Risk-adapted Therapy of Pediatric Hodgkin Lymphoma in Upper Egypt Ghazaly MH 1, Ali AM 2, Hamza HA 3, Mohamed AM 2

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1 Ghazaly et al. SECI Oncology 2014 Risk-adapted Therapy of Pediatric Hodgkin Lymphoma in Upper Egypt Ghazaly MH 1, Ali AM 2, Hamza HA 3, Mohamed AM 2 1 Department of Pediatrics, Faculty of Medicine, Assiut University 2 Pediatric Oncology Department, South Egypt Cancer Institute, Assiut University 3 Radiotheray Department, South Egypt Cancer Institute, Assiut University Correspondence should be addressed to Amira M Mohamed at Pediatric Oncology Department, South Egypt Cancer Institute, El-Methak St., Assiut, Egypt, amirasherit@yahoo.com Accepted 2 December 2014 Abstract Background: Hodgkin's lymphoma (HL) is a highly curable malignant disease. Risk-adapted therapy for children with HL is directed toward high survival, minimal toxicity and optimal quality of life. Objectives: To assess the outcome of the HL patients treated with risk-adapted therapy approach at pediatric oncology department in South Egypt Cancer Institute and to assess the prognostic factors of survival in pediatric HL patients. Methods: This prospective study was carried out from January 2009 to January 2014, with median follow up of 36.5 months (range 8-58 months). Thirty four patients were eligible for this study stratified into three risk groups: low risk (LR), intermediate risk (IMR) and high risk (HR). Patients treated with two, four and six cycles respectively of alternating ABVD/COEP chemotherapy followed by involved-field radiation therapy (IFRT): 15 Gy for patients achieved complete response, and 25.5 Gy for those achieved partial response. Results: Six patients were LR, 18 patients were IMR and 10 patients were HR. Six patients had events, progressive disease in 3 patients, relapse in 2 patients, and death in one patient due to fever neutropenia. The 3-years overall survival (OS) and event free survival (EFS) rates (± SE) were 91.2% ± 5.3% and 82.3% ± 7.3% respectively. Multivariate analysis revealed "B" symptoms and anemia were the significant independent factors for inferior EFS, however, hypoalbuminemia and anemia were the significant independent factor for lower OS. Conclusion: Risk-adapted combined-modality therapy with ABVD/COEP and involved-field radiation therapy has high efficacy and minimal toxicity in the treatment of pediatric HL. Introduction Hodgkin's lymphoma (HL) is a highly curable malignant disease. Contemporary treatment for children and adolescents with Hodgkin s disease often uses a combined-modality approach with multi-agent chemotherapy and involved-field radiotherapy. This approach has yielded excellent results, with long-term disease-free survival ranged from 85% to % in patients with early-stage disease and of more than 60% in those with more advanced disease [1]. Because cure is likely for the majority of children presenting with HL, attention to long-term treatment complications has become increasingly important. Risk-adapted therapy for children with HL is directed toward high survival, minimal toxicity and optimal quality of life. This approach assigns intensity of therapy according to the risk criteria at presentation, with the parameters most frequently used to assign risk are the presence of "B" symptoms, bulk of presenting mass, mediastinal lymphadenopathy, extra nodal extension, number of involved nodal regions and Ann Arbor stage [2]. The objectives of this study are to assess the outcome of the HL patients treated with risk-adapted therapy approach at pediatric oncology department in South Egypt Cancer Institute (SECI) and to assess the prognostic factors of survival in pediatric HL patients. Patients and Methods This prospective study was carried out at the Pediatric Oncology Department and Radiotherapy Department, SECI, Assiut University during the period from January 2009 to January Informed consent was obtained from patient's family, and the study was approved by our institutional review board. Eligible patients had histologically confirmed HL, previously untreated and aged 16 years. For each patient, pretreatment evaluation included history and physical examination, laboratory investigations {complete blood picture (CBC), liver enzymes, albumin, bilirubin, serum

2 Ghazaly et al. SECI Oncology 2014 Page 2 of 8 urea and creatinine, erythrocytic sedimentation rate (ESR), lactic dehydrogenase (LDH), thyroid function test (TFT), sex hormones and bone marrow biopsy was done for patients with systemic (B) symptoms or stages (II-IV)}, chest X-ray and cervical, thoracic, abdominal and pelvic computed tomography (CT) scan with contrast. Pulmonary function test and echocardiography were done as baseline for follow up. Excisional biopsy was obtained from presenting lymphadenopathy and specimens were subjected to morphological studies and immunohistochemical tests by using CD15, CD30 and CD20, histopathological classification was done according to Revised European American Lymphoma classification/ World Health Organization (REAL/WHO) classification system [3]. Patients were staged by Cotswolds' modification of Ann Arbor staging system [4]. Risk assessment: patients were categorized into three risk groups: low risk (LR): included patients with stage IA, IIA without unfavorable features ("B" symptoms, bulky disease 10 cm, hilar lymphadenopathy, involvement of more than 4 lymph node regions and extra nodal extension to contiguous structures), intermediate risk (IMR): localized disease (stage I, II) with one or more of unfavorable features and patients with stage IIIA, high risk (HR): stage IIIB and IV [5]. Treatment: All patients received combination chemotherapy followed by involved field radiotherapy. Combination Chemotherapy was in the form of ABVD cycle (Adriamycin, bleomycin, vincristine and doxorubicin) alternating with COEP cycle (cyclophosphamide, oncovin (vincristine), etoposide and prednisone), table (1) [6], patients received different number of cycles according to risk stratification. Two alternating cycles for low risk group, four alternating cycles for intermediate risk group and six alternating cycles for high risk group. Radiotherapy was delivered to all initially involved sites. Patients who achieved early complete remission (CR) after two cycles of chemotherapy received 15 Gy and patients who achieved partial response (PR) received 25.5 Gy with modification based on patient s age, the presence of bulky disease, normal tissue concerns and potential acute and long-term effects. Radiation therapy was given using antero-posterior/postero-anterior fields, and started within 4 weeks of last chemotherapy cycle. Gross target volume was enlarged lymph node, clinical target volume was the anatomical compartment of enlarged lymph node and planning target volume was 1 cm margin to clinical target volume. An anterior laryngeal block was used if it did not shield involved nodes in case of radiation therapy to cervical region. If the axillae were to be treated, humeral head blocks were used. Evaluation of remission: Patient's response was evaluated by physical examination, laboratory investigations according to initial positive findings and radiological examination CT scan according to the initial positive findings. Monitoring of response was done every 2 cycles of chemotherapy with early response after first 2 cycles. Complete response (CR): was defined as resolution of all tumor- related constitutional symptoms and disappearance of all measurable nodal disease (Patients with residual disease in the mediastinum will be considered as showing a CR if there is a >70% reduction of mediastinal tumor volume or abdominal tumor). Partial response (PR): was defined as at least 50% reduction in the sum of the products of 2 perpendicular diameters of all measurable lesions with disappearance of all constitutional symptoms if initially present. Stable disease (SD): was defined as neither sufficient shrinkage (< 50%) to qualify for partial response, nor sufficient increase (> 25%) nor appearance of new lesions to qualify for progressive disease. Progressive disease (PD): was defined as an increase in the product of two perpendicular diameters of any measurable lesion by >25% over the size at presentation or appearance of new lesions [7]. Table (1): Combination Chemotherapy [6] Drug Dose/Route Day(s) ABVD Protocol includes: Doxorubicin Bleomycin Vinblastin Decarbazine (repeat every 28 days) COEP Protocol includes: Cyclophosphamide Vincristine (Oncovin) Etoposide* Prednisone (repeat every 28 days) ICE protocol Ifosfamide with Mesna Carboplatin Etoposide (repeated every 21 days) 25 mg/ m2 IV 10 mg/ m2 IV 6 mg/ m2 IV 375 mg/ m2 IV 800 mg/ m2 IV 1.5 mg/ m2 IV 60 mg/ m2 IV 40 mg/ m2/ day PO 1800 mg/m2iv 450 mg/m2iv mg/m2iv d1, 15. d1, 15. d1, 15. d1, 15. d1,15 d1,15 d1,15 d1,15 then gradual withdrawal. D1 3 D1 D1 3 *Procarbazine is substituted by etoposide in COEP regimen. After-therapy monitoring: After completion of chemotherapy, patients was followed monthly in the first year, every 3 months in the 2 nd and 3 rd years.. Follow-up examinations was done by physical examination, chest X-ray, routine laboratory investigations (CBC and ESR) and CT scans according to initial presentation. Specific evaluation of late effects including hormonal assessment (TFT and sex hormones), pulmonary function test, echocardiography and examination of bone and soft tissues was done. Statistical analysis: Overall survival (OS) was calculated from the first day of chemotherapy to the date of the last follow up or death due to any cause. Event free survival (EFS) was calculated from the first day of chemotherapy to an event (death due to any cause, progression after PR, relapse or a second malignancy) or to the date of the last follow up contact for patients who did not experience any event. OS and EFS were estimated with Kaplan-Meier method and differences were assessed by the log-rank test. Coxregression was used in multivariate analysis.

3 Ghazaly et al. SECI Oncology 2014 Page 3 of 8 Results From January 2009 to January patients with previously untreated HL were enrolled into this study. Patients' characteristics: are shown in table (2). The median age was 8 years (range 4-16 years). Twenty patients (60%) were males and 14 patients (40%) were females with male to female ratio 1.4:1. Four patients (11.8%) were stage I, 16 patients (47.1%) were stage II, 12 patients (35.3%) were stage III and 2 patients (5.8%) were stage IV. Risk stratification revealed 6 patients (17.6%) in LR group, 18 patients (52.9%) in IMR group and 10 patients (29.4%) in HR group. Twenty one patients (61.8%) had systemic "B" symptoms. Bulky disease was reported in 9 patients (26.5%) with 6 patients (17.6%) had bulky mediastinal mass and 3 patients (8.8%) had bulky peripheral nodal mass. Cervical lymph node enlargement was the most predominant site 85.3% followed by axillary in 50%, abdomen in 47% and mediastinum in 28.6%. Extra nodal involvement was recorded in 9 patients (26.5%), splenomegaly in 17.6%, hepatomegaly in 14.7%. Nineteen patients (58.8%) had 4 nodal regions. Twenty six patients (76.5%) had mixed cellularity, 14 patients had nodular sclerosis and 3 patients had lymphocytic predominant. Four patients (11.8%) had leukocytosis, 19 patients (55.9%) had anemia, ESR was elevated in 14 patients (41.2%). Response to treatment: After 2 cycles of chemotherapy, 12 patients (35.3%) achieved CR (five patients (83.3%) in LR, 6 patients (33.3%) in IMR and one patient (10%) in HR), 22 patients (64.7%) had PR. At the end of chemotherapy, Thirty-three out of 34 patients (97.1%) evaluated, 30/33 patients (90.9%) had CR ( 6 patients (%) in LR, 17 patients (94.4%) in IMR and 7 patients (70%) in HR) and 3/33 patients (9.1%) had PD (one patient in IMR and 2 patients in HR). Treatment failure: There were 5 treatment failures, 3/33 patients (9.1%) had progressive disease (one patient of IMR group and two of HR group) and 2/30 patients (6.7%) had relapse (two of HR group). One patient relapsed outside the irradiated field, the other relapsed within and outside the irradiated field. They occurred at 7, 22 months after completion of radiotherapy. Both were salvaged by second line chemotherapy ICE (ifosfamide, carboplatin and etoposide) table (1) followed by radiotherapy with complete remission in one patient and partial remission in the other patient who died from hepatocellular failure. Toxicity: Morbidity was mostly observed in HR group. As regard to the early complications, bone marrow suppression was the most frequent complication (8.8%) followed by chest infection. Acute gonadal failure occurred in one patient (post pubertal) after receiving pelvic radiotherapy in spite of oophrepexy and she is now on hormonal therapy. Late effects of treatment were detected in patients on follow up in the form of hypothyroidism in 2 patients (8.8%) and restrictive pulmonary function in one patient (2.9%) while no cardiac complications occurred. Table (2): Patient Characteristics Patient Characteristics Age Range Mean ± SD Median Gender Male Female Ratio Systemic symptoms Absent Present Clinical presentation* Cervical lymphadenopathy Axillary lymphadenopathy Abdominal lymphadenopathy Mediastinal lymphadenopathy hepatomegaly Splenomegaly Bulky Disease No Yes Mediastinal Peripheral node No. of Nodal Regions <4 4 Stage I II III IV Risk Groups LR IMR HR White Blood Cells (10 3 /mm 3 ) 13.5 >13.5 Hemoglobin Level (g/dl) 11gm <11gm Serum Albumin (g/dl) 4gm <4gm Histological subtype Mixed cellularity Nodular sclerosis Lymphocytic rich All Patients (n=34) 4-16 y. 8.5 y. ± 3 8Y. 20(60%) 14(40%) 1.43:1 13(38.2%) 21(61.8%) 29(85.3%) 17(50%) 16(47.1%) 10(28.6%) 5(14.7%) 6(17.6%) 25(73.5%) 9(26.5%) 6(66.7%) 3(33.3%) 15(44.1%) 19(55.9%) 4(11.8%) 16(47.1%) 12(35.3%) 2(5.8%) 6(17.6%) 18(53%) 10(29.4%) 30(88.2%) 4 (11.8%) 16(47.1%) 18(52.9%) 15(44.1%) 19(55.9%) 26(76.5%) 5 (14.7%) 3 (8.8%) Survival analysis: The 3-years OS and EFS rates (± SE) were 91.2% ± 5.3% and 82.3% ± 7.3% respectively (Fig 1, 2). Factors affecting OS and EFS are shown in table (3). For patients with low, intermediate and high

4 Ghazaly et al. SECI Oncology 2014 Page 4 of 8 risk groups, 3-year OS were %, 94.4% ± 5.4% versus 80% ± 13.4% respectively (p=0.07) and 3-year EFS were %, 94.4% ± 5.4% versus 50% ± 17.4% respectively (p=0.005) (Fig 3, 4). For patients with B symptoms, 3-year EFS and OS were 71.4% ± 10.5%, 85.7% ± 7.9% respectively compared with patients without B symptoms % (p=0.048), % (p=0.21). 3-year EFS and OS for patients without bulky disease were 92% ± 5.8%, 96% ± 3.9% respectively which differ than those with bulky disease 55.6%± 17.3% (p=0.025), 77.8%± 15.3% (p=0.054). For patients without extra nodal extension, 3-year EFS and OS were 96%± 3.9%, % respectively that significantly differ than with extra nodal extension 44.4%± 16.6% (p=<0.001), 77.8%± 14.8% (p=0.02). The 3-year EFS for patients with stage I, II, III and IV was %, 93.8%± 6.1%, 75%± 12.5% and 0% respectively with significant difference in between (p= 0.007). Patients without leukocytosis had 3-year EFS and OS of 90% ± 11.6% and 93.3%± 5.2% compared with patients with leukocytosis 25%± 21.7% (p=0.006) and 75%±21.7% (p=0.391), 3-year EFS and OS for patients without lymphopenia 87.1%± 7.1%, 96.7%±3.2% respectively, compared with those with lymphopenia 33.3%± 21.2% (p=0.019) and 0.333± 21.2% (p=0.004). Three-year EFS for patients without anemia % is significantly better than those with anemia (66.7%±12.8%) (p= 0.018), 3-year EFS for patients with normal ESR is significantly better than with high ESR (p= 0.031) (95%± 4.9% versus 64.3%± 14.8%) and 3-year EFS for patients without hypoalbuminemia is significantly better than with hypoalbuminemia (p=0.018) (% versus 66.7%±12.8%). Multivariate analysis revealed that the significant independent factors for inferior EFS were "B" symptoms (p=0.047, HR: 2.1, 95% CI: ) and anemia (p=0.025, HR: 3.8, 95% CI: ). However, the significant independent factors for lower OS were hypoalbuminemia (p=0.013, HR: 5.4, 95% CI: ) and anemia (p= 0.048, HR: 2.6, 95% CI: ). Fig (2): Event Free Survival (EFS) in 34 HL patients Fig (3): Overall survival distributions by risk groups Fig (1): Overall Survival (OS) in 34 HL patients Fig (4): Event-free survival distributions by risk groups

5 Ghazaly et al. SECI Oncology 2014 Page 5 of 8 Table (3): Factors Affecting the Overall Survival (OS) and Event Free Survival (EFS) Variable 3-Year OS 3-Year EFS % SE (%) P value % SE (%) P value Risk Group Low Intermediate High Stage I II III IV Extra nodal Involvement Absent Present Systemic Symptoms Absent Present Bulky Disease Absent Present Leukocytosis (10 3 /mm 3 ) 13.5 >13.5 Lymphopenia (10 3 /mm 3 ) 600 >600 Hemoglobin Level (g/dl) 11 <11 ESR (mm/h) <50 50 Serum Albumin (g/dl) 4 gm <4gm Discussion Hodgkin lymphoma is a neoplasm in which survival and cure has improved dramatically over the 50 years with survival rate reaching 94%. Because cure is likely for the majority of children and adolescents presenting with HL, attention to long-term treatment complications has become increasingly important. Risk-adapted combined modality treatment protocols, which assign intensity of therapy according to risk features at diagnosis have become a standard treatment approach for pediatric malignancies that are highly curable with contemporary therapy while reducing therapy-related complications [8]. In the current study, the median age was 8 years which is less than that reported by El Badawy et al [8] and Ebeid et al [9] and similar to median age reported by Gao et al which was 7.7 years [10] this may be explained by the different number of patients reported in these studies: 121 patients in El Badawy et al, 27 patients in Ebeid et al. The majority of patient's age was found below 10 years (64.7%) which was in agreement with Gao et al [10] which was 71.4%, but less than that reported by Kelly et al [11] with most of patient's age above 10 years (89.8%). This can be explained by effect of low socio economic status, large family size and high incidence of EBV infection in our developing countries. There is slight predominance of males in our study (1.4:1) similar to that reported by Hudson et al [2] and Ali et al [12] but lower than the ratio reported by El Badawy et al [8]. In our study, the clinical presentation of nodal disease is comparable to what was reported in the literature as cervical lymphadenopathy was the most predominant site reported in (85.3%) followed by axillary, abdominal and mediastinal involvement which is also in agreement with other studies reported by El Badawy et al [8] and Kelly et al [11]. Extra nodal involvement occurred in 9 patients (26.5%) which in agreement to what was reported by Hudson et al [2]. 61.8% of patients had systemic "B" symptoms which is comparable to Schwatez et al [7] and El Badawy et al [8]. Bulky disease was seen in 9 patients (26.7%) (mediastinum in 6 patients and peripheral lymph nodes in 3 patients) which is similar to Ali et al [12]. Regarding the stage, 73.2% of our patients had an advanced stage disease, this is in agreement with what

6 Ghazaly et al. SECI Oncology 2014 Page 6 of 8 was reported by Schwartz et al [7] and Ebeid et al [9]. The majority of patients (58.8%) had 4 regions which is similar to Kulyova et al [13], and unlike what's reported by Morais et al [14]. The distribution of risk groups of our study was 17.6% in LR, 53% in IMR and 29.4% in HR group which was similar to Gao et al [10] and differ from the results reported by Ali et al [12]. Although nodular sclerosis histological subtype was reported to be the predominant histological subtype by Hudson et al [2] and Kelly et al [11]. In the current study, the mixed cellularity subtype form the predominant type (76.5%) followed by nodular sclerosis subtype and lymphocytic predominant subtype which is similar to El Badawy [8], Gao et al [10] and Ali et al [12]. Bazzeh et al [15] reported that mixed cellularity subtype was more prevalent in children less than 10 years old, but less likely in older children/adolescents which is in agreement with our study with the majority of patient's age was found below 10 years. The explanation of high prevalence of mixed cellularity subtype may be explained by increased risk factors in developing countries rather than developed countries which also can explain the high frequency of advanced stages and "B" symptoms which is associated with mixed cellularity subtype other than nodular sclerosis subtype. Leukocytosis recorded in 4 patients (11.8%) which is slightly less than that was reported by Hudson et al [2] and Smith et al [16]. Elevated ESR was found in 41.2% which is in agreement with Hudson et al [2] but Morais et al [14] found that the majority of patients had elevated ESR level 69.5%. Anemia occurred in 19 patients (55.9%) which is much higher than reported by Hudson et al [2], Morais et al [14] and Smith et al [16]. This may be due to associated malnutrition and low socioeconomic level in our country. Early response was reported in 12 patients (35.3%) 83.3% in LR, 35.3% in IMR and 10% in HR group which is higher than that reported by Hudson et al [2] and lower than that reported by Ali et al [12]. There were 5 treatment failures, either initial disease progression (9.1%) or relapse (6.7%) which is less than reported by El Badawy et al [8] and Krasin et al [17] and much lower than reported by Hudson et al [2] and Ali et al [12]. The difference may be related to number of patients in those studies. Combination chemotherapy is used alone or followed by low-dose involved field radiotherapy (IFRT) [16]. It had been evaluated by European and American investigators, in the most recent GPOH-HD 2002 study, the German investigators confirmed the efficacy of the OPPA/OEPA chemotherapy regimens and aimed to further decrease treatment intensity by omitting radiation therapy in patients with favorable risk only who achieved complete remission after chemotherapy [18]. In the United States, CCG-5942 results indicated a higher number of relapses in the group of patients who were not irradiated, patients with complete response who were randomized to receive radiation had superior disease control compared to patients randomized to no irradiation (3 year EFS 92% versus 87%) [19]. Also in COG- AHOD0431 with response-based therapy revealed lower EFS in patients of favorable risk with CR who didn't receive RT than patients with PR who received RT (2- year EFS 80% versus 88%) and they suggest that response to Chemotherapy alone not adequate to identify patients can be treated without RT after abbreviated chemotherapy [20]. Three years OS and EFS (± SE) were 91.2% ± 5.3% and 82.3%± 7.3% respectively. There is no significant difference in 3-year OS for patients with LR, IMR and HR groups (p=0.07), but 3-year EFS for patients with LR and IMR groups is significantly better than HR group (p=0.005) (%, 94.4%± 5.4% versus 50%± 17.4%). The 3-year OS and EFS of LR group in our result was (% and % respectively) which is comparable with Ali et al [12], Nachman et al [19] and Donaldson et al [21]. In our study, the 3-year OS and EFS of IMR group was 94.4%± 5.4% and 94.4%± 5.4% respectively which is in agreement to the result of El Badawy et al [8], Ali et al [ 12] and Ruhl et al [22]. Three-year OS and EFS 80%± 13.4% and 5%± 17.4% for HR group in the current study which is higher than what was reported by Gao et al [10] and Ali et al [12] and less than which was reported by Mauz- Korholz et al [18]. Univariate analysis of prognostic factors of OS and EFS revealed that there was significant influence of advanced stage, extra nodal involvement, "B" symptoms, bulky disease, leukocytosis, lymphopenia, anemia, hypoalbuminemia and elevated ESR on inferior EFS while this was not translated into significant affection of the OS except for extra nodal involvement and lymphopenia. In Egypt, Ali et al [12] reported that many factors greatly affect EFS and OS which were histology, "B" symptoms, disease bulk and response to therapy but Smith et al [16] reported that there were many factors affecting OS and DFS as stage, histology, "B" symptoms, bulky disease, number of nodal regions, leukocytosis, anemia and elevated ESR. There are multiple prognostic factors identified in selected multi-institutional studies, In the Stanford/St. Jude/Dana Farber Cancer Institute consortium, male gender; stage IIB, IIIB, or IV disease; white blood cell count of 11,500/mm 3 or higher; and hemoglobin lower than 11.0 g/dl were significant prognostic factors for inferior disease-free survival and overall survival (OS) [16], in the Society for Paediatric Oncology and Haematology (GPOH-95) study, "B" symptoms, histology, and male gender were adverse prognostic factors for EFS on multivariate analysis [23]. In the Children Cancer Group (CCG-5942) study, the combination of "B" symptoms and bulky disease was associated with an inferior outcome [19], and in St. Jude study, Hudson et al found that only leukocytosis and

7 Ghazaly et al. SECI Oncology 2014 Page 7 of 8 anemia were both associated with worse outcome (p=.046 and p=.003 respectively) [2]. In our study, multivariate analysis revealed that B symptoms (p=0.047, HR: 2.1, 95% CI: ) and hemoglobin <11gm (p=0.025, HR: 3.8, 95% CI: ) are the significant independent factors for inferior EFS. In Egypt, Ali et al [12] found that lymphocytic depletion pathological subtype was the only significant predictor of lower EFS and El- Badway et al [8] reported that only statistically significant prognostic indicator for OS and DFS was the relation between the DFS and the initial response to chemotherapy. OPPA OS PD PR REAL/WHO SD SE SECI TFT Oncovin, procarbazine, prednisone, and adriamycin. Overall survival. Progressive disease. Partial response. Revised European American Lymphoma classification/ World Health Organization. Stable disease. Standard error. South Egypt Cancer Institute. Thyroid function test. Conclusion Treatment results of HL in pediatric oncology department, SECI, Assiut University using risk-adapted combined-modality therapy with ABVD/COEP and IFRT has high efficacy with minimal toxicity. "B" symptoms and anaemia were the significant independent factors for lower EFS but hypoalbuminemia and anemia were significant factors for inferior OS. Conflict of Interests The authors declare that they have no conflict of interests. Authors Contribution All the work was done by the corresponding author under supervision and guidance by the remaining authors. Abbreviations ABVD Adriamycin, bleomycin, vinblastine, and decarbazine.. CBC Complete blood count. CCG Children cancer group. CI Confidence interval. COEP Cyclophosphamide, vincristine, etoposide, prednisone. COG Children s Oncology Group. CR Complete response. CT Computed tomography. EFS Event-free survival. ESR Erythrocytic sedimentation rate. GPOH German paediatric oncology and haematology. Gy Gray HL Hodgkin lymphoma. HR High risk. ICE Ifosfamide, carboplatin and etoposide. IFRH Involved field radiotherapy. IMR Intermediate risk LDH Lactic dehydrogenase. LR Low risk. OEPA Oncovin, etoposide, prednisone, and adriamycin. References [1] Pacquement H, Landman-Parker J, Leblanc T, Habrand JL, Terrier-Lacombe MJ, Bertrand Y, Perel Y,Robert A, Coze C, Thuret I, Donadieu J, Schaison G, Leverger G, Lemerle J and Oberlin O.: Localized childhood Hodgkin s disease: Response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy Results of the French Society of Pediatric Oncology Study MDH90. J Clin Oncol, : p [2] Hundson MM, Krasin M, and Link MP, Donaldson SS, Billups C, Merchant TE, Kun L, Billet AL, Kaste S, Tarbell NJ, Howard S, Friedmann AM, Hurwitz CA, Young JA, Marcus KC, Rai S, Cowan T and Weinstein HJ: Risk-adapted, combined- Modality therapy with VAMP/ COP and response- based, Involved- field radiation for Unfavorable Pediatric Hodgkin's Disease. Journal of Clinical Oncology, (22): p [3] Eberle FC, Mani H and Jaffe ES: Histopathology of Hodgkin s Lymphoma. Cancer J, (2009). 15: [4] Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA and Tubiana M: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin s disease: Cotswolds meeting. J Clin Oncol, (11): [5] Tsuji SY, Chan LW, Dophne A and Kogan H: Pediatric (non-cns) Trs. In: Handbook of Evidence-Based Radiation Oncology. 2 nd Ed, 2010: [6] Lanzkowsky P: Hodgkin lymphoma. In: Manual of Pediatric Hematology and Oncology, 5 th ed. 2011, [7] Schwartz CL, Constine LS, Villaluna D, London WB, Hutchison RE, Sposto R, Lipshultz SE, Turner CS, Alarcon PA and Chauvenet A: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood, : [8] El Badawy S, Aboulnaga S, Abou Gamal A, Mokhless A, Zamzam M, Sidhom I, Ebeid E and

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