Pediatric Hodgkin Lymphoma; Experience with Euronet Pediatric Hodgkin Lymphoma Protocol in a Developing Country

Research Article

Ann Hematol Oncol. 2018; 5(6): 1214.

Pediatric Hodgkin Lymphoma; Experience with Euronet Pediatric Hodgkin Lymphoma Protocol in a Developing Country

Tariq Ghafoor1,2*, Raheel Iftikhar¹, Imtenan Sharif¹, Tanveer Ashraf², Shakeel Ahmed², Farrah Bashir²

¹Armed Forces Bone Marrow Transplant Centre, Pakistan

²Department of Paediatric Oncology, Pakistan

*Corresponding author: Tariq Ghafoor, Paediatric Oncologist and Bone Marrow Transplant Specialist, Armed Forces Bone Marrow Transplant Centre, CMH Medical Complex, Rawalpindi, Pakistan

Received: September 03, 2018; Accepted: September 24, 2018; Published: October 01, 2018


Objective: To analyse outcome of Paediatric Hodgkin Lymphoma (HL) patients treated with Euronet Paediatric Hodgkin Lymphoma treatment protocol in a developing country.

Patients and Methods: This is a prospective study conducted at Paediatric Oncology department at Combined Military Hospital (CMH) Rawalpindi, Pakistan. All newly diagnosed cases of HL, less than 18years registered from January 2012 onwards that completed their treatment until 30th June 2018 were included. Data regarding age, sex, staging, histopathology and outcome were analysed.

Results: Total 102 patients including 80 (78.4%) males and 22 (21.6%) females were analysed. The mean age was 7.54±2.77 years. B symptoms were present in 58 (56.9%) patients. Ten (9.8%) patients had stage I disease, 33 (32.4%) stage II, 41 (40.2%) stage III and 18 (17.6%) stage IV disease. Mixed cellularity was the commonest histological subtype seen in 74 (72.5%) patients. Involved field radiotherapy was given to 17 (16.7%) patients having inadequate response after 2 cycles of OEPA chemotherapy. Eight (7.8%) patients died of treatment related complications and 10 (9.8%) patients relapsed. Nine of the relapsed (90%) cases responded to 2nd line treatment including one requiring autologous stem cell transplant. One relapsed patient died of progressive disease. Overall Survival (OS) and Event Free Survival (EFS) was 91.2% and 82.4% respectively.

Conclusion: In Pakistan, mixed cellularity is the commonest HL subtype seen in young males. Long duration of disease before presentation, malnutrition, presence of B symptoms, bone marrow and lungs involvement and advanced disease is associated with decreased OS and EFS.

Keywords: Hodgkin lymphoma; Treatment outcome; Developing country; Pakistan; Euronet PHL protocol


Treatment of Paediatric Hodgkin Lymphoma (PHL) is one of the important success stories of the previous century. Treatment protocols of PHL have evolved over many years with a consideration of reduction of acute and long-term toxicity of chemotherapy and radiotherapy. Initial treatment protocols incorporated unacceptably high radiation doses for children.

In the study GPOH-HD 95, radiotherapy was restricted to patients not in complete remission after chemotherapy [1]. Current treatment protocols are based upon a risk-based and response-adapted approach in which patients receive multi-agent chemotherapy with or without low-dose involved-field or involved-site radiation therapy [2].

Most European centres are following protocols formulated by European Network for Paediatric Hodgkin Lymphoma (EuroNet- PHL) while the Paediatric Oncology Group and Children’s Cancer Group have merged to form the Children’s Oncology Group (COG), widely practised in North and South America. In developed countries, the 5-year survival rate of PHL increased from 81% to more than 95% between 1975 and 2010 [3]. However, survival in developing countries is still significantly lower, because of late presentation, abandonment of therapy and inadequate supportive and critical care [4-6]. Data of few published studies from Pakistan shows overall survival ranging from 76% to 84% [7]. There is no uniform protocol for treatment of PHL in Pakistan. We conducted this study using treatment as per The EuroNet-PHL-C1 protocol.

Materials and Methods

This is a prospective on-going study being carried out in the department of Paediatric Oncology at Combined Military Hospital Rawalpindi, Pakistan. The hospital ethical committee approved the study and informed consent was obtained from parents of the patients. Data collection was started in January 2012. All newly diagnosed patients with histologically confirmed primary diagnosis of classical HL, less than 18 years of age were included in the study. Patients having prior chemotherapy or radiotherapy for other malignancies, pre-treatment of HL, (except for 7-10 days steroid pre-phase of a large mediastinal tumor), diagnosis of lymphocyte-predominant Hodgkin’s lymphoma, post-transplant Hodgkin lymphoma and patients abandoning the treatment, were excluded from the study.

Detailed medical history, clinical examination, excision biopsy of the involved lymph node for histopathology and immunohistochemistry, echocardiography, LDH, ESR and baseline chemistry was performed for all patients. All the patients were weighed at the time of admission before start of the chemotherapy. The weight was recorded in kilograms and plotted on the standard WHO Z-score chart for age and sex. The patients were categorized as No Malnutrition, Moderate Malnutrition and Severe Malnutrition if they had Z score >-2, between =-2 to >-3 and =-3 respectively.

The disease was classified as per World health organization 2008 classification of HL. For staging purpose, Contrast Enhanced Computed Tomography (CECT) of neck, chest, abdomen, pelvis was done in all cases. Bulky disease was considered when the lymph node was 7 cm or more in size on CT, or when the mediastinal mass occupied more than one-third of the chest diameter. Because of limited availability, Positron Emission Tomography (PET) scanning was done in few cases. All patients with a stage >IIA had bilateral bone marrow aspiration and trephine biopsy. Ann Arbor staging with Cotswolds modification was used for staging purpose.

Eligible patients received chemotherapy as per EURONET-PHL protocol 2006 and were stratified into three Treatment Groups (TG). TG-1: patients of stages IA/B & IIA without bulk and without ESR =30 mm/hr, TG-2: patients of stages IEA/B, IIEA, IIB or III A and patients of stages IA/B and IIA with bulk and/or =30 mm/hr and TG-3: patients of stages IIEB, IIIEA/B, IIIB or IVA/B. All patients received 2 cycles of OEPA (Vincristine, Etoposide, Prednisolone, and Adriamycin) chemotherapy. Patients in TG-1 had no further chemotherapy while patients in TG-2 and TG-3 had two and four courses of COPDAC (Cyclophosphamide, Vincristine, Prednisolone, Dacarbazine) chemotherapy respectively. After two courses of OEPA chemotherapy response assessment was done with CECT scan or PET scan.

Patients with Inadequate Response (IR) received involved field radiotherapy after the end of chemotherapy. Radiotherapy dose was 19.8 Gy to all initially involved fields. Those patients with a poor response (less than 75% reduction of tumor volume in some areas or a residual mass of more than 100 ml) received another 10 Gy boost to these regions. Patients were followed up three monthly in first 2 years, four monthly in third year and six monthly in fourth and fifth year after achieving remission. Patients having relapsed or refractory disease had 2nd line chemotherapy; ABVD (Doxorubicin, Bleomycin, Vinblastine and Dacarbazine) and IEP (Ifosfamide, Etoposide and Prednisone) chemotherapy.

Supportive care

All patients were hospitalized for the initiation of chemotherapy. Subsequent chemotherapy was given as inpatient or in day care as outdoor cases. Outdoor cases were admitted immediately in case of fever or any other problem. Patients not admitted in the hospital were reviewed at least twice weekly in outdoor clinics. No prophylactic antimicrobials and colony stimulating factors were used during neutropenic period. However, all cases of febrile neutropenia were treated as inpatient with broad-spectrum intravenous antibiotics. Fever was defined as a single oral temperature of >38°C or 2 readings >37.5°C at least 2 hours apart. Neutropenia was defined as Absolute Neutrophil Count (ANC) of < 1000 cells per microliter. Febrile patients with ANC < 1000 were treated with a combination of Pipracillin-Tazobactam and Amikacin. Vancomycin or Teicoplanin were added if central venous line infection was suspected. Pipracillintazobactam was swapped with Meropenam if fever continued after 48 hours. Amphotericin B was added empirically if fever continued beyond 96hours.

Blood and blood products transfusion was given on regular basis. Haemoglobin transfusion threshold was 8.0g/dL. Thresholds for Platelet transfusion were 10x109/L for asymptomatic patients, and 20x109/L for febrile patients.

Statistical analysis

Survival analyses were performed using the Kaplan-Meier method in SPSS 22. Chi-square test was applied and frequencies and percentages calculated. Relapse-Free Survival (RFS) was defined as the time from completion of treatment until progression of disease or relapse (RFS). Overall Survival (OS) was defined as the time from the date of diagnosis till last follow-up or death from any cause (OS). Log rank tests were used to compare survival differences. P = 0.05 was considered statistically significant.


During the study period, total 102 new patients of Hodgkin lymphoma were enrolled in the Paediatric oncology department at Combined Military Hospital Rawalpindi. Age at diagnosis ranged from 2.5 to 15 years and the mean and median age was 7.54 (± 2.77) years and 7.0 years respectively. Majority of cases, 60 (58.8%) were between 5 and 10 years of age. There were 80 (78.4%) males and 22 (21.6%) females. There were 76 (74.5%) well-nourished and 26 (25.5%) under-nourished children. The mean duration between symptom onset and consultation of oncologist was 8.97 ± 8.65 months (range from 1.0 to 48 months. Cervical lymphadenopathy was the most common presentation seen in 85 (83.3%) cases. Twenty (19.6%) patients received anti-tuberculosis treatment for variable duration before being referred to pediatric oncologist. Mixed cellularity was the most common histological subtype seen in 74 (72.5%) cases followed by nodular sclerosis in 23 (22.5%) cases. Immunohistochemistry demonstrated CD 30 positivity in 91 (89.2%) patients and CD 15 positivity in 50 (49%) patients. Demographic characteristics of the study group are summarized in (Table 1).