Laboratory tests included a complete blood count, erythrocyte sedimentation rate (ESR), liver and renal chemistries, serum lactate dehydrogenase (LDH). The clinical and laboratory findings evaluated for prognostic significance on event-free survival (EFS) and overall survival (OS) were: Age, gender, stage (I-II vs. III-IV), histology, presence of mediastinal bulky disease (a mediastinal mass of >one third of the transthoracic diameter on an upright chest radiograph) and/or peripheral bulky disease (peripheral lymph node of >6 cm in maximal axial diameter), presence of B symptoms, number of involved nodal areas (<3 vs. ≥3), hemoglobin level (<11 g/dl vs. ≥11 g/dl), WBC (<13.500/mm³ vs. ≥13.500/mm³), ESR (<20 mm/h vs. ≥20 mm/h), serum lactate dehydrogenase level (LDH: <500 IU/L and ≥500 IU/L) and type of chemotherapy (GPOH 90 vs. COPP-ABVD based regimen). Presence of extranodal disease was not included in this analysis because of small number of patients. The number of the patients with other histological types was small, so histology was analyzed as nodular sclerosis (NS) vs. mixed cellular (MC) subtype only.

Treatment protocol
The primary chemotherapy regimens according to the stages are shown at table 1. The chemotherapy regimens were COPP (cyclophosphamide, vincristine, prednisone, procarbazine) or MOPP (mechlorethamine, vincristine, prednisone, procarbazine) and/or ABVD (adriamycin, bleomycin, vincristine, dacarbazine) based in 24 patients (63%). Since 1989, we used standard COPP/ABVD based regimens, and then we started to treat our patients according to the GPOH 90 protocol [8] in 1997. Thirteen (31.5%) patients received GPOH 90 regimen until 2000. However, five out of these 13 (39%) cases experienced relapse including three early relapses (≤18 months). Therefore, we returned to use the COPP/ABVD-based regimens after 2000. Only one patient with an early stage nodular lymphocyte- predominant HL received CHOP regimen.

Table 1: The primary chemotherapy regimens according to the stages

In our pediatric HL treatment protocol, low dose (1980- 2520 cGy) radiotherapy was administered in patients with complete response after chemotherapy. When there was initial bulky disease, 540 cGy boost dose was given to the bulky site. Doses higher than 3060 cGy were delivered to patients having residual disease after chemotherapy or progressive disease. Dose levels up to 4140 cGy were tailored according to the response to initial chemotherapy. Radiotherapy was delivered with megavoltage units (6 MvX or Co60) to the involved field in early or to the bulky site in advanced stage patients. Parallelly opposed, antero-posterior isocentric fields were simulated in all patients and critical structures were shielded with individual cerrobend alloy blocks. 1980 to 4140 cGy was delivered with 180 cGy per fraction to the reference isodose encompassing the treatment volume calculated in computerized treatment planning system. The whole lymphatic region of initially involved lymph node was irradiated in early stage patients.

Statistical analysis
EFS was determined from the date of diagnosis to the date of event (relapse, progression, death, or the most recent follow-up examination). OS was calculated from the initiation of the treatment to the date of death or was censored at last follow-up. Clinical factors at diagnosis were investigated with univariate analysis using log rank test. Kaplan-Meier product-limit method was used to determine survival probabilities for both EFS and OS at 5 and 10 years. All calculations were performed with SPSS version 11.0 statistical software.

There were 51 children and adolescents with HL. Thirteen patients were excluded due to following reasons: patients who had been still on anticancer treatment (n:4), patients who were admitted because of relapse HL (n:2) or primary resistant disease (n:1), patients whose diagnosis and/or some part of the treatment protocol was given elsewhere (n:1), patients who had to complete part of their treatment in other centers (n:5).

A total of 38 patients were included in the analysis. The median age was 10 years (range: 2-18 years) and there were 24 boys and 14 girls, and the M:F ratio was 1.7. The most common histological subtype was nodular sclerosis (55.3%) followed by mixed cellular (31.6%). Twelve patients had B symptoms (31.6%). There were 23 patients (60%) with Stage I-II and 15 patients (40%) with Stage III-IV disease. Some patient characteristics are shown at table 2.

Table 2: Some clinical and demographic characteristics of study population

The number of involved lymph node regions was <3 in 22 (58%) patients, and ≥3 in 16 cases (42%). The most common nodal sites involved were cervical (n:32, 84%) and mediastinal (n:27, 71%). Five of 38 (13%) children had extranodal disease at diagnosis. Anatomical locations involved were lungs (n:3) and liver (n:2). Bulky disease was present in 25 (66%) patients during the diagnosis. Nine (36%) of them had mediastinal and 12 (48%) had peripheral bulky disease, and four (16%) patients had both mediastinal and peripheral bulky disease. Five (13%) of 38 children had extranodal disease at diagnosis. Anatomical locations mostly involved were lungs (n:3) and liver (n:2).

The number of chemotherapy courses according to the stage were as follows: 2-4 courses for stage I-IIA patients (n:20), 4-6 courses for stage IIB-IIIA patients (n:9), 6-8 courses for stage IIIB-IV patients (n:9).

All patients except one stage IVSB were irradiated initially with doses between 1980 to 3960 cGy to the primary site.

Relapse patterns
There were nine treatment failures. One patient with Stage IVsB HL developed refractory disease. There were eight patients (21%) who developed relapse in this study group. The time to relapse was the first 18 months (9-18 months) for 5 patients and 55, 74, 77^th month of diagnosis for the other three cases. Table 3 shows some clinical features and treatment details for patients with relapse disease. Among these, one patient (patient no:8) had only a true infield recurrence in the irradiated site. He was initially staged as IB left cervical disease. He recurred at the initial site despite 3600 cGy bilateral cervical and 3960 cGy to the left cervical area. He is alive after 6 cycles of COPP without evidence of disease.

Table 3: Some clinical features and treatment details for patients with relapsed disease

Patient no:3 had a mediastinal recurrence just on the lower border of the treatment field. Before this marginal relapse, he was initially irradiated to the cervical and mediastinal area with a dose of 3400 cGy. He is in complete remission after 6 cycles of chemotherapy.

In another patient (no:5) with stage IIA, infield mediastinal relapse was associated with an outfield axillary relapse after 2520 cGy of modified mantle, including cervical, supraclavicular and mediastinal lymphatics. He remains in complete remission after 3 cycles of COPP and 3 cycles of ABVD.

One patient (no:7) with Stage IIIA HL, lymphocyte predominant histology experienced two relapses. He was initially treated with 5 cycles of chemotherapy followed by mantle and para-aortic (2520 cGy) radiotherapy. The first relapse (para-aortic at the irradiated and pelvic-spleen at the unirradiated site) was at 30th month of diagnosis and he reached CR with salvage therapy including ABVD [3]/ COPP [3] and pelvic 3060 cGy RT. He remained in continuous complete remission since he developed a second relapse at 6th year of diagnosis where autologous bone marrow transplantation (ABMT) was done after achieving a partial response with second salvage treatment. However, he eventually died with progressive disease.

Cervico-mediastinal radiotherapy at a dose of 2520 cGy was effectuated to the patient no:6 after 3 cycles of chemotherapy. He also received 900 cGy boost dose to the bilateral cervical region. He had infield supraclavicular and outfield axillary relapse. He is alive with complete remission after 6 cycles of ABVD and axillary radiotherapy.

Patient no:4 with stage IVsB was not initially irradiated because of inexistence of bulky disease. She had cervical, mediastinal and para-aortic recurrence after 8 cycles of chemotherapy. She received 3 cycles of ABVD, mantle and inverted Y irradiation and ABMT as salvage treatment and is in complete remission.

In patient no:1 with stage IVA, mediastinal and paraaortic irradiation was planned after 8 cycles of chemotherapy. She experienced an abdominal relapse during the mediastinal irradiation. After accelerating the mediastinal irradiation, the patient received chemotherapy and paraaortic radiotherapy as salvage treatment. She is alive with complete remission.

The last patient (no:2) with initial stage IIIsA received 2520 cGy cervico-mediastinal radiotherapy after 4 cycles of chemotherapy. He had para-aortic and splenic recurrence and after splenectomy he received 6 cycles of chemotherapy and para-aortic radiotherapy.

Survival rates
Median follow-up time was 105 months (range: 3- 186). The 5-year EFS and OS rates for the whole study group were 77% and 96%, respectively (Figure 1). The 10-year EFS and OS rates were 73% and 92%, respectively. The prognosis for early disease (Stage I-II) vs. advanced disease (Stage III-IV) patients was as follows:

Fig 1: OS and EFS for the whole study group

- Stage I-II patients: EFS was 90%, and 82%, at 5 and 10 years, respectively. OS was 100% at both 5 and 10 years (Figure 2).

Fig 2: OS and EFS in Stage I-II vs. Stage III-IV disease

- Stage III-IV patients: EFS was 59 % at 5 and 10 years. OS was 92% at 5 year and 81% at 10 year (Figure 2).

Univariate analysis
None of the pretreatment prognostic factors was found significant (p >0.05) for EFS and OS.

The EFS and OS rates also did not show any signifi- cant difference between Stage I-II disease and Stage IIIIV disease (p=0.09 and p=0.10, respectively) (Figure 2). Moreover, there was no significant difference between the OS and EFS rates of patients who received GPOH 90 regimen and COPP-ABVD based regimens (p=0.55 and 0.11, respectively) (Figure 3).

Fig 3: EFS according to the therapy regimen (COPP-ABVD based vs. GPOH 90)

Late Effects
Only one patient developed therapy-related AML after ABMT. Another patient developed two osteochondromas; one within and one outside the RT field. None of the patients experienced pulmonary or chronic cardiotoxicity. A male patient is infertile due to procarbazine. Two female patients gave birth to healthy children.

The incidence rates for 1073 children with lymphoma and solid tumors registered to the Turkish Pediatric Oncology Group (TPOG) Pediatric Tumor Registry 2002 revealed that lymphomas (26.8%) were the most common pediatric malignant disorder excluding leukemias, followed by CNS tumors (21.1%) [10]. The data including childhood leukemias was only available after the collaboration of the Turkish Pediatric Oncology Group (TPOG) and Turkish Pediatric Hematology Associations in 2005. The national data from these two associations showed the distribution of the most common cancer types in 1435 children as follows; leukemia 27.2%, lymphomas & reticuloendothelial system (RES) 16.7% (Hodgkin’s lymphoma 9.9%), CNS/intracranial/intraspinal 11.6% [11]. These results were consistent with a developing country pattern. The incidence of lymphoma tends to be higher in the Middle East Cancer Consortium (MECC) countries than in Europe [12]. However, our own data showed similar figures with the developed countries [9]. Although we didn’t have an analysis on socio-economic status of this patient population, this striking difference can be explained with different socio-economic and cultural profile of our patients or may be due to some genetic differences. In accordance with our incidence rates, the results from the İzmir Cancer Registry shows that the childhood cancer patterns in İzmir region mostly resembles the western population’s figures; leukemias (30.6%) followed by CNS tumors (21.3%), and lymphomas (15%) were the most common malignant diseases in İzmir [7]. In our region, besides the ranking of tumors, the total and site specific incidence rates are very close to the developed countries [12,13].

The median age of our patients was 10 years. The most recent data on pediatric HL in Turkey showed a median age lower (8 y) than in developed countries [6]. Previously published data from the other regions of Turkey were also consistent with this result (Table 4). We had only four patients (10%) younger than 5 years of age during the initial diagnosis. In other series from Turkey, this ratio was higher: 29.7% was ≤ 5 years of age; 17.6% was <5 years of age and 32.3% was <7 years of age, respectively [3-5]. Reports from other developing countries show that pediatric HL occurs at a younger age with as many as 15 to 30% of cases occurring before 5 years of age, against some 5% in developed countries [1,8,14-17]

Table 4: Epidemiologic and histopathologic data from some Turkish pediatric HL series

In this study group, M:F ratio was 1.7:1. The other series reported a higher M:F ratio up to 5.3 (Table 4). Pediatric HL presents a slight male predominance in Western countries with an M:F ratio close to 1.5:1. However, there is a large male excess in less economically developed countries, with an M:F ratio between 2.5:1 and 5:1 [1].

In contrast to the general national figures as well as the data from other developing countries, which all showed a MC predominant histopathologic subtype, the predominance of NS (NS) histology (55%) was the most prominent feature of our study population. However, 31% of our cases had MC histology, a proportion higher than the incidence observed at the developed countries [9,18,19].

Distribution of HL cases over age, gender, geographical areas and socio-economic settings have long suggested multiple etiologically distinct entities for HL, rather than a single disease. The prevalent type in developing countries is the MC histological subtype, predominates in young children, particularly in males, mostly presents as advanced stage disease. These features could be partly explained by the hypothesis of an etiologic role of EBV in the pathogenesis of HL. Studies have shown a causal relationship between infectious mononucleosis and subsequent Epstein-Barr virus (EBV)-positive HL [20-25]. Çavdar et al. [3] showed the high frequency of EBV-related LMP-1 positivity (73.6%) in pediatric HL cases. Childhood Hodgkin’s lymphoma in developed countries affects mainly older children, mostly presenting as NS histological subtype and might be explained with a delayed exposure to common infectious agents as there is an increased male susceptibility to viral and bacterial infection in childhood, which is more marked in the first five years of life [1,18].

Most of the data coming from the other centers, as well as the TPOG data including 1823 children from 22 different centers from all over the country is consistent with a developing country pattern of HL (type I) characterized by a high incidence of MC histological subtype, a younger median age and a male predominance (Table 4). Our data, reflecting the figures from the extreme west part of our country was more consistent with the data from affluent countries [18,26-29]. The higher socio-economic and cultural status of this geographical area may be a contributing factor for this striking difference.

Nine patients had (23%) treatment failures in our study, one of them being resistant disease (Table 3). This patient with Stage IVsB HL with extensive pulmonary metastasis during the initial presentation developed resistant disease after 6 courses of COPP. She received three courses of ABED (Adriamycin, Bleomycin, Etoposide, Dacarbazine) and mediastinal radiotherapy, followed by BEAM protocol (Carmustin, Etoposide, Ara-C, Melphalan) and autologous stem cell transplantation. She reached complete remission but developed therapy related AML at 39th month of ABMT and died with progressive disease.

Five of these relapse cases had NS histology. They all initially achieved complete remission but relapsed at a median of 18 months. Four relapses occurred at the primary site (two in the irradiated, two in the unirradiated site), two occurred at both the primary and out-of-primary sites and only one occurred at out of the primary site (Table 3). All relapsed patients, except one with stage IVSB HL, were initially irradiated with doses between 1980 to 3960 cGy to the primary site. It should be noted that these doses were adequate for controlling disease.

The 5-year EFS was 77% and OS was 96% in this patient group. The 10-year EFS and OS rates were 73% and 92%, respectively. Even though it was not statistically significant, EFS and OS rates in advanced disease were lower than in the early stage disease. These survival rates are comparable with some other series from Turkey [4-6]. Although no significance could be shown, The EFS in patients receiving GPOH 90 protocol was lower (5 and 10 year EFS was 55%) than the patients who received COPP/ABVD based regimens (5 and 10 year OS were 100% and 83% respectively). Our results with GPOH-HD 90 protocol were less satisfactory as compared with those reported by DAL/GPOH-HD study groups of OS and EFS 98% and 91% for all stages [8]. Inferior survival rates, compared with the results of the GPOH-HD group, has been reported in Iranian children who also received German- Austrian DAL-HD 85-90 protocol (5 and 16 year OS 94.4% and 88.1%, EFS 79.2% and 75.4%, respectively) [30]. Although the number of patients was not enough to draw a conclusion, one should consider some other poor prognostic factors which could not be shown with this patient size, such as the high number of patients with bulky disease (66%.) There might also be some undetermined histological risk factors such as subtypes of NS histology (NS1 vs. NS2). A recent large scale study from the DALHD- 90 group showed that NS2 histology had a major negative impact on treatment outcome in HL [29]. Another pediatric study from Turkey showed that NS histologic subtype resulted in a significant decrease (p=0.02) in EFS (49.2 months for NS and 72.2 months for the other subtypes), however they did not have any subclassification of NS subtype since it had not been a common practice in pediatric HL [5]. At another center in Turkey, treatment protocol had been tailored according to the histological subtype, long before the industrialized countries have started to search for risk-based treatment regimens: they used to give ABVD+IFRT (involved field RT) for stage I-II patients with NS and lymphocyte depletion subtypes, where other stage I-II patients were given COPP+ IFRT between June1984 and December 1992 [4].

Beside histological subtypes, many other factors could be contributing on the outcome of HL patients. Saunders et al. [19] showed that EFS rate of patients with unfavorable disease was lower in underprivileged countries as compared to that at the industrialized countries, even when the same therapy regimen was used. Each population has its own characteristics, so any therapy regimen resulting in an excellent outcome under given conditions does not necessarily lead to the same outcome under different conditions. Considerable differences have been shown in the distribution of histological types as well as the survival rates of pediatric HL among the regions of Europe [18]. These variables may also be differing within the different geographic regions of a large country.

The outcome of children with HL has greatly improved with 5-year overall survival rates greater than 95%, and 5- year EFS greater than 90% for all stages for the last two decades [1-5]. Treatment results have shown considerable improvement even in developing countries. The main challenge today is finding a balance between maximizing cure and minimizing the late effects [31]. Therefore, emphasis is now on tailoring therapy according to the risk groups which should be based on well-defined prognostic factors. Several study groups from the developed countries have been searching for the efficacy of risk-based therapies using risk factors determined in their own populations [27-29,32-34]. Since epidemiologic and clinicopathologic features of HL show considerable variations even within our country, we need to define our own prognostic factors. This major objective could only be achieved with multicentric national clinical trials.

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