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Risk-based combined-modality therapy of pediatric Hodgkin's lymphoma: A retrospective study
Leukemia Research 34 (2010) 1447–1452
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Risk-based combined-modality therapy of pediatric Hodgkin’s lymphoma: A retrospective study Amany Ali a , Heba Sayed a , Ahmed Farrag a , Mohamed El-Sayed b,∗ a b
Department of Pediatric Oncology, South Egypt Cancer Institute (SECI), Assiut University, Assiut, Egypt Department of Radiation Oncology, South Egypt Cancer Institute (SECI), Assiut University, Al-Mthaq St., 71111 Assiut, Egypt
a r t i c l e
i n f o
Article history: Received 4 December 2009 Received in revised form 12 June 2010 Accepted 13 June 2010
Keywords: Multimodal treatment Childhood Hodgkin’s disease Disease-free survival
a b s t r a c t We conducted a retrospective analysis to investigate the clinical outcome of combined-modality therapy using multiagent chemotherapy and involved-field radiotherapy in treatment of children with Hodgkin’s lymphoma. Fifty eight cases with newly diagnosed Hodgkin’s lymphoma were analyzed. The median follow-up duration was 46 months (range 3–72 months). The 4-year overall and event-free survival rates were 91.5% and 69.7% respectively. High-risk disease (stage IIIB and IV), presence of B symptoms, lymphocyte depletion subtype, bulky disease and late response to chemotherapy were poor prognostic factors. Stage-adapted combined-modality therapy resulted in satisfactory outcome in treatment of pediatric Hodgkin’s lymphoma. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Patients and methods
Treatment for children and adolescents with Hodgkin’s lymphoma often uses a combined-modality approach with multiagent chemotherapy and low-dose involved-field radiotherapy (LDIFRT). This approach has yielded excellent results, with long-term disease-free survival (DFS) of 88–100% in patients with earlystage disease [1,2] and of more than 60% in those with more advanced disease [2]. Because cure is likely for the majority of children presenting with Hodgkin’s lymphoma, attention to long-term treatment complications has become increasingly important [3]. Stage-adapted therapy, which assigns intensity of therapy according to the stage at diagnosis, is a standard treatment approach for pediatric malignancies that are highly curable, as it maintains disease control and reduces therapy-related complications [4]. We report outcomes after a stage-adapted, combined-modality treatment approach for children with Hodgkin’s lymphoma. The goal of the study was to evaluate the efficacy of ABVD chemotherapy regimen (Doxorubicin, Blomycin, Vinblastin, and Decarbazine) alternating with COEP regimen (Cyclophosphamide, Vincristine, Etoposide, and Prednisone) and IFRT, a combined-modality regimen in children with Hodgkin’s lymphoma.
2.1. Study subjects
∗ Corresponding author. Tel.: +20 122953887; fax: +20 882348609. E-mail address: [email protected] (M. El-Sayed). 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.06.012
This retrospective study was carried out in the Pediatric Oncology and radiation therapy Departments, SECI, Assiut University during the period from January 2003 and December 2008. Informed consent was obtained for all patients and the protocol was approved by institutional review board at our center. Eligible patients had histologically confirmed Hodgkin’s lymphoma, and were previously untreated. For each patient, initial staging evaluation was done by history and physical examination; hemogram, erythrocyte sedimentation rate (ESR), routine chemistry profile, chest X-ray, cervical, thoracic, abdomen and pelvis computed tomography (CT) scan with contrast. Bone marrow biopsy was done in patients with stage II–IV disease and in patients with B symptoms. Histopathologic diagnosis was obtained from presenting lymphadenopathy and for uncertain cases; immunohistochemistry using CD15 and 30 was done. Patients were staged by Ann Arbor staging system [5] and histopathologic classification was done according to REAL/WHO classification system [6,7]. 2.2. Treatment schedule Treatment included combination chemotherapy, in the form of ABVD cycle alternating with COEP cycle, with the number of cycles varied according to disease stage. Two alternating cycles were given to patients with stage I–stage II A (low risk group), four alternating cycles to patients with stage IIB–stage III A (intermediate risk group), and six alternating cycles to patients with stage IIIB–stage IV disease (high-risk group). The schedule of administration and dosing were shown in Table 1 [7]. After the second cycle in patients with stage I–stage II A, and those with stage IIB–stage III A (low and intermediate risk groups respectively) and after the fourth cycle in patients with stage IIIB–stage IV disease (high-risk group), patients were evaluated for early chemotherapy response by clinical examination, bone marrow biopsy and CT scan according to the initial presentation. Complete response (CR) was defined as resolution of all tumor-related constitutional symptoms and disappearance of all measurable nodal disease. Partial response (PR) was defined as at least 50% reduction in the sum of the products of two perpendicular diameters of all measurable lesions and disappearance of constitutional symptoms if initially present [8]. After completion of all cycles of chemotherapy, radiation therapy was
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A. Ali et al. / Leukemia Research 34 (2010) 1447–1452 Table 2 Patients’ characteristics.
Table 1 Chemotherapy protocols. Drug
Dose/Route
Day(s)
ABVD protocol Doxorubicin Bleomycin Vinblastin Decarbazin
25 mg/m2 IV 10 mg/m2 IV 6 mg/m2 IV 375 mg/m2 IV
D1, 15 D1, 15 D1, 15 D1, 15
COEP protocol Cyclophosphamide Vincristine Etoposide Prednisone
800 mg/m IV 1.4 mg/m2 IV 100 mg/m2 IV 60 mg/m2 per day PO
D1, 15 D1, 15 D1, 15 D1–15 then gradual withdrawal
ICE protocol Ifosfamide with Mesna Carpoplatin Etoposide
1800 mg/m2 IV 450 mg/m2 IV 100 mg/m2 IV
D1–3 D1 D1–3
2
directed to standardized treatment volumes, involved-field radiation therapy was given to all patients. The radiation dose was 25.5 Gy in 1.5-Gy fractions to all patients with stage IIB–IV disease (intermediate and high-risk groups), initially bulky sites (bulky mediastineal mass was considered if it was more than one-third the intrathoracic ratio measured on an upright postero-anterior chest radiograph, and/or a node aggregate larger than 10 cm in greatest dimension), or sites with a PR, and was 15 Gy in 1.5-Gy fractions to patients with stage I and IIA disease (low risk group), nonbulky sites and with a CR after the first 2 cycles of chemotherapy. Radiation therapy was given using antero-posterior/postero-anterior fields, and started within 4 weeks of last chemotherapy cycle. Gross target volume (GTV) was enlarged lymph node, clinical target volume (CTV) was the anatomical compartment of enlarged lymph node and planning target volume (PTV) was 1 cm margin to CTV. An anterior laryngeal block was used if it does not shield involved nodes in case of radiation therapy to cervical region. If the axillae were to be treated, humeral head blocks were used. Splenic irradiation was used in patients with splenic involvement but renal dose was limited to mean < 10.5 Gy using CT based planning.
Patients’ characteristics
No (%)
Age Median Range
9.5 years 3–15 years
Gender Male Female
36 (62.1%) 22 (37.9%)
Clinical presentation Cervical lymphadenopathy Abdominal lymphadenopathy Mediastinal lymphadenopathy Axillary lymphadenopathy Splenomegally
44 (76%) 24 (41%) 22 (38%) 11 (19%) 6 (10%)
Bone marrow infiltration
11 (19%)
Risk group Low risk (stage I and IIA) Intermediate risk (stage IIB and IIIA) High-risk (stage IIIB and IV)
21 (36.2%) 16 (27.6%) 21 (36.2%)
Histopathology Lymphocyte predominate (LP) Nodular sclerosis (NS) Mixed cellularity (MC) Lymphocyte depletion (LD)
7 (12.1%) 20 (34.5%) 20 (34.5%) 7 (12.1%)
Constitutional symptoms B symptoms A symptoms
26 (44.8%) 32 (55.2%)
Tumor bulk Bulky lymphadenopathy Non-bulky lymphadenopathy
13 (22.4%) 45 (77.6%)
Number of sites of lymphadenopathy Less than 3 sites 3 sites
36 (62.1%) 22 (37.9%)
2.3. After-therapy monitoring After completion of therapy, patients were followed up regularly every 3 months for 1 year, every 6 months for the next 2 years, and annually thereafter. Follow-up examinations included physical examination, chest X-ray, and routine laboratory studies (hemogram, and ESR). CT scans were done at 1 and 2 years off therapy according to initial presentation. Additional imaging procedures were performed as clinically indicated in patients presenting with clinical signs or symptoms suggestive of recurrent disease. Patients with disease relapse were given 6 cycles of salvage chemotherapy, in the form of frontline chemotherapy regimen (ABVD cycle alternating with COEP cycle) was given to patients with disease-free interval (DFI) of ≥12 months and in the form of ICE regimen (Ifosfamide, carbopltin, and etoposide) (Table 1) to patients with DFI of <12 months. After 4 cycles of salvage chemotherapy, relapsed patients were evaluated for response to chemotherapy, by physical examination, laboratory studies (hemogram, and ESR), and CT scans. Assessment for treatment-related organ toxicity was recommended during treatment and after completion of therapy during follow-up. The specific evaluations undertaken included, physical examination of bones and soft tissues, echocardiogram and ECG for all patients, and menstrual cycle history in pubertal girls. 2.4. Statistical methods The study cutoff point was December, 2008. Event-free survival (EFS) was defined as the interval from enrollment of patients to the date of first event (relapse, progression, or death from any cause) or to the date of last follow-up. Overall survival (OAS) was defined as the interval from enrollment to the date of death from any cause or to last follow-up. Event-free survival and OAS rates were estimated using Graphed prism program. The Log-rank test was used to examine differences in EFS and OAS rates. Cox-regression multivariate analysis was done to determine the independent prognostic factors affecting survival.
stage I and IIA (low risk group) in 21 patients (36%), stage IIB and IIIA (intermediate risk group) in 16 patients (28%), and stage IIIB and IV (high-risk group) in 21 patients (36%). Twenty six patients presented with B symptoms (44.8%). Thirteen patients (22%) had bulky disease. Sites of bulky disease included mediastinum in 7 patients (12%) and lymph nodes in 6 patients (10%). The most common histology was mixed cellularity (MC) and was found in 24 patients (41%), followed by nodular sclerosing (NS) (20 patients; 34.5%) (Table 2). The median follow-up from the date of enrollment was 46 months and ranged from 3 to 72 months.Response to treatment and outcomeResponse data by risk group After 2 cycles of chemotherapy in patients with low and intermediate risk disease {stage I–IIIA}, all patients with low risk disease (21 patients) and 7 out of 16 patients (43.8%) with intermediate risk disease (4 patients with stage IIB and 3 patients with stage IIIA) showed complete response (CR) [i.e. early response]. The remaining patients in the intermediate risk group (9 patients) showed partial remission (PR). After 4 chemotherapy cycles in patients with highrisk disease (stage IIIB and IV), 2 patients died during treatment due to febrile neutropenia, and the remaining 19 patients showed PR. After completion of chemotherapy cycles (4 cycles in patients with intermediate risk and 6 cycles in high-risk disease), the 28 patients with PR (9 patients with intermediate risk, and 19 patients with high-risk disease), showed CR [i.e. late response].
3. Results 3.1. Patients characteristics The median age at the time of study enrollment was 9.5 years (range 3–15 years). Thirty six patients were male (62%) and 22 were females (38%). Distribution of patients according to risk groups was
3.2.2. Relapse data Seventeen out of 56 patients at risk (30.4%) were relapsed at a median follow-up of 17 months (range; 7–41 months) after finishing treatment [with exclusion of 2 patients (of high-risk group) who died during treatment]. They included 3 out of 21 patients (14.3%), and 3 out of 16 (18.8%) and 11 out of 19 patients
A. Ali et al. / Leukemia Research 34 (2010) 1447–1452 Table 3 Factors affecting relapse rates among 56 patients (After exclusion of 2 patients who died during chemotherapy administration). Variable Gender Males (34 patients) Females (22 patients) Risk group Low risk [stage I and IIA (21 patients)] Intermediate risk [stage IIB and IIIA (16 patients)] high-risk [stage IIIB and IV (19 patients)] Histolopathology LP (7 patients) NS (20 patients) MC (24 patients) LD (5 patients) Constitutional symptoms B symptoms (24 patients) A symptoms (32 patients) Tumor bulk Bulky lymphadenopathy (11 patients) Nonbulky lymphadenopathy (45 patients) Response to chemotherapy Early CR (28 patients) Late CR (28 patients) Number of sites <3 sites (35 patients) 3 sites (21 patients)
No (%)
P value P > 0.05
12 (35.3%) 5 (22.7%) P = 0.0055 3 (14.3%) 3 (18.8%) 11 (57.9%) P = 0.0021 1 (14.3%) 3 (15%) 8 (33.3%) 5 (100%) P = 0.0083 12 (50%) 5 (18.7%) P < 0.0001 11 (100%)
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Table 4 Four-year EFS and OAS among 58 patients with Hodgkin’s lymphoma. Variable
4-Year EFS
Gender Males Females
65.9% 76.5%
Risk group Stage I and IIA Stage IIB and IIIA Stage IIIB and IV
89.6% 79.6% 40.7%
Histopathology LP NS MC LD
85.7% 83.7% 70% 14.3%
Const. symptoms B symptoms A symptoms
52.2% 84.4%
Disease bulk Bulky disease Nonbulky disease
0 90.5%
Response to chemotherapy Early CR Late CR
87.6% 52.2%
Number of sites <3 sites 3 sites
75% 58%
P value
4-Year EFS
P > 0.05
P value P > 0.05
88.9% 95.5% P = 0.0002
P = 0.008 100% 100% 76.2%
P < 0.0001
P = 0.003 100% 100% 91.3% 57.1%
P = 0.012
P = 0.0098 80.8% 100%
P < 0.0001
P < 0.0001 61.5% 100%
P = 0.002
P > 0.05 96.6% 85.7%
6 (13.3%)
P = 0.019
P > 0.05
4 (14.3%) 13 (46.4%) P > 0.05 8 (22.9%) 9 (42.9%)
(57.9%) with low, intermediate and high-risk disease respectively. The relapse occurred outside radiation field in most of relapsed patients (stage II, III, and IV disease). Relapse rate was significantly higher in patients with high-risk group than those with low and intermediate risk groups (P = 0.0055), patients with lymphocyte depletion (LD) histological subtype than those with other subtypes (P = 0.0021), patients with B symptoms than those with no B symptoms (P = 0.0083), patients with bulky lymphadenopathy than those with non bulky disease (P < 0.0001) and in patients with late CR than those with early CR (P = 0.019) (Table 3). 3.2.3. Management of relapse Salvage chemotherapy in the form of 6 cycles of frontline chemotherapy regimen (ABVD cycle alternating with COEP cycle) was given to patients with disease-free interval (DFI) of ≥12 months [10 patients distributed in low risk group (3 patients), intermediate risk (3 patients) and high-risk group (4 patients)] and in the form of 6 cycles of ICE regimen (Ifosfamide, carbopltin, and etoposide) (Table 1) to patients with DFI of <12 months [7 patients of high-risk group]. After 4 cycles of salvage chemotherapy, relapsed patients were evaluated for response to chemotherapy, where, 14 patients entered in second remission and 3 patients (of high-risk group and salvaged by ICE regimen) did not respond and subsequently died of progressive disease.
Fig. 1. EFS according to early or late CR.
100%, 76.2% respectively (P = 0.008) (Table 4 and Figs. 2 and 3). For patients with B symptoms, 4-year EFS and OAS rates were 52% and 80.8% respectively, compared to 84% (P = 0.012) and 100% (P = 0.0098) for those without B symptoms (Table 4 and Fig. 4). According to histopathological subtypes, patients with LP, NS, MC, LD showed 4-year EFS of 86%, 84%, 70%, and 14% respectively (P < 0.0001), while OAS rates were 100%, 100%, 91%, and 57% respectively (P = 0.003) (Table 4 and Figs. 5 and 6). Patients with nonbulky
3.3. Survival analysis Four-year EFS and OAS rates were 69.7% and 91.4%. Patients with early CR to chemotherapy showed 4-year EFS and OAS of 87.6% and 97% respectively, compared to 52% (P = 0.002) and 86% (P > 0.05) for those with late CR (Table 4 and Fig. 1). For patients with low, intermediate, and high-risk disease, 4-year EFS rates were 89.6%, 79.6% and 40.7% respectively (P = 0.0002) and 4-year OAS rates were 100%,
Fig. 2. EFS according to risk group.
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Fig. 7. EFS according to disease bulk. Fig. 3. OAS according to risk group.
3.4. Acute toxicity and late effects Therapy was well tolerated; hospitalization for febrile neutropenia or infectious complications was uncommon where only two patients (of high-risk group) died from septicemia due to febrile neutropenia. There was also one patient (of high-risk group) developed chest infection after relapse. Chest X-ray, CT chest and pulmonary functions tests revealed pulmonary fibrosis and this patient died in relapse. There is no late toxicity developed during the study period. 4. Discussion Fig. 4. EFS according to B symptoms.
Fig. 5. EFS according to histological subtypes.
disease showed 4-year EFS and OAS rates of 100% and 90.5% respectively, compared to 61.5% (P < 0.0001) and 0% (P < 0.0001), for those with bulky disease (Table 4 and Fig. 7). Multivariate analysis of unfavorable prognostic factors confirmed LD pathological subtype as independent prognostic factor for EFS (P = 0.015, HR: 14.21, 95% CI: 1.7–121.9).
Fig. 6. OAS according to histological subtypes.
Childhood Hodgkin’s lymphoma is considered to be a curable malignancy, but therapies for this disease can have significant long-term toxicity. Contemporary treatment programs use a risk-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field irradiation (LD-IFRT) [6,7]. In the last decade, two major pediatric trials [9,10] have evaluated the utility of LD-IFRT in the treatment of Hodgkin’s lymphoma. In a trial of the Children’s Cancer Group (CCG), 501 patients were randomized to receive LD-IFRT or no further therapy. The 3year EFS rates were 93 ± 1.7% for patients receiving LD-IFRT, and 85 ± 2.3% for patients receiving no further therapy (P = 0.057) [9]. In 1995, the German Pediatric Hematology Oncology (GPOH) initiated a study to assess the effect on EFS and OAS of eliminating radiation for all patients achieving complete resolution of disease following chemotherapy [10]. More relapses occurred in patients who achieved a CR and received no radiation (21/222, 9.5%) than in patients who achieved a PR and received radiation (43/758, 5.7%). Overall EFS was 92% for patients receiving radiation and 88% for those receiving no radiation (P = 0.05). For patients with stage IA, IB, and IIA Hodgkin’s lymphoma who achieved a CR after chemotherapy, EFS was 97%, which is similar to the EFS of 94% in patients achieving a PR who then received radiation therapy. For all other patients, however, EFS after CR to chemotherapy was 79%, compared with 91% for patients who achieved a PR and then received radiation therapy (P = 0.01). In both the German GPOH-95 and CCG5942 studies, the benefit of radiation therapy on EFS was greater in patients with advanced-stage disease at presentation. However, the optimal strategy for identifying the high-risk patient who will not respond to or maintain remission after frontline therapy has not been established. Suboptimal risk-adapted therapy may be associated with delayed recurrence [3]. Furthermore, controversy exists regarding minimal required therapy for low risk patients [11]. For now, combined-modality therapy remains the standard of care which may be due to better EFS with chemotherapy and LD-IFRT compared to chemotherapy alone. The combination of both treatment modalities allows one to reduce the intensity and duration of chemotherapy as well as the dose and volume of radiation therapy in order to reduce toxicity [12]. Furthermore, modern radiation
A. Ali et al. / Leukemia Research 34 (2010) 1447–1452
techniques with LD-IFRT have decreased treatment-related toxicity compared to standard dose RT [9]. In our retrospective study, our patients were stratified according to risk group. The aim of this study was to evaluate the efficacy of combined-modality regimen (ABVD alternating with COEP chemotherapy and LD-IFRT). In our series, the median age of patients was 9.5 years (range: 3–15 years). The median age was higher in the reported studies, and ranged from 13.3 [11] to 15.3 years [3,13]. The higher figures in the reported study than those in the current study, may be due to higher number of patients; 110 patients [11], 159 patients [3], and 195 patients [13]. In our study, 44 patients (75.8%) presented with cervical lymphadenopathy, 24 patients (41.3%) presented with abdominal lymphadenopathy, and 22 patients (37.9%) with mediastinal mass, which was bulky in one third of them (7 patients). Approximately, one quarter of patients had bulky disease (13 patients; 22.4%). This is comparable with most of the reported series, where approximately 80% of patients presented with painless adenopathy, commonly in the supraclavicular or cervical area, about 35% of young children with Hodgkin’s lymphoma had mediastinal presentation, and 20% of patients had bulky adenopathy [9,10]. In the current study, B symptoms were present in 26 patients (44.8%). This is comparable to Hudson et al. [3], who reported a 43% incidence of B symptoms. However, a relatively high incidence of B symptoms was found in patients with stage I disease (6 out of 14 patients; 43%). This may be explained by the unfavorable distribution of the histopathological subtypes among those patients (MC in 6, NS in 4 and LP in only 4 patients), as well as by the relatively high age of them. Weinstein and Tarbell [14], found higher incidence of B symptoms in adolescents than in younger children. According to risk group distribution among our patients, 36% of patients were in high-risk group (stage IIIB and IV), and this is comparable to most of the reported studies, where advanced disease was present in the range of 37% [13], and 40% [15]. The most common pathological subtypes among our patients were mixed cellularity (MC) (41.3%), followed by nodular sclerosis (NS) (34.5%). This is matched with figures reported in recent studies [16,17] who stated that, MC subtype was the predominant histological subtype (80% and 38.5% respectively). This is also confirmed by Armstrong et al. [18] who stated that there is a very high incidence of mixed cellularity histology in childhood Hodgkin’s lymphoma seen in developing countries. In developing countries with suboptimal socioeconomic conditions, histologic subtypes associated with poor prognosis are predominant. Histologic differences may be largely dependent on variable host response which may be influenced by genetic and environmental factors [16]. Therefore, LD subtype is more common in developing countries than in developed countries and ranged between 8% and 20% [16,19,20]. Pretreatment factors associated with an adverse outcome in most studies [8,9,21–26] include advanced stage of disease, the presence of B symptoms, the presence of bulk disease [24], histology [25], and the rapidity of response to initial cycles of chemotherapy [22,26]. Prognosis was also associated with the number of adverse factors [23]. In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome [9]. The relapse rates were significantly higher in patients who were found in high-risk group than in those who were of low or intermediate risk disease (P = 0.0055), in patients with B symptoms than in those without B symptoms (P = 0.0083), in patients with bulky disease than in those with nonbulky disease (P < 0.0001) and in patients with LD subtype than in those with other subtypes (P = 0.0021). These results are confirmed with Krasin et al. [13], where the cumulative incidences of local failure were significantly higher in patients with bulky disease than in those with no bulky disease (P = 0.005), and in patients with NS subtype than in those
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with other subtypes (P = 0.027). The high relapse rate in our patients with LD subtype may be explained by the fact that, lymphocyte depletion HD is a biologically aggressive subtype and carries a poor prognosis [25,27]. The reported study, however, did not state that LD subtype had the highest relapse rate and this may be due to the very low incidence of LD subtype (<2%) among patients. The overall 4-year survival of our study (91.5%), suggests that the retrieval rate after recurrence is reasonably high, providing some support for use of a less toxic frontline treatment in newly diagnosed patients. Response to initial chemotherapy has been shown to predict for improved EFS [28]. In the present study, patients with early CR showed higher 4-year EFS than those with late CR (87.6% versus 52.2%; P = 0.002), but this did not translated into overall survival advantage. This is in agreement with Donaldson et al. [29] who stated that the projected 5-year EFS for the CR patients with assessable disease was 100%, whereas for the PR patients it was 87% (P = 0.04). With longer follow-up, the 10-year EFS rates were 95% and 84.5% for patients with early CR and late CR respectively (P = 0.02). The overall survival difference were of marginal significance (P = 0.07) [11]. In the present study, there were significant difference of 4-year EFS rate, in favor of patients with low and intermediate risk disease (stage I and IIA group and IIB and IIIA group respectively) compared to those with high-risk disease (P = 0.0002) and in favor of patients with no B symptoms compared to those with B symptoms (P = 0.012). These advantages for favorable risk groups and for absence of B symptoms translated into better OAS advantages compared to OAS in those with high-risk group (P = 0.008) and those with B symptoms (P = 0.0098). This is in agreement with Smith et al. [2] where the 5-year DFS and OAS among patients with stage IIB, IIIB, IVA, and IVB disease were significantly worse than in those with stage IA, IB, IIA, and IIIA disease (P < 0.001). This is also confirmed by a more recent study conducted by Oguz [17] who stated that advanced stages were associated with inferior EFS, both by univariate and by multivariate analyses. It was also reported that, EFS rates were significantly inferior in patients with B symptoms than in those without B symptoms [2,30]. According to distribution of histopathological subtypes among our patients, 4-year EFS was significantly lower in patients with LD subtype (P < 0.0001) and this translated to overall survival advantage (P = 0.003). Multivariate analysis of unfavorable prognostic factors that predicted lower 4-year EFS revealed that LD pathological subtype was the only significant predictor of lower EFS (P = 0.015, HR: 14.21, 95% CI: 1.7–121.9). Most of the reported studies showed significant impact of histological subtype on EFS. However, in contrast to our finding that LD was worst subtype; the reported studies found that NS subtype had the worst impact on EFS [2,28] and on overall survival [2], when compared to other subtypes. This may be explained by the different distribution of NS and LD subtypes among patients in the current study (34% and 12% respectively) and in the reported studies, where incidence of NS subtype ranged from 53% to 70%, and LD subtype constituted <5% of patients. Furthermore, the lower EFS in patients with LD subtype in the current study may be due to the fact that, most of those patients presented with more advanced stages [IIIB and IV disease] (5 out of 7 patients; 71.4%), than those with other pathological subtypes (1 out of 7; 14.3% for LP patients, 7 out of 20; 35% for NS patients, and 8 out of 24; 33.3% for MC patients). In the present study, the 4-year EFS was significantly higher in patients with nonbulky disease than those with bulky disease (P < 0.0001). This advantage for patients with nonbulky disease resulted in overall survival advantage compared to those with bulky disease (P < 0.0001). This is confirmed in reported studies where there were a lower 5-year EFS (P = 0.04) [30], and (P < 0.001) [2], and 5-year overall survival (P < 0.001) [2], for patients with bulky compared with nonbulky disease.
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The retrospective nature of the study, small sample size, and small number of patients in all subgroups, are the major limitations of the current study. Further analysis is needed in a prospective randomized trials with larger number of patients, regarding the efficacy of ABVD chemotherapy regimen alternating with COEP regimen and IFRT, a combined-modality regimen in children with advanced stages of Hodgkin’s lymphoma, especially of biologically aggressive histopathological subtypes. Future attempts to reduce late treatment sequelae should be considered carefully, as longterm disease control may be compromised. 5. Conclusion Risk-based, combined-modality therapy with the ABVD/COEP chemotherapy regimens, with involved-field radiation therapy to all patients, produces satisfactory results in pediatric patients with Hodgkin’s lymphoma. Future attempts to reduce late treatment sequelae should be considered carefully, as long-term disease control may be compromised.
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Conflict of interest [17]
The authors declare that they have no conflict of interests. [18]
Acknowledgement [19]
The authors received no financial or other support for the research reported in this manuscript. Contributions. AMA, and HAS carried out collection of patients’ data, patient diagnosis, chemotherapy administration and followup. AAF shared in collection of patients’ data, and patient diagnosis. MIE carried out radiation therapy administration, follow-up, statistical analysis, general coordination, drafting of the manuscript and writing of the final manuscript. All authors have read and approved the final manuscript. References [1] Landman-Parker J, Pacquement H, Leblanc T, et al. 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 2000;18(7):1500–7. [2] Smith RS, Chen Q, Hudson MM, et al. Prognostic factors for children with Hodgkin’s disease treated with combined-modality therapy. J Clin Oncol 2003;21(10):2026–33. [3] Hudson MM, Krasin M, Link MP, et al. Risk-adapted, combined-modality therapy with vamp/cop and response-based involved-field radiation for unfavorable pediatric Hodgkin’s disease. J Clin Oncol 2004;22(22):4541–50. [4] Vecchi V, Pileri S, Burnelli R, et al. Treatment of pediatric Hodgkin disease tailored to stage, mediastinal mass, and age: an Italian (AIEOP) multicenter study on 215 patients. Cancer 1993;72:2049–57. [5] Magrath IT. Hodgkin’s lymphomas in children. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. 4th ed. Philadelphia: J.B. Lippincott Williams and Wilkins; 2006. p. 537–75. [6] Pinkeraton. Hodgkin’s lymphoma. In: Pediatric oncology. 3rd ed; 2004. pp. 254–266. [7] Lanzkowsky. Hodgkin lymphoma in manual of pediatric hematology and oncology. 4th ed; 2005. pp. 491–511. [8] Schellong G, Potter R, Bramswig J, et al. High cure rates and reduced long-term toxicity in pediatric Hodgkin’s disease: the German-Austrian multicenter trial
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DAL-HD-90—The German-Austrian Pediatric Hodgkin’s Disease. J Clin Oncol 1999;17:3736–44. Nachman JB, Sposto R, Herzog P, et al. Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve a complete response to chemotherapy. J Clin Oncol 2002;20(18):3765–71. Rühl U, Albrecht M, Dieckmann K, et al. Response-adapted radiotherapy in the treatment of pediatric Hodgkin’s disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 2001;51(5):1209–18. Donaldson SS, Link MP, Wienstien HJ, et al. Final results of a prospective clinical trial with VAMP and low dose involved field radiation for children with low risk Hodgkin’s disease. J Clin Oncol 2007;25:3081–7. Viani GA, Castilho MS, Novaes PE, et al. Chemotherapy followed by low dose radiotherapy in childhood Hodgkin’s disease: retrospective analysis of results and prognostic factors. Radiat Oncol 2006;1:38. Krasin MJ, Rai SN, Kun LE, et al. Patterns of treatment failure in pediatric and young adult patients with Hodgkin’s disease: local disease control with combined-modality therapy. J Clin Oncol 2005;23(33):8406–13. Weinstein HJ, Tarbell NJ. Leukemias and lymphomas of childhood. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. 1997. pp. 2145–2165. Chow LML, Nathan PC, Hodgson DC, et al. Survival and late effects in children with Hodgkin’s lymphoma treated with mopp/abv and low-dose extendedfield irradiation. J Clin Oncol 2006;24(36):5735–41. Parikh SK, Shukla SN, Shah PM, Patel KM, Parikh BJ, Anand AS, Talati SS, Shah SA, Panchal HP, Patel AA. Paediatric Hodgkin’s disease—a study of 232 cases seen at Gujarat Cancer & Research Institute, Ahmedabad. Indian J Med Pediatric Oncol 2004;25(4):5–9. Oguz A. Prognostic factors and treatment outcome in childhood Hodgkin disease. Pediatr Blood Cancer 2005;45(5):670–5. Armstrong AA, Alexander FE, Cartwright R, et al. Epstein-Barr virus and Hodgkin’s disease: further evidence for the three disease hypothesis. Leukemia 1998;12(8):1272–6. Jacobs P, Wood L, Ruff P. Hodgkin’s lymphoma in developing countries. An African perspectives with a note on Asia and Latin America. In: Hope RT, Mauch PT, Armittage JO, Diehl V, Weiss LM, editors. Hodgkin’s lymphoma. 2nd ed. 2007. pp. 427–448. Coskun HS, Eser B, Cetin M, Unal A, Altinbas M, Karahacioglu E, Kaplan B. Hodgkin’ disease results of a single center in central Anatolia. Turk J Hematol 2001;18(2):117–21. Hutchinson RJ, Fryer CJ, Davis PC, et al. MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin’s disease in children: results of the children’s cancer group phase III trial. J Clin Oncol 1998;16:897–906. Weiner MA, Leventhal BG, Marcus R, et al. Intensive chemotherapy and low-dose radiotherapy for the treatment of advanced-stage Hodgkin’s disease in pediatric patients: a Pediatric Oncology Group study. J Clin Oncol 1991;9:1591–8. Smith RS, Chen Q, Hudson M, et al. Prognostic factors in pediatric Hodgkin’s disease [Abstract]. Int J Radiat Oncol Biol Phys 2001;51(3):119. Metzger ML, Castellino SM, Hudson MM, et al. Effect of race on the outcome of pediatric patients with Hodgkin’s lymphoma. J Clin Oncol 2008;26(8):1282–8. Shankar AG, Ashley S, Radford M, et al. Does histology influence outcome in childhood Hodgkin’s disease? Results from the United Kingdom children’s cancer. J Clin Oncol 1997;15(7):2622–30. Carde P, Koscielny S, Franklin J, et al. Early response to chemotherapy: a surrogate for final outcome of Hodgkin’s disease patients that should influence initial treatment length and intensity? Ann Oncol 2002;13(Suppl. 1):86–91. Tubiana M, Attie E, Flamant R, Gerard-Marchant R, Hayat M. Prognostic factors in 454 cases of Hodgkin’s disease. Cancer Res 1971;31:1801–10. Weiner MA, Leventhal B, Brecher ML, et al. Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin’s disease in pediatric patients: A Pediatric Oncology Group Study. J Clin Oncol 1997;15:2769–79. Donaldson SS, Hudson MM, Lamborn KR, et al. VAMP and low dose involved field radiation for children and adolescents with favorable, early stage Hodgkin’s disease: results of a prospective clinical trial. J Clin Oncol 2002;20(14):3081–7. Dieckmann K, Potter R, Hofmann J, et al. Does bulky disease at diagnosis influence outcome in childhood Hodgkin’s disease and require higher radiation doses? Results from the German-Austrian pediatric multicenter trial DAL-HD90. Int J Radiat Oncol Biol Phys 2003;56(3):644–52.
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Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Risk-based combined-modality therapy of pediatric Hodgkin’s lymphoma: A retrospective study Amany Ali a , Heba Sayed a , Ahmed Farrag a , Mohamed El-Sayed b,∗ a b
Department of Pediatric Oncology, South Egypt Cancer Institute (SECI), Assiut University, Assiut, Egypt Department of Radiation Oncology, South Egypt Cancer Institute (SECI), Assiut University, Al-Mthaq St., 71111 Assiut, Egypt
a r t i c l e
i n f o
Article history: Received 4 December 2009 Received in revised form 12 June 2010 Accepted 13 June 2010
Keywords: Multimodal treatment Childhood Hodgkin’s disease Disease-free survival
a b s t r a c t We conducted a retrospective analysis to investigate the clinical outcome of combined-modality therapy using multiagent chemotherapy and involved-field radiotherapy in treatment of children with Hodgkin’s lymphoma. Fifty eight cases with newly diagnosed Hodgkin’s lymphoma were analyzed. The median follow-up duration was 46 months (range 3–72 months). The 4-year overall and event-free survival rates were 91.5% and 69.7% respectively. High-risk disease (stage IIIB and IV), presence of B symptoms, lymphocyte depletion subtype, bulky disease and late response to chemotherapy were poor prognostic factors. Stage-adapted combined-modality therapy resulted in satisfactory outcome in treatment of pediatric Hodgkin’s lymphoma. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Patients and methods
Treatment for children and adolescents with Hodgkin’s lymphoma often uses a combined-modality approach with multiagent chemotherapy and low-dose involved-field radiotherapy (LDIFRT). This approach has yielded excellent results, with long-term disease-free survival (DFS) of 88–100% in patients with earlystage disease [1,2] and of more than 60% in those with more advanced disease [2]. Because cure is likely for the majority of children presenting with Hodgkin’s lymphoma, attention to long-term treatment complications has become increasingly important [3]. Stage-adapted therapy, which assigns intensity of therapy according to the stage at diagnosis, is a standard treatment approach for pediatric malignancies that are highly curable, as it maintains disease control and reduces therapy-related complications [4]. We report outcomes after a stage-adapted, combined-modality treatment approach for children with Hodgkin’s lymphoma. The goal of the study was to evaluate the efficacy of ABVD chemotherapy regimen (Doxorubicin, Blomycin, Vinblastin, and Decarbazine) alternating with COEP regimen (Cyclophosphamide, Vincristine, Etoposide, and Prednisone) and IFRT, a combined-modality regimen in children with Hodgkin’s lymphoma.
2.1. Study subjects
∗ Corresponding author. Tel.: +20 122953887; fax: +20 882348609. E-mail address: [email protected] (M. El-Sayed). 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.06.012
This retrospective study was carried out in the Pediatric Oncology and radiation therapy Departments, SECI, Assiut University during the period from January 2003 and December 2008. Informed consent was obtained for all patients and the protocol was approved by institutional review board at our center. Eligible patients had histologically confirmed Hodgkin’s lymphoma, and were previously untreated. For each patient, initial staging evaluation was done by history and physical examination; hemogram, erythrocyte sedimentation rate (ESR), routine chemistry profile, chest X-ray, cervical, thoracic, abdomen and pelvis computed tomography (CT) scan with contrast. Bone marrow biopsy was done in patients with stage II–IV disease and in patients with B symptoms. Histopathologic diagnosis was obtained from presenting lymphadenopathy and for uncertain cases; immunohistochemistry using CD15 and 30 was done. Patients were staged by Ann Arbor staging system [5] and histopathologic classification was done according to REAL/WHO classification system [6,7]. 2.2. Treatment schedule Treatment included combination chemotherapy, in the form of ABVD cycle alternating with COEP cycle, with the number of cycles varied according to disease stage. Two alternating cycles were given to patients with stage I–stage II A (low risk group), four alternating cycles to patients with stage IIB–stage III A (intermediate risk group), and six alternating cycles to patients with stage IIIB–stage IV disease (high-risk group). The schedule of administration and dosing were shown in Table 1 [7]. After the second cycle in patients with stage I–stage II A, and those with stage IIB–stage III A (low and intermediate risk groups respectively) and after the fourth cycle in patients with stage IIIB–stage IV disease (high-risk group), patients were evaluated for early chemotherapy response by clinical examination, bone marrow biopsy and CT scan according to the initial presentation. Complete response (CR) was defined as resolution of all tumor-related constitutional symptoms and disappearance of all measurable nodal disease. Partial response (PR) was defined as at least 50% reduction in the sum of the products of two perpendicular diameters of all measurable lesions and disappearance of constitutional symptoms if initially present [8]. After completion of all cycles of chemotherapy, radiation therapy was
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A. Ali et al. / Leukemia Research 34 (2010) 1447–1452 Table 2 Patients’ characteristics.
Table 1 Chemotherapy protocols. Drug
Dose/Route
Day(s)
ABVD protocol Doxorubicin Bleomycin Vinblastin Decarbazin
25 mg/m2 IV 10 mg/m2 IV 6 mg/m2 IV 375 mg/m2 IV
D1, 15 D1, 15 D1, 15 D1, 15
COEP protocol Cyclophosphamide Vincristine Etoposide Prednisone
800 mg/m IV 1.4 mg/m2 IV 100 mg/m2 IV 60 mg/m2 per day PO
D1, 15 D1, 15 D1, 15 D1–15 then gradual withdrawal
ICE protocol Ifosfamide with Mesna Carpoplatin Etoposide
1800 mg/m2 IV 450 mg/m2 IV 100 mg/m2 IV
D1–3 D1 D1–3
2
directed to standardized treatment volumes, involved-field radiation therapy was given to all patients. The radiation dose was 25.5 Gy in 1.5-Gy fractions to all patients with stage IIB–IV disease (intermediate and high-risk groups), initially bulky sites (bulky mediastineal mass was considered if it was more than one-third the intrathoracic ratio measured on an upright postero-anterior chest radiograph, and/or a node aggregate larger than 10 cm in greatest dimension), or sites with a PR, and was 15 Gy in 1.5-Gy fractions to patients with stage I and IIA disease (low risk group), nonbulky sites and with a CR after the first 2 cycles of chemotherapy. Radiation therapy was given using antero-posterior/postero-anterior fields, and started within 4 weeks of last chemotherapy cycle. Gross target volume (GTV) was enlarged lymph node, clinical target volume (CTV) was the anatomical compartment of enlarged lymph node and planning target volume (PTV) was 1 cm margin to CTV. An anterior laryngeal block was used if it does not shield involved nodes in case of radiation therapy to cervical region. If the axillae were to be treated, humeral head blocks were used. Splenic irradiation was used in patients with splenic involvement but renal dose was limited to mean < 10.5 Gy using CT based planning.
Patients’ characteristics
No (%)
Age Median Range
9.5 years 3–15 years
Gender Male Female
36 (62.1%) 22 (37.9%)
Clinical presentation Cervical lymphadenopathy Abdominal lymphadenopathy Mediastinal lymphadenopathy Axillary lymphadenopathy Splenomegally
44 (76%) 24 (41%) 22 (38%) 11 (19%) 6 (10%)
Bone marrow infiltration
11 (19%)
Risk group Low risk (stage I and IIA) Intermediate risk (stage IIB and IIIA) High-risk (stage IIIB and IV)
21 (36.2%) 16 (27.6%) 21 (36.2%)
Histopathology Lymphocyte predominate (LP) Nodular sclerosis (NS) Mixed cellularity (MC) Lymphocyte depletion (LD)
7 (12.1%) 20 (34.5%) 20 (34.5%) 7 (12.1%)
Constitutional symptoms B symptoms A symptoms
26 (44.8%) 32 (55.2%)
Tumor bulk Bulky lymphadenopathy Non-bulky lymphadenopathy
13 (22.4%) 45 (77.6%)
Number of sites of lymphadenopathy Less than 3 sites 3 sites
36 (62.1%) 22 (37.9%)
2.3. After-therapy monitoring After completion of therapy, patients were followed up regularly every 3 months for 1 year, every 6 months for the next 2 years, and annually thereafter. Follow-up examinations included physical examination, chest X-ray, and routine laboratory studies (hemogram, and ESR). CT scans were done at 1 and 2 years off therapy according to initial presentation. Additional imaging procedures were performed as clinically indicated in patients presenting with clinical signs or symptoms suggestive of recurrent disease. Patients with disease relapse were given 6 cycles of salvage chemotherapy, in the form of frontline chemotherapy regimen (ABVD cycle alternating with COEP cycle) was given to patients with disease-free interval (DFI) of ≥12 months and in the form of ICE regimen (Ifosfamide, carbopltin, and etoposide) (Table 1) to patients with DFI of <12 months. After 4 cycles of salvage chemotherapy, relapsed patients were evaluated for response to chemotherapy, by physical examination, laboratory studies (hemogram, and ESR), and CT scans. Assessment for treatment-related organ toxicity was recommended during treatment and after completion of therapy during follow-up. The specific evaluations undertaken included, physical examination of bones and soft tissues, echocardiogram and ECG for all patients, and menstrual cycle history in pubertal girls. 2.4. Statistical methods The study cutoff point was December, 2008. Event-free survival (EFS) was defined as the interval from enrollment of patients to the date of first event (relapse, progression, or death from any cause) or to the date of last follow-up. Overall survival (OAS) was defined as the interval from enrollment to the date of death from any cause or to last follow-up. Event-free survival and OAS rates were estimated using Graphed prism program. The Log-rank test was used to examine differences in EFS and OAS rates. Cox-regression multivariate analysis was done to determine the independent prognostic factors affecting survival.
stage I and IIA (low risk group) in 21 patients (36%), stage IIB and IIIA (intermediate risk group) in 16 patients (28%), and stage IIIB and IV (high-risk group) in 21 patients (36%). Twenty six patients presented with B symptoms (44.8%). Thirteen patients (22%) had bulky disease. Sites of bulky disease included mediastinum in 7 patients (12%) and lymph nodes in 6 patients (10%). The most common histology was mixed cellularity (MC) and was found in 24 patients (41%), followed by nodular sclerosing (NS) (20 patients; 34.5%) (Table 2). The median follow-up from the date of enrollment was 46 months and ranged from 3 to 72 months.Response to treatment and outcomeResponse data by risk group After 2 cycles of chemotherapy in patients with low and intermediate risk disease {stage I–IIIA}, all patients with low risk disease (21 patients) and 7 out of 16 patients (43.8%) with intermediate risk disease (4 patients with stage IIB and 3 patients with stage IIIA) showed complete response (CR) [i.e. early response]. The remaining patients in the intermediate risk group (9 patients) showed partial remission (PR). After 4 chemotherapy cycles in patients with highrisk disease (stage IIIB and IV), 2 patients died during treatment due to febrile neutropenia, and the remaining 19 patients showed PR. After completion of chemotherapy cycles (4 cycles in patients with intermediate risk and 6 cycles in high-risk disease), the 28 patients with PR (9 patients with intermediate risk, and 19 patients with high-risk disease), showed CR [i.e. late response].
3. Results 3.1. Patients characteristics The median age at the time of study enrollment was 9.5 years (range 3–15 years). Thirty six patients were male (62%) and 22 were females (38%). Distribution of patients according to risk groups was
3.2.2. Relapse data Seventeen out of 56 patients at risk (30.4%) were relapsed at a median follow-up of 17 months (range; 7–41 months) after finishing treatment [with exclusion of 2 patients (of high-risk group) who died during treatment]. They included 3 out of 21 patients (14.3%), and 3 out of 16 (18.8%) and 11 out of 19 patients
A. Ali et al. / Leukemia Research 34 (2010) 1447–1452 Table 3 Factors affecting relapse rates among 56 patients (After exclusion of 2 patients who died during chemotherapy administration). Variable Gender Males (34 patients) Females (22 patients) Risk group Low risk [stage I and IIA (21 patients)] Intermediate risk [stage IIB and IIIA (16 patients)] high-risk [stage IIIB and IV (19 patients)] Histolopathology LP (7 patients) NS (20 patients) MC (24 patients) LD (5 patients) Constitutional symptoms B symptoms (24 patients) A symptoms (32 patients) Tumor bulk Bulky lymphadenopathy (11 patients) Nonbulky lymphadenopathy (45 patients) Response to chemotherapy Early CR (28 patients) Late CR (28 patients) Number of sites <3 sites (35 patients) 3 sites (21 patients)
No (%)
P value P > 0.05
12 (35.3%) 5 (22.7%) P = 0.0055 3 (14.3%) 3 (18.8%) 11 (57.9%) P = 0.0021 1 (14.3%) 3 (15%) 8 (33.3%) 5 (100%) P = 0.0083 12 (50%) 5 (18.7%) P < 0.0001 11 (100%)
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Table 4 Four-year EFS and OAS among 58 patients with Hodgkin’s lymphoma. Variable
4-Year EFS
Gender Males Females
65.9% 76.5%
Risk group Stage I and IIA Stage IIB and IIIA Stage IIIB and IV
89.6% 79.6% 40.7%
Histopathology LP NS MC LD
85.7% 83.7% 70% 14.3%
Const. symptoms B symptoms A symptoms
52.2% 84.4%
Disease bulk Bulky disease Nonbulky disease
0 90.5%
Response to chemotherapy Early CR Late CR
87.6% 52.2%
Number of sites <3 sites 3 sites
75% 58%
P value
4-Year EFS
P > 0.05
P value P > 0.05
88.9% 95.5% P = 0.0002
P = 0.008 100% 100% 76.2%
P < 0.0001
P = 0.003 100% 100% 91.3% 57.1%
P = 0.012
P = 0.0098 80.8% 100%
P < 0.0001
P < 0.0001 61.5% 100%
P = 0.002
P > 0.05 96.6% 85.7%
6 (13.3%)
P = 0.019
P > 0.05
4 (14.3%) 13 (46.4%) P > 0.05 8 (22.9%) 9 (42.9%)
(57.9%) with low, intermediate and high-risk disease respectively. The relapse occurred outside radiation field in most of relapsed patients (stage II, III, and IV disease). Relapse rate was significantly higher in patients with high-risk group than those with low and intermediate risk groups (P = 0.0055), patients with lymphocyte depletion (LD) histological subtype than those with other subtypes (P = 0.0021), patients with B symptoms than those with no B symptoms (P = 0.0083), patients with bulky lymphadenopathy than those with non bulky disease (P < 0.0001) and in patients with late CR than those with early CR (P = 0.019) (Table 3). 3.2.3. Management of relapse Salvage chemotherapy in the form of 6 cycles of frontline chemotherapy regimen (ABVD cycle alternating with COEP cycle) was given to patients with disease-free interval (DFI) of ≥12 months [10 patients distributed in low risk group (3 patients), intermediate risk (3 patients) and high-risk group (4 patients)] and in the form of 6 cycles of ICE regimen (Ifosfamide, carbopltin, and etoposide) (Table 1) to patients with DFI of <12 months [7 patients of high-risk group]. After 4 cycles of salvage chemotherapy, relapsed patients were evaluated for response to chemotherapy, where, 14 patients entered in second remission and 3 patients (of high-risk group and salvaged by ICE regimen) did not respond and subsequently died of progressive disease.
Fig. 1. EFS according to early or late CR.
100%, 76.2% respectively (P = 0.008) (Table 4 and Figs. 2 and 3). For patients with B symptoms, 4-year EFS and OAS rates were 52% and 80.8% respectively, compared to 84% (P = 0.012) and 100% (P = 0.0098) for those without B symptoms (Table 4 and Fig. 4). According to histopathological subtypes, patients with LP, NS, MC, LD showed 4-year EFS of 86%, 84%, 70%, and 14% respectively (P < 0.0001), while OAS rates were 100%, 100%, 91%, and 57% respectively (P = 0.003) (Table 4 and Figs. 5 and 6). Patients with nonbulky
3.3. Survival analysis Four-year EFS and OAS rates were 69.7% and 91.4%. Patients with early CR to chemotherapy showed 4-year EFS and OAS of 87.6% and 97% respectively, compared to 52% (P = 0.002) and 86% (P > 0.05) for those with late CR (Table 4 and Fig. 1). For patients with low, intermediate, and high-risk disease, 4-year EFS rates were 89.6%, 79.6% and 40.7% respectively (P = 0.0002) and 4-year OAS rates were 100%,
Fig. 2. EFS according to risk group.
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Fig. 7. EFS according to disease bulk. Fig. 3. OAS according to risk group.
3.4. Acute toxicity and late effects Therapy was well tolerated; hospitalization for febrile neutropenia or infectious complications was uncommon where only two patients (of high-risk group) died from septicemia due to febrile neutropenia. There was also one patient (of high-risk group) developed chest infection after relapse. Chest X-ray, CT chest and pulmonary functions tests revealed pulmonary fibrosis and this patient died in relapse. There is no late toxicity developed during the study period. 4. Discussion Fig. 4. EFS according to B symptoms.
Fig. 5. EFS according to histological subtypes.
disease showed 4-year EFS and OAS rates of 100% and 90.5% respectively, compared to 61.5% (P < 0.0001) and 0% (P < 0.0001), for those with bulky disease (Table 4 and Fig. 7). Multivariate analysis of unfavorable prognostic factors confirmed LD pathological subtype as independent prognostic factor for EFS (P = 0.015, HR: 14.21, 95% CI: 1.7–121.9).
Fig. 6. OAS according to histological subtypes.
Childhood Hodgkin’s lymphoma is considered to be a curable malignancy, but therapies for this disease can have significant long-term toxicity. Contemporary treatment programs use a risk-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field irradiation (LD-IFRT) [6,7]. In the last decade, two major pediatric trials [9,10] have evaluated the utility of LD-IFRT in the treatment of Hodgkin’s lymphoma. In a trial of the Children’s Cancer Group (CCG), 501 patients were randomized to receive LD-IFRT or no further therapy. The 3year EFS rates were 93 ± 1.7% for patients receiving LD-IFRT, and 85 ± 2.3% for patients receiving no further therapy (P = 0.057) [9]. In 1995, the German Pediatric Hematology Oncology (GPOH) initiated a study to assess the effect on EFS and OAS of eliminating radiation for all patients achieving complete resolution of disease following chemotherapy [10]. More relapses occurred in patients who achieved a CR and received no radiation (21/222, 9.5%) than in patients who achieved a PR and received radiation (43/758, 5.7%). Overall EFS was 92% for patients receiving radiation and 88% for those receiving no radiation (P = 0.05). For patients with stage IA, IB, and IIA Hodgkin’s lymphoma who achieved a CR after chemotherapy, EFS was 97%, which is similar to the EFS of 94% in patients achieving a PR who then received radiation therapy. For all other patients, however, EFS after CR to chemotherapy was 79%, compared with 91% for patients who achieved a PR and then received radiation therapy (P = 0.01). In both the German GPOH-95 and CCG5942 studies, the benefit of radiation therapy on EFS was greater in patients with advanced-stage disease at presentation. However, the optimal strategy for identifying the high-risk patient who will not respond to or maintain remission after frontline therapy has not been established. Suboptimal risk-adapted therapy may be associated with delayed recurrence [3]. Furthermore, controversy exists regarding minimal required therapy for low risk patients [11]. For now, combined-modality therapy remains the standard of care which may be due to better EFS with chemotherapy and LD-IFRT compared to chemotherapy alone. The combination of both treatment modalities allows one to reduce the intensity and duration of chemotherapy as well as the dose and volume of radiation therapy in order to reduce toxicity [12]. Furthermore, modern radiation
A. Ali et al. / Leukemia Research 34 (2010) 1447–1452
techniques with LD-IFRT have decreased treatment-related toxicity compared to standard dose RT [9]. In our retrospective study, our patients were stratified according to risk group. The aim of this study was to evaluate the efficacy of combined-modality regimen (ABVD alternating with COEP chemotherapy and LD-IFRT). In our series, the median age of patients was 9.5 years (range: 3–15 years). The median age was higher in the reported studies, and ranged from 13.3 [11] to 15.3 years [3,13]. The higher figures in the reported study than those in the current study, may be due to higher number of patients; 110 patients [11], 159 patients [3], and 195 patients [13]. In our study, 44 patients (75.8%) presented with cervical lymphadenopathy, 24 patients (41.3%) presented with abdominal lymphadenopathy, and 22 patients (37.9%) with mediastinal mass, which was bulky in one third of them (7 patients). Approximately, one quarter of patients had bulky disease (13 patients; 22.4%). This is comparable with most of the reported series, where approximately 80% of patients presented with painless adenopathy, commonly in the supraclavicular or cervical area, about 35% of young children with Hodgkin’s lymphoma had mediastinal presentation, and 20% of patients had bulky adenopathy [9,10]. In the current study, B symptoms were present in 26 patients (44.8%). This is comparable to Hudson et al. [3], who reported a 43% incidence of B symptoms. However, a relatively high incidence of B symptoms was found in patients with stage I disease (6 out of 14 patients; 43%). This may be explained by the unfavorable distribution of the histopathological subtypes among those patients (MC in 6, NS in 4 and LP in only 4 patients), as well as by the relatively high age of them. Weinstein and Tarbell [14], found higher incidence of B symptoms in adolescents than in younger children. According to risk group distribution among our patients, 36% of patients were in high-risk group (stage IIIB and IV), and this is comparable to most of the reported studies, where advanced disease was present in the range of 37% [13], and 40% [15]. The most common pathological subtypes among our patients were mixed cellularity (MC) (41.3%), followed by nodular sclerosis (NS) (34.5%). This is matched with figures reported in recent studies [16,17] who stated that, MC subtype was the predominant histological subtype (80% and 38.5% respectively). This is also confirmed by Armstrong et al. [18] who stated that there is a very high incidence of mixed cellularity histology in childhood Hodgkin’s lymphoma seen in developing countries. In developing countries with suboptimal socioeconomic conditions, histologic subtypes associated with poor prognosis are predominant. Histologic differences may be largely dependent on variable host response which may be influenced by genetic and environmental factors [16]. Therefore, LD subtype is more common in developing countries than in developed countries and ranged between 8% and 20% [16,19,20]. Pretreatment factors associated with an adverse outcome in most studies [8,9,21–26] include advanced stage of disease, the presence of B symptoms, the presence of bulk disease [24], histology [25], and the rapidity of response to initial cycles of chemotherapy [22,26]. Prognosis was also associated with the number of adverse factors [23]. In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome [9]. The relapse rates were significantly higher in patients who were found in high-risk group than in those who were of low or intermediate risk disease (P = 0.0055), in patients with B symptoms than in those without B symptoms (P = 0.0083), in patients with bulky disease than in those with nonbulky disease (P < 0.0001) and in patients with LD subtype than in those with other subtypes (P = 0.0021). These results are confirmed with Krasin et al. [13], where the cumulative incidences of local failure were significantly higher in patients with bulky disease than in those with no bulky disease (P = 0.005), and in patients with NS subtype than in those
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with other subtypes (P = 0.027). The high relapse rate in our patients with LD subtype may be explained by the fact that, lymphocyte depletion HD is a biologically aggressive subtype and carries a poor prognosis [25,27]. The reported study, however, did not state that LD subtype had the highest relapse rate and this may be due to the very low incidence of LD subtype (<2%) among patients. The overall 4-year survival of our study (91.5%), suggests that the retrieval rate after recurrence is reasonably high, providing some support for use of a less toxic frontline treatment in newly diagnosed patients. Response to initial chemotherapy has been shown to predict for improved EFS [28]. In the present study, patients with early CR showed higher 4-year EFS than those with late CR (87.6% versus 52.2%; P = 0.002), but this did not translated into overall survival advantage. This is in agreement with Donaldson et al. [29] who stated that the projected 5-year EFS for the CR patients with assessable disease was 100%, whereas for the PR patients it was 87% (P = 0.04). With longer follow-up, the 10-year EFS rates were 95% and 84.5% for patients with early CR and late CR respectively (P = 0.02). The overall survival difference were of marginal significance (P = 0.07) [11]. In the present study, there were significant difference of 4-year EFS rate, in favor of patients with low and intermediate risk disease (stage I and IIA group and IIB and IIIA group respectively) compared to those with high-risk disease (P = 0.0002) and in favor of patients with no B symptoms compared to those with B symptoms (P = 0.012). These advantages for favorable risk groups and for absence of B symptoms translated into better OAS advantages compared to OAS in those with high-risk group (P = 0.008) and those with B symptoms (P = 0.0098). This is in agreement with Smith et al. [2] where the 5-year DFS and OAS among patients with stage IIB, IIIB, IVA, and IVB disease were significantly worse than in those with stage IA, IB, IIA, and IIIA disease (P < 0.001). This is also confirmed by a more recent study conducted by Oguz [17] who stated that advanced stages were associated with inferior EFS, both by univariate and by multivariate analyses. It was also reported that, EFS rates were significantly inferior in patients with B symptoms than in those without B symptoms [2,30]. According to distribution of histopathological subtypes among our patients, 4-year EFS was significantly lower in patients with LD subtype (P < 0.0001) and this translated to overall survival advantage (P = 0.003). Multivariate analysis of unfavorable prognostic factors that predicted lower 4-year EFS revealed that LD pathological subtype was the only significant predictor of lower EFS (P = 0.015, HR: 14.21, 95% CI: 1.7–121.9). Most of the reported studies showed significant impact of histological subtype on EFS. However, in contrast to our finding that LD was worst subtype; the reported studies found that NS subtype had the worst impact on EFS [2,28] and on overall survival [2], when compared to other subtypes. This may be explained by the different distribution of NS and LD subtypes among patients in the current study (34% and 12% respectively) and in the reported studies, where incidence of NS subtype ranged from 53% to 70%, and LD subtype constituted <5% of patients. Furthermore, the lower EFS in patients with LD subtype in the current study may be due to the fact that, most of those patients presented with more advanced stages [IIIB and IV disease] (5 out of 7 patients; 71.4%), than those with other pathological subtypes (1 out of 7; 14.3% for LP patients, 7 out of 20; 35% for NS patients, and 8 out of 24; 33.3% for MC patients). In the present study, the 4-year EFS was significantly higher in patients with nonbulky disease than those with bulky disease (P < 0.0001). This advantage for patients with nonbulky disease resulted in overall survival advantage compared to those with bulky disease (P < 0.0001). This is confirmed in reported studies where there were a lower 5-year EFS (P = 0.04) [30], and (P < 0.001) [2], and 5-year overall survival (P < 0.001) [2], for patients with bulky compared with nonbulky disease.
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The retrospective nature of the study, small sample size, and small number of patients in all subgroups, are the major limitations of the current study. Further analysis is needed in a prospective randomized trials with larger number of patients, regarding the efficacy of ABVD chemotherapy regimen alternating with COEP regimen and IFRT, a combined-modality regimen in children with advanced stages of Hodgkin’s lymphoma, especially of biologically aggressive histopathological subtypes. Future attempts to reduce late treatment sequelae should be considered carefully, as longterm disease control may be compromised. 5. Conclusion Risk-based, combined-modality therapy with the ABVD/COEP chemotherapy regimens, with involved-field radiation therapy to all patients, produces satisfactory results in pediatric patients with Hodgkin’s lymphoma. Future attempts to reduce late treatment sequelae should be considered carefully, as long-term disease control may be compromised.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Conflict of interest [17]
The authors declare that they have no conflict of interests. [18]
Acknowledgement [19]
The authors received no financial or other support for the research reported in this manuscript. Contributions. AMA, and HAS carried out collection of patients’ data, patient diagnosis, chemotherapy administration and followup. AAF shared in collection of patients’ data, and patient diagnosis. MIE carried out radiation therapy administration, follow-up, statistical analysis, general coordination, drafting of the manuscript and writing of the final manuscript. All authors have read and approved the final manuscript. References [1] Landman-Parker J, Pacquement H, Leblanc T, et al. 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 2000;18(7):1500–7. [2] Smith RS, Chen Q, Hudson MM, et al. Prognostic factors for children with Hodgkin’s disease treated with combined-modality therapy. J Clin Oncol 2003;21(10):2026–33. [3] Hudson MM, Krasin M, Link MP, et al. Risk-adapted, combined-modality therapy with vamp/cop and response-based involved-field radiation for unfavorable pediatric Hodgkin’s disease. J Clin Oncol 2004;22(22):4541–50. [4] Vecchi V, Pileri S, Burnelli R, et al. Treatment of pediatric Hodgkin disease tailored to stage, mediastinal mass, and age: an Italian (AIEOP) multicenter study on 215 patients. Cancer 1993;72:2049–57. [5] Magrath IT. Hodgkin’s lymphomas in children. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. 4th ed. Philadelphia: J.B. Lippincott Williams and Wilkins; 2006. p. 537–75. [6] Pinkeraton. Hodgkin’s lymphoma. In: Pediatric oncology. 3rd ed; 2004. pp. 254–266. [7] Lanzkowsky. Hodgkin lymphoma in manual of pediatric hematology and oncology. 4th ed; 2005. pp. 491–511. [8] Schellong G, Potter R, Bramswig J, et al. High cure rates and reduced long-term toxicity in pediatric Hodgkin’s disease: the German-Austrian multicenter trial
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