods: Retrospective data analysis of patients aged 10 to 19 years diagnosed in the Pediatric Oncology Unit, Children s Hospital Ain Shams University, Cairo, Egypt, during the period from January 1, 2000 to January 1, Results: There were 158 patients (20% of total number of patients diagnosed during the same period), 84 male (53.2%) and 74 female (46.8%). Hematological malignancies were the most common (91.8%), with acute lymphoblastic leukemia being the most prevalent malignancy (61.5%), and solid tumors represented 8.2% of the total number of patients. The 5- and 10-year overall survival rates were 45.2% and 40.2%, respectively. The 5- and 10-year event-free survival rates for hematological malignancies were 39.9% and 37.3%, and for solid tumors it was 36.4%. Infection was the main cause of death (50%). Conclusions: Age-related survival gap exists for adolescent cancer patients compared with children. Further studies are needed to provide evidence about optimal treatment regimens in this age group. Key Words: adolescents, cancer, overall survival, event-free survival (J Pediatr Hematol Oncol 2014;36:e346 e352) The adolescents and young adults population (AYA) has been variably defined internationally but is most commonly identified as individuals aged 15 to 30 years of age. 1 In contrast, The Food and Drug Administration and the World Health Organization consider adolescents to be individuals aged 10 to19 years. 2 Received for publication May 24, 2013; accepted January 8, From the *Pediatric Hematology/Oncology Unit, Children s Hospital, Faculty of Medicine, Ain Shams University, Cairo; and wdepartment of Cancer Epidemiology and Biostatistics, Clinical Oncology Nutrition, National Cancer Institute, Cairo University, Giza, Egypt. All the authors contributed equally. The authors declare no conflict of interest. Reprints: Nayera H. K. El Sherif, MD, Pediatric Hematology/Oncology Unit, Children s Hospital, Faculty of Medicine, Ain Shams University, 24 B Anour El Mofty, Nasr City, Cairo, Egypt ( nayeraelsherif@hotmail.com). Copyright r 2014 by Lippincott Williams & Wilkins Despite unique tumor epidemiology, a higher cancer incidence, and a modest survival improvement compared with pediatric patients, AYA aged 15 to 30 years have not been considered as a separate, special group of patients in the frame of medical oncology. 3 The incidence of cancer among adolescents in Surveillance, Epidemiology, and End Results (SEER) areas from 1975 to 2000 was 203 per million (2% of all invasive cancer). There were 2.7 times more patients diagnosed with cancer during the second 15 years of life than during the first 15 years. The risk of developing cancer among AYA was explained by age-dependent mechanisms, as telomerase shortening or mutation-to-malignancy rate that increases constantly with age. 1 The age distribution of cancer in the Middle East populations varies widely. The percentage of cancer patients under the age of 20 years was reported to be higher in Jordanians (52%), Egyptians (48%), and Israeli Arabs (50%) than in Cypriots (31%), Israeli Jews (35%), and the US SEER population (29%). 4 The spectrum of cancers reported worldwide among AYA is distinctive, with higher risks for lymphomas, bone tumors, and soft-tissue sarcomas. Nevertheless, the rates of specific cancer types differed substantially by sex and by race and these differences were most remarkable for thyroid cancer that was much more common in females. 5 There has been a lack of survival improvement among older AYAs, particularly in males. However, the 5-year survival rates are high in certain types of cancer reaching Z90% in Hodgkin disease and germ cell tumors, possibly because of recruitment in clinical trials or centralized treatment for certain cancers in this age group. 6 This work is designed to evaluate the epidemiology and risk factors of adolescent cancer among patients aged 10 to 19 years, and to study the trend in survival among this age group. METHODS This retrospective study has been conducted in the Pediatric Oncology Unit, Children s Hospital, Ain Shams University in Cairo, Egypt. It included cancer patients with age at diagnosis ranging from 10 to 19 years, who were diagnosed and treated in the unit during the period from January 1, 2000 to January 1, The data were collected by reviewing the patients files and follow-up sheets, as well as by personnel communication with the patients and/or their caregivers, and patient clinical examination, when feasible. Special emphasis was laid on: sex, age at diagnosis, pathologic diagnosis, clinical presentation, risk criteria, protocol given, and complications during or after treatment, and causes of death during e346 J Pediatr Hematol Oncol Volume 36, Number 6, August 2014

2 J Pediatr Hematol Oncol Volume 36, Number 6, August 2014 Survival Analysis of Adolescent Malignancy TABLE 1. Characteristics of Patients Age at Diagnosis (y) N (%) Mean ± SD 12.2 ± 1.8 Median (range) 12.0 (10-17) Sex Male 84 (53.2) Female 74 (46.8) Cancer type Hematological 145 (91.8) Solid 13 (8.2) Hematological malignancy (n = 145) Leukemia 104 (71.7) Lymphoma 39 (26.9) LCH 2 (1.4) Types of leukemia (n = 104) ALL 64 (61.5) AML 34 (32.7) CML 4 (3.8) Biphenotypic 2 (1.9) ALL phenotype B cell 45 (70.3) T cell 19 (29.7) Types of lymphoma (n = 39) NHL 18 (11.4) HL 21 (13.3) Solid types (n = 13) Neuroblastoma 4 (30.8) Osteosarcoma 3 (23.1) Germ cell tumor 3 (23.1) Ewing s sarcoma 1 (7.7) Adenocarcinoma 1 (7.7) PNET 1 (7.7) Protocol of therapy ALL CCG91 HL ABVD NHL BFM90 Ewing/PNET POG9354/CCG7942 Neuroblastoma COG3961/POG Osteosarcoma CCG7921 Germ cell tumor POG9048 ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; HL, Hodgkin lymphoma; LCH, Langerhans cell histiocytosis; NHL, non-hodgkin lymphoma; PNET, peripheral neuroectodermal tumor. the defined period of the study. Evaluation of treatment response (remission and relapse rate) was done according to the assigned protocol of therapy. Patients were classified into patients with hematological malignancies and patients with solid tumors. Patients with hematological malignancies included: (1) patients with acute leukemia (having Z25% blasts in bone marrow examination) who were further subdivided into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) based on flow cytometry; (2)patients with chronic myeloid leukemia (CML) were diagnosed clinically and by bone marrow examination; (3) patients with lymphoma were diagnosed by lymph nodes and/or mass biopsy, and further subdivided into non-hodgkin (NHL) and Hodgkin lymphoma (HL) based on immunohistochemistry; and (4) patients with Langerhans cell histiocytosis (LCH) were diagnosed by characteristic bone lesions, pathology, and immunohistochemistry. Patients with solid tumors included: neuroblastoma, osteosarcoma, Ewing sarcoma and peripheral neuroectodermal tumor (PNET), germ cell tumors, and adenocarcinoma. They were diagnosed by the pathology of the tumor mass and immunohistochemistry, supported by specific serum or tissue tumor markers. Event-free survival (EFS) and overall survival (OS) were calculated from the date of diagnosis to date of events. For EFS, events were identified as resistance, relapse, death, or whichever occurred first. For OS, event was identified as death from any cause. For OS analysis, living patients or patients lost to follow-up were censored on last known alive date. For EFS patients who neither relapsed, showed resistance, nor died were censored at last assessment before the lost follow-up. The protocol of the study was approved by the local ethical committee of the Pediatric Department, Faculty of Medicine, Ain Shams University and an informed consent was taken from patients and/or their parents. Statistical Methodology Statistical analysis was performed using Statistical Package for Social Sciences, Version 14.0 (SPSS Inc., Chicago, IL) for Windows. Description of quantitative variables was done as mean, SD, median, and range, and qualitative variables were described as number and percentage. Kaplan and Meier procedure was used to estimate the OS rates and disease-free rates, and comparisons between the different prognostic factors were made using the log-rank test. FIGURE 1. The number of newly diagnosed adolescent cancer cases in the last 10 years according to their diagnosis. e347

3 Tantawy et al J Pediatr Hematol Oncol Volume 36, Number 6, August 2014 TABLE 2. Event-free Survival Among Adolescent Patients Event-free Survival (%) Median N 1y 5y 10y (95% CI) (mo) P All patients (0-45.4) Age at diagnosis (y) < (0-60.3) Z (0-43.3) Sex Male (0-62.3) Female (0-51.2) Tumor type Hematological (0-46.0) Solid NA 7.4 (0-35.3) Hematological cancer Leukemia ( ) < Lymphoma NA Leukemia phenotype Lymphoid lineage ( ) Myeloid lineage ( ) CI indicates confidence interval; NA, not applicable. RESULTS A total of 158 patients were diagnosed over the studied 10 years, which represent 20% of the total number of cancer patients diagnosed in the pediatric oncology unit during the same period. The male to female ratio was 1.13:1, and their age ranged between 10 and 17 years (mean, 12.2 ± 1.8 y). Almost 80% of the patients were residents of Cairo and the Delta region, whereas only 20% were from Upper Egypt. Sixteen patients were lost to follow up after initial diagnosis, so were censored at last assessment prior to loss to follow-up. Patients received pediatric protocols for malignancies (Table 1). Types of Cancer Hematological malignancies were present in 145 patients (91.8%), with leukemia being the most frequent (71.7%), distributed as ALL (61.5%), AML (32.7%), and CML (3.8%). Lymphomas were the next common (24.7%), including HL (13.3%) and NHL (11.4%), whereas 1.4% of patients had LCH. Fifteen patients had solid tumors (8.2%), including neuroblastoma (30.8%), osteosarcoma (23.1%), and germ cell tumor (23.1%), Ewing/PNET (13.3%), and adenocarcinoma (6.7%), as demonstrated in Table 1. The Sex Distribution According to the Type of Malignancy Comparing the sex distribution among the studied patients revealed a higher frequency of neuroblastoma and CML among female patients (80% and 75%, respectively), whereas AML was more common among male patients (70%). In contrast, there was no difference in sex distribution in lymphoma patients. The Number of Newly Diagnosed Adolescent Cancer Cases in the Last 10 Years According to Their Diagnosis The incidence of newly diagnosed adolescent cancer cases was heterogenous over the 10-year study period. In most of the years, the incidence of ALL was the highest, and the year 2008 showed the highest rate of solid tumors among adolescent cancer patients. The frequency of AML was higher in the first 5 years (79.4%) compared with the last 5 years (20.6%). In the year 2009, all hematological malignancies were ALL (Fig. 1). EFS and OS The 5- and 10-year EFS rates for adolescent cancer patients were 39.7% and 37.2%, respectively. Patients aged FIGURE 2. Event-free survival in patients with hematological malignancies and solid tumors. e348

4 J Pediatr Hematol Oncol Volume 36, Number 6, August 2014 Survival Analysis of Adolescent Malignancy FIGURE 3. Event-free survival in patients with hematological malignancies. 13years and above and those aged below 13 years had comparable 5- and 10-year EFS (P = 0.63). We found no sex difference with regard to the 5- and 10-year EFS (P = 0.8) (Table 2). There was no significant difference in the 5- and 10-year EFS when comparing patients with hematological malignancies with those with solid tumors (P = 0.99); however, lower 5- and 10-year EFS rates were observed among patients with AML compared with ALL patients (P = 0.007). Patients with lymphoma had significantly higher 5- and 10-year EFS compared with leukemia patients (P < 0.001) (Figs. 2, 3). The 5- and 10-year OS rates for the whole group were 45.2% and 40.2%, respectively. Patients aged 13 years and above and those aged below 13 years had comparable 5- and 10-year OS (P = 0.7). However, male patients had relatively higher 5- and 10-year OS than female patients (P = 0.5) (Table 3). There were no statistically significant differences between patients with hematological malignancies and those with solid tumors with regard to the 5- and 10-year OS (P = 0.8) (Fig. 4). Among patients with hematological malignancies, lymphoma patients had higher 5- and 10-year OS compared with ALL and AML patients (P = 0.004) (Fig. 5). We found no difference in the 5- and 10-year OS among patients with NHL and HL (P = 0.13), pre-b-cell, and T-cell ALL (P = 0.61). Residency We found no significant difference in the 5- and 10- year EFS of patients living in Cairo, Delta region, and Upper Egypt (P = 0.35), Table 4. In addition, the 5- and 10-year OS rates of adolescent patients coming from Cairo, Delta region, and Upper Egypt were comparable (P = 0.38), (Table 5). Causes of Death Infection was the main cause of death, responsible for 50% of deaths. Thirty percent of deaths occurred due to cancer therapy refractoriness or relapse, 15% were related to severe methotrexate toxicity, and 6% due to liver cell failure. TABLE 3. Overall Survival Among Adolescent Cancer Patients Overall Survival (%) Median N 1y 5y 10y (95% CI) (mo) P All patients (0-57.3) Age at diagnosis (y) < (0-69.2) Z (0-53.6) Sex Male ( ) Female (0-51.2) Tumor type Hematological (0-54.4) Solid NA 7.4 Hematological malignancy* Leukemia ( ) Lymphoma NA Leukemia phenotype Lymphoid lineage ( ) Myeloid lineage (0-6.3) CI indicates confidence interval; NA, not applicable. e349

5 Tantawy et al J Pediatr Hematol Oncol Volume 36, Number 6, August 2014 FIGURE 4. Overall survival in patients with hematological malignancies and solid tumors. Patients Lost to Follow-up Sixteen patients were lost to follow-up after initial diagnosis, 11 female and 5 male (8 had ALL, 5 NHL, 1 patient had germ cell tumor, 1 LCH, and 1 AML M3). No data were available for these patients as regard the response to therapy, relapse, resistance or death, and thus were censored at last assessment before loss to follow-up. DISCUSSION The incidence of cancer in AYA patients aged 15 to 30 years is higher and rising faster than in children. Data from the National Cancer Institute s SEER program and the UK cancer registry indicate that the incidence of cancer in adolescents 15 to 19 years old is 50% higher than in younger persons. However, there is evidence that this incidence has declined, after a peak in the late 1980s and early 1990s. 7 9 In our center, 158 adolescents aged from 10 to 19 years were diagnosed with cancer over the period of 10 years (20% of total number of diagnosed cancer patients), which is an underestimated incidence because many adolescent patients were diagnosed and treated in the adult Oncology center. Published data show that the most common tumors reported in adolescents were testicular cancer and Hodgkin disease, followed by central nervous system (CNS) tumors, NHL, thyroid cancer, and ALL. 9,10 A previous study reported that ALL is less common among adolescents than in children (6% compared with 30% of all cancers). 10 Whyte and Smith 11 stated that, whereas ALL, NHL, CNS tumors, and bone tumors are as common in adolescence as in childhood, Hodgkin disease and germ cell tumors occur at an incidence of 3 to 6 times higher in adolescents than in children. In our study, leukemia was the most common cancer (40.5%), with ALL being the most common hematological malignancy, next followed by lymphomas. Solid tumors represented only 8.2% of adolescent cancer, surprisingly with neuroblastoma being the most common (30.8%); this may be because we included the age group 10 to 15 years that may be considered in some centers as a pediatric age. The lower incidence of other solid tumors such as germ cell tumor, carcinoma, and CNS tumors is explained by the fact that most of these cases were referred to adult oncology centers. There was no sex difference in the overall frequency of adolescent tumors, as previously reported. 12 Birch et al 9 described a higher incidence of ALL, NHL, Ewing sarcomas, osteosarcomas and brain tumors, and thyroid carcinoma malignancies among adolescent male patients, whereas melanomas and Hodgkin disease were more common in female patients. In our study, AML was more FIGURE 5. Overall survival in patients with hematological malignancies. e350

6 J Pediatr Hematol Oncol Volume 36, Number 6, August 2014 Survival Analysis of Adolescent Malignancy TABLE 4. Event-free Survival Among Adolescent Patients in Relation to Residency Event-free Survival (%) Median (95% CI) Factor N 1 y 5 y 10 y (mo) P Residency Cairo ( ) 0.35 Delta ( ) Upper Egypt and Red Sea (0-25) CI indicates confidence interval. common in male patients, whereas ALL, CML, and neuroblastoma were more frequent among female patients. In the current study, the incidence of malignancies among adolescent patients varied from year to year. In most of the years, the incidence of ALL was the highest, yet the year 2008 showed the highest frequency of solid tumors among adolescents. There were more AML patients diagnosed in the first 5 years (79.4%) compared with the last 5 years (20.6%). This heterogenous frequency over the study period may be related to epidemiologic factors (demographic, perinatal, and environmental exposures). Recent studies showed improved outcomes for AYAs treated with pediatric protocols compared with those treated with adult protocols A French study reported a 5-year EFS of 69.0% among adolescent cancer patients, 85% for lymphomas, 55% for malignant bone tumors, and 41% for leukemia. 10 In the current study, the 5-year EFS for the whole group was 39.7%, with 39.9% for hematological malignancies and 36.4% for solid tumors. The reported 5-year EFS rates for AYA patients with ALL, AML, and HL were lower compared with younger patients (68.0%, 31%, and 43.6%) Similarly, in our study, we report a lower EFS compared with pediatric patients (ALL 28.4%, AML 15.4%, lymphomas 72.2%) versus (73.4% and 87% in pediatric ALL and lymphomas, respectively). 21,22 In our study, there was no difference in the 5- and 10-year EFS between hematological malignancies and solid tumors; however, significantly lower 5- and 10-year EFS rates were found between AML patients compared with ALL, and a significantly lower EFS rate among patients with leukemia compared with lymphoma patients. This could be explained by the higher rate of deaths from infections, relapses, and refractoriness among leukemia patients, especially AML compared with lymphoma patients. Smith et al 12 reported an overall 5-year survival for adolescents with cancer of 77%. In contrast, we found a lower 5- and 10-year OS for the whole group being 45.2% and 40.2%, respectively. Probably the difference is partially related to the higher incidence of neuroblastoma among our adolescent patients accounting for the lower OS. The (SEER) analysis found an annual drop to <0.5% in the survival of 15- to 24-year-old patients compared with children below 15 years. However, we found a comparable 5- and 10-year OS among patients aged 13years and above and those aged below 13 years. In a published Australian study, adolescent patients with ALL had an improved 5-year survival from 40% in 1982 to 1989 to 74% in 2000 to 2004, but was still lower than children (88%).They reported 5-year OS survival in 2000 to 2004 of 74% for AML, Z95% for HL, and Z81% for NHL. 23 Similarly, Bleyer 1 and Birch et al 9 reported the worse outcomes in adolescent AML, ALL, and sarcomas (bone and soft tissue), with a lower mean 5-year survival rate than that in younger patients lagging behind by 20% to 30%. This comes in agreement with our data, where we report 5- and 10-year OS of 40.2% and 32.1% in ALL, 22.4% in AML, and 76.9% in lymphoma, which is lower than the reported data in pediatrics in our center (in ALL 84.6%). 22 Among patients with hematological malignancies, those with lymphoma had the highest 5- and 10- year OS, whereas patients with AML had a significantly lower OS than those with ALL. In our study, male patients had relatively higher 5- and 10-year OS compared with female patients. On the contrary, Geraci et al 24 found that the mortality rate for adolescent male patients (72.4%) was significantly higher than for female patients (58.6%) in almost all cancers. CONCLUSIONS In our center, the incidence of cancer in young patients aged 10 to 19 years is rising. The frequency of different types of malignancies among newly diagnosed adolescent patients varies from year to year; however, as reported in most of the international centers, the hematological malignancies were the most frequent. We report here a low EFS and the OS of adolescent patients with malignancies probably related to the different biology of the malignancy with adverse karyotypic and molecular markers, less adherence to therapy, and greater toxicity of treatment. Further efforts are needed to provide an optimal treatment TABLE 5. Overall Survival Among Adolescent Patients in Relation to Residency Overall Survival (%) Factor N 1 y 5 y 10 y Median (95% CI) (mo) Residency Cairo ( ) 0.38 Delta (0-155) Upper Egypt and Red Sea (0-25) CI indicates confidence interval. P e351

7 Tantawy et al J Pediatr Hematol Oncol Volume 36, Number 6, August 2014 regimen among adolescents based on risk factors and molecular markers to improve survival. REFERENCES 1. Bleyer A. The adolescent and young adult gap in cancer care and outcome. Curr Probl Pediatr Adolesc Health Care. 2005;35: World Health Organization. Young people s health - a challenge for society. Available at: trs/who_trs_731_fre.pdf Accessed January 9, Pentheroudakis G, Pavlidis N. Review: Juvenile cancer: improving care for adolescents and young adults within the frame of medical oncology. Ann Oncol. 2005;16: National Cancer Institute. Available at: publications/mecc. Cancer Incidence in Four Member Countries (Cyprus, Egypt, Israel, and Jordan) of the Middle East Cancer Consortium (MECC) Compared with US SEER. Accessed January 9, Linabery MA, Ross JA. Childhood and adolescent cancer survival in the US by race and ethnicity (diagnostic period ). Cancer. 2008;113: Stiller C. Epidemiology of cancer in adolescents. Med Pediatr Oncol. 2002;39: Parkin DM, Kramarova E, Draper GJ, et al. International Incidence of Childhood Cancer. Vol II, IARC Scientific Publication no 144. Lyon, France: International Agency for Research on Cancer; Ries LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, Bethesda, MD: National Cancer Institute; Available at: CSR1973_1998/ Birch JM, Alston RD, Kelsey AM, et al. Classification and incidence of cancer in adolescents and young adults in England Br J Cancer. 2002;87: Desandes E, Lacour B, Sommelet D, et al. Cancer incidence among adolescents in France. Pediatr Blood Cancer. 2004;43: Whyte F, Smith L. A literature review of adolescence and cancer. Eur J Cancer. 1997;6: Smith MA, Gurney JG, Ries LAG. Cancer in adolescents years old. In: Ries LAG, Smith MA, Gurney JG, et al, eds. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program , SEER Program 1999; NIH Pub no Bethesda, MD: National Cancer Institute; 1999: Boissel N, Auclerc MF, Lhéritier V, et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol. 2003;21: De Bont JM, Holt B, Dekker AW, et al. Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs. adult protocols in the Netherlands. Leukemia. 2004;18: Hallbo o k H, Gustafsson G, Smedmyr B, et al. Treatment outcome in young adults and children >10 years of age with acute lymphoblastic leukemia in Sweden: a comparison between a pediatric protocol and an adult protocol. Cancer. 2006;107: Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer. 2007;48: Stock W, La M, Sanford B, et al. Adolescents and young adults with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric oncology cooperative group treatment regimens: a comparison of Children s Cancer Group (CCG) and Cancer and Leukemia Group B (CALGB) studies. Blood. 2008;112: Wells RJ, Woods WG, Buckley JD, et al. Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study. J Clin Oncol. 1994;12: Herbertson RA, Evans LS, Hutchinson J, et al. Poor outcome in adolescents with high-risk Hodgkin lymphoma. Int J Oncol. 2008;33: Larsen E, Raetz EA, Winick NJ, et al. Outcome in adolescent and young adult (AYA) patients compared with younger patients treated for high-risk B-precursor acute lymphoblastic leukemia (HR-ALL): a report from the Children s Oncology Group study AALL0232. J Clin Oncol, 2012 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2012;30(suppl):, CRA Tantawy AA, El-Rashidy FH, Ragab IA, et al. Outcome of childhood acute lymphoblastic leukemia in Egyptian children: a challenge for limited health resource countries. Hematology. 2013;18: Mokhtar GM, Abdelmaksoud AA, Ezz-Elarab SS, et al. Survival and treatment related deaths in pediatric oncology patients: a single center retrospective cohort study. Egypt J Hematol. 2010;35: Pinkerton R, Wills Rachael-Anne, Coory Michael D, et al. Survival from haematological malignancy in childhood, adolescence and young adulthood in Australia: is the agerelated gap narrowing? Med J Aust. 2010;193: Geraci M, Birch JM, Alston RD, et al. Cancer mortality in 13 to 29-year-olds in England and Wales, Br J Cancer. 2007;97: e352