Clinical Presentation and Outcome of Hodgkin's Lymphoma in Children: A Retrospective Study

Clinical Presentation and Outcome of Hodgkin's Lymphoma in Children: A Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Presentation and Outcome of Hodgkin's Lymphoma in Children: A Retrospective Study Amol Dongre, Karan Sood, Trupti Dongare, Brijesh Arora This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5990461/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Hodgkin’s Lymphoma (HL) is one of the most curable malignancies of childhood, with chemotherapy alone or in combination with radiotherapy (RT) being the preferred treatment modality, albeit associated with significant acute and late toxicities. Therefore, this retrospective study aims to comprehend clinical-biological differences from the west, analyse local prognostic factors, and evaluate outcomes and toxicity with current therapy. Methods This retrospective study included 355 treatment-naive patients with classical HL. All patients received 4–8 cycles of upfront ABVD-based chemotherapy followed by involved field radiotherapy (IFRT) to the bulky/residual sites. Relapsed patients received one of the commonly used salvage regimens (GDP, ICE, or MINE). Analyses were conducted for interim response assessment and end-of-treatment response. Results Out of the 355 patients evaluated, 167 presented with advanced-HL (Stage IIBX, III & IV), and 15 of these 167 were ineligible for the final analysis due to various reasons. The median age was 9.7 years, and the male-to-female ratio was 5.9:1. The primary histologic subtype was mixed cellularity. The majority (73%) had stage III disease, with 80 out of 152 (53%) presenting 'B' symptoms and 69 out of 152 (45%) having bulky disease. Extranodal involvement was observed in 26% of patients. The first-line treatment regimen was ABVD for all patients, with IFRT in 68 (44.7%) cases. At the end of therapy, 83% of patients achieved complete remission (CR), while 32 (21%) progressed or relapsed. The median follow-up was 37 months, and the overall survival (OS) and event-free survival (EFS) rates were 83.6% and 78% at three years, respectively. These survival rates were lower than those reported in studies from the west. The CHIPS score was a prognostic factor that evaluated four of the mentioned factors (Stage IV, bulky mediastinal disease, serum albumin, and fever). The event-free survival rate was 83% for patients with a CHIPS score of 0 or 1, 70% for those with a CHIPS score of 2, and 61% for those with a CHIPS score of 3 or 4. Conclusion The CHIPS score can predict the outcome of children with advanced HL treated with ABVD-based therapy but requires prospective validation. HL chips score clinical presentation clinico-biological differences therapy-outcome Figures Figure 1 Figure 2 Figure 3 Background HL (HL) comprises 6% of all childhood cancers. It is a rare cancer before the age of 5 years, with the highest incidence occurring between years 15–30. It has a bimodal presentation peak, with the second peak occurring after age 55 [ 1 ]. Childhood HL is defined as affecting those less than 15 years of age. There is an inverse relationship between the incidence of HL in children and young adults within countries according to their economic development. Based on limited data from India, HL is more common than NHL, has a lower age peak, and is more common in males with a predominance of mixed cellularity phenotype and a significant association with EBV. Although many Western studies have identified prognostic factors, in local studies, there is limited data from India or validation of Western factors in Indian studies. The treatment of HL in the West is different from that in India. Most centres in India use 2–6 cycles of ABVD chemotherapy followed by IFRT for bulky and residual lymphoma, unlike the alkylator and anthracycline-free regimens like OEPA/OPPA, VAMP, ABVE for low-risk HL, and dose-intensive regimens like ABVE-PC, BEACOPP for high-risk HL. In India, there is limited published data on outcome, which shows variable 5-year survival ranging from 65–94%, which seems lower than 85–95% survival in the west [ 2 – 5 ]. Modern strategies focus on reducing late effects while maintaining excellent cure rates using response-adapted therapies. FDG PET avidity after two cycles of chemotherapy is a good predictor of treatment failure in adults but has been evaluated in children. There is limited data on the clinical presentation and outcome of HL in children from India. Tata Memorial Hospital is the largest pediatric oncology centre in the country, treating more than 1500 children with cancer per year, including approximately 100 children with HL. This study has helped us understand the clinical-biological differences from the West, dissecting the local prognostic factors, assessing the outcome and toxicity with current therapy, and optimizing the future treatment for this highly curable disease while minimizing the acute and late toxicities. Materials & Methods The primary aim was to assess event-free survival, overall survival and tumour response. The secondary aim was to assess the local clinic-biological features and compare them with the west, evaluate the local prognostic factors with the current therapy, examine the value of CHIPS score in predicting outcomes in advanced lymphoma at TMH, and evaluate for acute toxicity of therapy. Methodology : This retrospective observational study includes pediatric patients (up to 15 years) with HL who had registered at the pediatric oncology OPD at our hospital from January 2005 to December 2010. This study was approved by the Hospital Ethics Committee, and a waiver of consent was granted since the patients had received treatment before initiating the retrospective analysis. The medical records of these patients are available from our medical record department. Medical records and lymphoma clinic charts were reviewed for presenting symptoms, examination findings, laboratory investigations and treatment done outside, if any, prior to our hospital presentation. The investigations done at our hospital to confirm the diagnosis, stage of the disease, and risk stratification of the patients were collected. Treatment at our hospital was recorded, including chemotherapy regimen, number of chemotherapy cycles, and second and subsequent lines of treatment. Radiation therapy charts for field, volumes and dose were obtained. The response and toxicity to each line of treatment were recorded from the charts as per the guidelines. The investigations done for interim response assessment and end-of-treatment response were recorded. The restaging and response assessment investigations were recorded in case of a relapse, along with the treatment given. The patient’s disease status till the last followup was recorded. Here, we report our results of advanced-stage HL patients. Current therapy of HL: Early favourable HL: Stage I & II without RF: 2–4 cycles of ABVD & low dose IFRT. Early Unfavourable HL: Stage I & II with RF, IIIA: Four cycles of ABVD & low dose IFRT to bulky/residual sites. Advanced HL Stage III & IV: Six cycles of ABVD with low dose IFRT to bulky/residual sites. RF (Risk factors): Bulky disease lymphoma, B-symptoms and > three nodal sites. Inclusion Criteria: All consecutive newly diagnosed children up to 15 years with HL who have registered in Pediatric oncology OPD from January 2005 till December 2010 were included in the study protocol. Exclusion criteria: 1. Any prior chemotherapy or radiotherapy. 2. Incomplete treatment details. 3. Nodular lymphocyte predominant HL. Analysis of the variables : Tumor responses were classified according to the COG response criteria based on CT and PET-CT scans. Complete Response (CR) All of the criteria must be fulfilled in order to achieve CR. 1. Resolution of pathologic palpable lymphadenopathy. At least 80% reduction in the PPD of each nodal mass, or return to normal size. No residual nodal mass, except the mediastinal mass, may be greater than 2.0 cm in maximal transverse diameter. A mediastinal mass may be larger than 2 cm, provided it has demonstrated at least 80% reduction in the PPD. Individual nodes that were previously confluent must have regressed by more than 80% of the sum of the products of their perpendicular diameters (SPPD) compared with the size of the original mass. 2. Nodal masses that have not regressed at least 80% in their PPD or returned to normal size may reflect residual disease or fibrotic changes, and biopsy should be considered. 3. No residual disease in non-measurable assessable lesion sites. 4. No new lesion(s). 5. FDG-PET or Gallium negative. Partial Response (PR): 1. At least a 50% reduction in the PPD of each area of measurable disease, or return to normal nodal size, but not constituting a CR. 2. Individual nodes that were previously confluent must have regressed by more than 50% in their SPPD compared to the size of the original mass. 3. No progression of non-measurable assessable disease sites. 4. No new lesion(s). 5. FDG-PET or Gallium may be positive or negative. Stable disease (SD): 1. Less than a partial response but not progressive disease. Progressive disease (PD): (any of the following) 1. At least a 50% increase in the PPD of any involved nodes or nodal masses. 2. New lesion(s). 3. Progression of a non-measurable assessable disease site. RER and SER Definitions: 1. Rapid Early Response (RER): Complete Response (CR) or very good partial response (VGPR) following two cycles of chemotherapy. 2. Slow Early Response (SER): Less than CR following two cycles of chemotherapy. Statistical Analysis: Descriptive variables were used to include numbers, tables, charts, and graphs to describe, organize, summarize and present raw data. Progression-free survival and Overall survival were calculated from the date of diagnosis to the date of relapse/progression and the date of the last follow-up, respectively. Event-free survival was calculated from the date of diagnosis to the date of any event, i.e. relapse, progression or death due to any cause. Kaplan-Meier graphs were plotted for survival curves. The Cox- proportional hazards model was used to determine variables affecting the above outcomes. Results We enrolled 355 HL patients from January 2005 to December 2010. One hundred sixty-five patients had advanced stage HL (stage IIBX, III & IV). One hundred fifty-two patients were included in the final analysis of advanced-stage HL. Thirteen patients were excluded due to the following reasons: patients who had no treatment after diagnosis (n:10), patients with diagnoses other than classical HL (n:1) or patients who had to complete part of their treatment in different centres (n:2). Clinical Characteristics: Table 1 shows the characteristics of 152 advanced-stage HL patients in this study. The median age was 9.27 years (range 3-15 years). Eighty-five per cent (130/152) of the patients were males. The M: F ratio was 5.9:1. The most common histologic subtype was mixed cellularity (49.3%) followed by nodular sclerosis (30%), Classical-NOS (not otherwise specified) (11.2%), Lymphocyte predominant (8%) and others (3%). Fifty-three per cent (81/152) had B symptoms at presentation. Stage IIBx, III and stage IV lymphomas were seen in 3% (5/152), 72% (109/152), and 25% (38/152) patients, respectively. Bone marrow involvement was seen in 9% (20/223) of patients. Twenty-five per cent of patients (38/152) had one or more areas of extra-nodal participation at diagnosis. Anatomical locations mostly involved were marrow (n: 15), liver (n: 11), lung (n: 11), skeletal (n: 3), peritoneal (n: 2) and gonadal (n:1). Twenty per cent of patient (31/152) had intermediate-risk disease while 80% (121/152) had high-risk disease. Bulky disease was seen in 46% (69/152) patients. Fifty per cent of patients (74/152) had anaemia at baseline presentation as defined by haemoglobin level of less than 10.0gm%, raised ESR, LDH & β2 microglobulin levels were present in 44.7%, 77.6% and 36% of patients at baseline. Table 1: Baseline characteristics of all patients Characteristics TOTAL (n=152) Western data 8,17 Male 130 (85.5%) 49 Female 22 (14.5%) 49 Male: Female 5.9:1 1:1 Median Age (years): 9.27 (3-15) 14 (4-20) Stage: IIB 5 (03%) 23 (23%) Stage: III 109 (72%) 17 (17%) Stage: IV 38 (25%) 58 (59%) Bulky disease* 69 (46%) 64 (63%) Risk Grouping: Intermediate 31 (20%) 30 (30%) Risk Grouping: High 121 (80%) 68 (70%) CHIPS score: 0,1 70 (46%) 589 (76.4%) CHIPS score: 2 57 (37.5%) 141(18.3%) CHIPS score: 3,4 25 (16.4%) 32 (4.2%) B symptoms: 81 (53%) 69 (70%) Note: *Bulky disease is defined as a nodal mass whose greatest dimension is > 7 cm in size and/or a widening of the mediastinum (middle chest by > 1/3rd) Treatment response: Forty-five per cent of patients (68/152) received radiation therapy with doses ranging from 19.8 Gy to 30.6 Gy to the residual and bulky disease sites. CR and PR rates observed were 84% (127/152) and 8% (12/152), respectively, for the whole group, while thirteen patients (9%) had PD at the end of completion of first-line chemotherapy ± IFRT. Median number of treatment cycles received was six (range 4 to 8). Mid-cycle evaluation was done in 110 patients (73%). Fifty-seven per cent of patients (63/110) were in CR, thirty-nine per cent (43/110) in PR, and three per cent of patients (4/110) had progressive disease at interim response evaluation. Fifty-three per cent of patients (81/152) had an interim response evaluation done by PET-CT scan, which showed a CR, PR and progressive disease of 66.7%, 28.4% & 5.1%, respectively. The OS and EFS were 94% and 94% for rapid early responders, whereas OS and EFS were 72% and 68% for slow early responders, with statistically significant differences in OS and EFS. (for OS: p =0.002; EFS:p = 0.001) for CR versus non-CR patients at a median followup of 37 months when evaluated by interim PET-CT scan, as shown in Figure 1. Out of the 54 patients who achieved CR at interim PET-CT scan, one patient expired due to treatment complication (Bleomycin toxicity), while three patients relapsed. All three patients received salvage chemotherapy and were alive at the last followup. A total of six patients (4%) underwent autologous bone marrow transplant (ABMT). Two patients were in PR, and the remaining four were in CR at the time of ABMT. Two patients received MINE, while four received GDP as a salvage chemotherapy. Toxicity : Hematological : Only three patients developed febrile neutropenia while on chemotherapy. None of the patients required ICU. Admission during chemotherapy. None of the patients developed grade 4 thrombocytopenia or anaemia due to chemotherapy requiring transfusions. Non-haematological : Five per cent of patients (8/152) developed clinical bleomycin-induced lung toxicity requiring stoppage of bleomycin, as evidenced by a decline in pulmonary functions and radiological confirmation. Baseline echocardiography was done in 141 (92%) patients. None of the patients developed clinical cardiotoxicity with anthracycline-based chemotherapy till the last followup. Outcome & Survival Rates: The median follow-up time was 37 months (2-80 months). Twenty-one per cent of patients (32/152) progressed or relapsed in the cohort. Eleven patients (7%) had primary progressive disease, while eight (5%) and thirteen patients (8.6%) had early and late relapses, respectively. Relapses were more frequent in patients with a bulky disease than in non-bulky patients. Of the 21 relapsed patients, 11 (52%) received RT during the course of initial treatment. Ninety per cent (19/21) of patients had relapsed at their primary site, while only two patients relapsed at sites other than primary. (1 patient relapses in the liver; 1 in skeletal tissue and spleen). None of them had received RT for primary disease. The study group's 3-year EFS and OS rates were 77% and 83%, respectively, as shown in Figure 2 . A total of 18 patients died in the studied cohort, of which two patients died during ongoing chemotherapy (2 died of bleomycin-induced lung toxicity), 4 had progressive disease & remaining 12 patients had disease relapsed, which was refractory. No patients died during followup. At the last followup (median 37 months), 88% (134/152) of patients were alive. Three patients were still on treatment for relapse. The factor that was statistically significant on univariate analysis, as shown in Table 2 for OS, was β2 microglobulin levels, while for EFS, β2 microglobulin levels, stage of the disease and haemoglobin levels were substantial. Factors analyzed in multivariate analysis, as shown in Table 3 for OS, were a stage, bulky disease, B symptoms, haemoglobin, β2 microglobulin, risk group, and histology (mixed cellularity versus non-MC). None of the factors were statistically significant for overall survival. For EFS, factors evaluated on multivariate analysis, as shown in Table 4 , were B symptoms, bulky disease, risk group, haemoglobin level, β2 microglobulin, and histology, and the factors that were found statistically significant for EFS were risk group and haemoglobin levels. Table 2: Univariate analysis for prognostic factors Sr.No Prognostic factors OS (P value) EFS (P value) 1 Histology : MC versus non MC 0.145 0.202 2 Bulky disease : yes/no 0.12 0.24 3 B symptoms; presence or absence 0.21 0.10 4 Stage: II/III/IV 0.09 0.008* 5 Risk group: Intermediate vs High 0.15 0.10 6 Serum LDH; 191 0.63 0.67 7 Beta 2 microglobulin2.4 0.01* 0.002* 8 ESR: 20 0.33 0.136 9 Hemoglobin: 10 0.14 0.005* 10 Serum albumin:3.5 0.87 0.988 Table 3: Multivariate analysis for OS B SE Wald df Sig. H.R 95.0% CI for Exp(B) Lower STAGE -1.110 1.095 1.028 1 0.311 0.330 0.039 B-Symptoms -.111 0.613 0.033 1 0.856 0.895 0.269 Bulky disease -.260 0.659 0.156 1 0.693 0.771 0.212 Risk Group -1.032 1.203 0.736 1 0.391 0.356 0.034 Hemoglobin -.624 0.653 0.914 1 0.339 0.536 0.149 β 2 microglobulin -.462 0.604 0.584 1 0.445 0.630 0.193 Histology -.764 0.618 1.528 1 0.216 0.466 0.139 According to Childhood Hodgkin's International Prognostic Score (CHIPS), 46% (70/152) patients had a score of 0-1, 37.5% (57/152) patients had a score of 2 and 16.4% (25/152) patients had a score of 3-4. We evaluated the CHIPS score as a prognostic factor for event-free survival rate; EFS, as depicted in Figure 3, was 92% for patients with a CHIPS score of 0 or 1, 82% for those with a CHIPS score of 2, and 70% & 61% for those with a CHIPS score of 3 or 4 (EFS: p = 0.065). Table 4: Multivariate analysis for EFS B SE Wald df Sig. H.R 95.0% CI for Exp(B) Lower Upper B-Symptoms 0.325 0.502 0.420 1 0.517 1.384 0.518 3.702 Bulky-disease 0.350 0.530 0.436 1 0.509 1.419 0.502 4.012 Risk-Group -2.212 1.126 3.858 1 0.050 0.110 0.012 0.995 Hemoglobin -1.874 0.636 8.674 1 0.003 0.154 0.044 0.534 β 2 microglobulin -.485 0.566 0.734 1 0.392 0.616 0.203 1.866 Histology -.348 0.495 0.495 1 0.482 0.706 0.268 1.862 Discussion HL treatment is one of the success stories of modern medicine. There is a unified pathologic classification schema, a noninvasive staging evaluation, and an increasingly sophisticated approach to therapy with risk and response-adapted therapies in pediatric and adult patients. Survival rates have continued to improve while treatment modifications to decrease late effects are studied across all populations. However, a strong age gradient exists with respect to patient outcomes, with younger patients faring somewhat better than their adult counterparts and older adults faring significantly worse. There has been a growing appreciation for the differences in epidemiology across age groups and the potential differences in lymphoma biology. Novel approaches to prognostic stratification and therapy based on these differences may be necessary to maximize cure and minimize late effects across the ages. Epidemiology of HL in India: In India, HL exceeds non-HL, a pattern opposite to the West. This is due to the result of a higher incidence of HL in male children. A study by Arora et al. [ 6 ] has shown a remarkable 12-fold increase in the incidence of HL in males in Delhi. The incidence of HL in India ranges from 8.2–19.6 per million children per year compared to 5.7 in the USA and 6.4 in Britain [ 7 ]. In developing countries, it occurs predominantly during childhood, with its incidence decreasing. In contrast, it occurs more commonly in industrialized countries in adolescents or young adults than young children. The patterns are similar to the occurrences of Epstein-Barr virus (EBV), tuberculosis and poliomyelitis infections. Childhood HL also shows a predilection for the male gender, with the M: F ratio being 1.5:1 in the West compared to adult HL, which occurs equally in both sexes. India shows a significant male predominance in HL, much higher than in any other type of childhood cancer. Various studies have shown different sex distributions from M: F of 1.8:1 in Bangalore to 7.4:1 in Delhi and 6:1 in Mumbai [ 8 ]. The sex distribution discrepancy is not yet fully understood. In the case of India, it could also be due to poor healthcare access for females, reflecting the cultural disinterest in the female child. EBV's association with HL has been shown by various epidemiological, serological and pathological studies. EBV infection is more commonly associated with mixed cellularity histology in childhood HL (< 10 years) and less developed regions. In India, EBV was found in 78% of all ages HL cases and 91–98% of children. This leads to an earlier incidence peak in India compared to 16–30 years in the West. HL could be caused by a genetically determined abnormal immune response to a childhood infection. This hypothesis is supported by the increased incidence of HL among patients with immune deficiency states, such as ataxia telangiectasia or HIV infection. There is a threefold to sevenfold increased risk of HL for the siblings of young adults with HL, and siblings of the same sex as the affected person have a risk double that of siblings of the opposite sex [ 5 ]. The WHO classification of lymphomas divides HL into classical HL and nodular lymphocyte predominant HL. Classical HL occurs more commonly (90 to 95 per cent of cases) than nodular lymphocyte-predominant HL and is subdivided into four subtypes: Nodular sclerosis (NS), Mixed cellularity (MC), Lymphocyte predominant(LP) and Lymphocyte depleted(LD). In the West, NS is the most common form of pediatric HL, representing 70 to 80 per cent of cases in adolescents and 40 to 50 per cent of cases in children younger than ten years of age. However, in India, mixed cellularity represents the most common form of HL. The incidence of MC decreases with age, from 30 to 35 per cent in younger children to 10 to 15 per cent in adolescents. LD and LR are rare events, accounting for fewer than 5% of all HL cases. Advanced HL (Stage IIBX, III & IV) in children requires more aggressive therapy. The data from various international study groups show that outcomes can be improved significantly by increasing the dose intensity of treatment. Modern CMT trials report 5-year EFS rates greater than 80% in advanced lymphoma [ 9 – 12 ]. Hybrid regimens using ABVD/ABV alternating with MOPP/COPP provide disease control in about 75% of stage IIB-IV patients without RT [ 11 ]. Still, stage IV patients do poorly with such conventional therapy, whether additional IFRT is administered or not. Prognostic factors in Pediatric HL: Prognostic factors have been identified in adult patients with HL, and several prognostic indices have been developed to guide therapy decisions. However, these indices may not be relevant for children with HL. Prognostic factor analysis has been reported in two studies of children with advanced HL. The Pediatric Oncology Group (POG) found stage IV lymphoma and male sex as prognostic for inferior event-free survival. In contrast, the Children's Cancer Group found stage, ESR, liver size, and mediastinal bulk among stage III patients as prognostic for inferior event-free survival [ 13 ]. Recently, CHIPS scores, like the IPSS score (Hesenclever index) for adult HL, have been found to be a useful tool to prognosticate pediatric HL in the West, and it may be a valuable tool to predict outcomes in advanced HL in India, but it needs validation due to different lymphoma biology and therapeutic strategy [ 9 ]. Treatment of Pediatric HL: HL in children is one of the most curable malignancies of childhood. Chemotherapy alone or in combination with radiotherapy (RT) is the preferred mode of treatment, both being associated with significant acute and late toxicities. Combining chemotherapy and radiotherapy broadens the spectrum of toxicity while reducing the incidence and severity of individual drug and radiation toxicity. Therapy at TMH includes 2–6 cycles of ABVD chemotherapy followed by IFRT to bulky and residual lymphoma. ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) developed in the 1970s made long-term survival possible for patients with advanced and unfavourable (e.g., bulky, symptomatic) HL [ 14 ]. The response rate and outcome of advanced-stage HL with an ABVD regimen is around 80–84%. ABVD-related sequelae include a dose-related risk of cardiopulmonary toxicity related to doxorubicin and bleomycin. The cumulative dose of these agents is proactively restricted in pediatric patients to reduce this risk. Commonly used regimens in the West for early stages include four cycles of VAMP plus LD-IFRT or four cycles of COPP/ABV plus LD-IFRT or ABVE administered for two to four courses depending on the response, followed by LD-IFRT or OEPA for males or OPPA for females followed by LD-IFRT, depending upon the initial response to chemotherapy [ 11 ]. Similarly, commonly used dose-intense regimens in advanced lymphoma include BEACOPP, ABVE-PC or COPP/ABV without IFRT. Efforts have also been made to try to eliminate RT from the treatment strategy. However, the survival advantage was noted with combined modality therapy over chemotherapy alone. Intensification of therapy using dose-intense hybrid regimens has improved the outcomes in advanced-stage HL and patients having unfavourable factors. The role of IFRT in this group of patients has been studied with mixed results. Some studies showed EFS and OS advantages with the addition of IFRT to chemotherapy, while the POG 8725 study showed no difference in EFS or OS. The various dose-intensified chemotherapy protocols, such as Stanford V (nitrogen mustard, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisolone) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone) along with G-CSF improved the outcome of adults with advanced HL with acceptable toxicity [ 15 ]. The first attempt to treat children with stage IIB, IIIB or IV with four doses of escalated BEACOPP [ 16 ] as induction therapy has shown feasibility and good tolerance in children. The rapid early responders received either four cycles of COPP/ABV (girls) or 2 ABVD plus IFRT (boys), while slow early responders received four more BEACOPP cycles plus IFRT. The results show a significant improvement in EFS (91%) and OS (98%), but further follow-up is necessary to evaluate the effectiveness and long-term toxicity of dose-intensive chemotherapy in children. The role of additional RT in involved sites in stage III or IV disease remains controversial. The overall consensus is that the use of IFRT improves the event-free survival by 5–15% across various studies but not the overall survival. Recent studies indicate that the outcome of patients with unfavourable risk factors has improved with the intensification of chemotherapy. In the German HL-DAL 90 protocol [ 17 ], after two cycles of OPPA or OEPA, for intermediate- and high-risk HL, an additional 2 or 4 cycles of COPP (cyclophosphamide, vincristine, procarbazine, and prednisone) were given. All patients received 20- to 35 Gy IFRT, including those with stage III and IV disease. Five-year EFS in the intermediate- and high-risk groups was 93% and 86%, respectively. The EFS in these groups was comparable to that seen in the low-risk group, with all three risk groups experiencing 5-year OS rates ≥ 94%. In the HD-95 trial, which used the same chemotherapy, but IFRT was omitted in complete responders, the EFS for intermediate- and high-risk patients was 91% and 84%, respectively [ 2 ]. Substitution of dacarbazine for procarbazine (OEPA-COPDAC) in boys produces comparable results to standard OPPA-COPP in girls when used in combination with IFRT for intermediate- and high-risk patients [ 2 ]. In the CCG 5942 protocol children with intermediate-risk disease received six cycles of COPP/ABV; those with high-risk disease received two courses of intensive multidrug chemotherapy with cytarabine/etoposide, COPP/ABV, and cyclophosphamide, vincristine, doxorubicin, and methylprednisolone/prednisone with granulocyte colony-stimulating factor support. The children who achieved complete remission were randomly assigned to 21 Gy IFRT or no further therapy. Three-year EFS rates for patients receiving IFRT were 93% vs 85% for those not receive IFRT [ 12 ]. Other studies have also used low-dose IFRT after chemotherapy in intermediate-risk with good disease control. The Pediatric Oncology Group trial has used response-based, risk-adapted therapy utilizing dose-dense ABVE-PC (prednisone and cyclophosphamide) for unfavourable advanced-stage patients in combination with 21 Gy IFRT. A dose-dense, early response-based treatment approach with ABVE-PC permitted a reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response after three ABVE-PC cycles. Five-year EFS was comparable for rapid early responders (86%) and slow early responders (83%) treated with three and five cycles of ABVE-PC, respectively, followed by 21 Gy radiation [ 18 ]. Based on the above studies, intensification of chemotherapy can overcome the adverse features of many patients with intermediate and high-risk diseases. Treatment with 4 to 6 cycles of multiagent chemotherapy followed by low-dose IFRT can produce good results, although achieving EFS > 90% in high-risk patients remains challenging. Notably, the use of RT in the management of advanced-stage pediatric HL differs considerably from the usual practice for adult HL. In both the GPOH HD-9520 and CCG 5942, the benefit of IFRT in reducing relapse rates was most pronounced among high-risk patients. In the HD-95 study, intermediate- and high-risk patients who received IFRT had significantly better EFS than those who did not, despite the latter group achieving a better response to chemotherapy. In the CCG 5942, IFRT was associated with an 11%, 5%, and 12% improvement in 3-year EFS among low-, intermediate-, and high-risk patients, respectively [ 12 ]. Accordingly, IFRT remains an important component of treatment in intermediate- and high-risk diseases in most multi-institutional pediatric protocols. There is limited data on the clinical presentation and outcome of HL in children from India. This study at Tata Memorial Hospital was our attempt to understand the clinicobiological differences from the West, dissecting the local prognostic factors, assessing the outcome & toxicity with current therapy and optimizing the future treatment for this highly curable lymphoma while minimizing the acute & late toxicities. Risk-adapted treatment in children with HL based on pretreatment factors attempts to spare patients with favourable lymphoma presentations from the potential toxicity of aggressive treatment while reserving this therapy for those with a high risk of relapse after conventional treatment. However, many pretreatment factors must be systematically analyzed to determine their relationship to the outcome. We undertook this study to understand the local biology of HL, identify pretreatment characteristics prognostic for outcome, validate the western prognostic subgroups in our cohort, analyze the outcome with ABVD-based chemotherapy and incorporate them into a prognostic index that could stratify pediatric patients into risk groups on which to base treatment decisions. Biology: The median age of our patients was 9.7 years. We had only 21 patients (13%) younger than five during the initial diagnosis. In our study group, the M: F ratio was 5.9:1, which is similar to studies published by AIIMS and PGIMER Chandigarh, where the median age of presentation was eight years and 7.9 ± 2.6 years, whereas the M: F ratio of 8:1 and 10.6:1 respectively. We had only 21 patients (13%) younger than five during the initial diagnosis. 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 five years of age, against some 5% in developed countries 4,16,17 Pediatric HL also 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 8:1 and 10:1. Similar to the general national figures as well as the data from other developing countries, MC histopathologic subtype (50%) was the most common in our study population which was very similar to other published studies from India. However, 30% of our cases had NS histology, a proportion lower than those observed in developed countries. Fifty-three percent (81/152) had B symptoms at presentation. Stage III and stage IV diseases were seen in 72% (109/152) and 25% (38/152) patients, respectively, with 80% percent of patients being high risk. Bulky disease was seen in 46% (69/152) patients. Fifty per cent of patients (74/152) had anaemia at baseline presentation as defined by haemoglobin level of less than 10.0gm%, raised ESR, LDH & β2 microglobulin levels were present in 44.7%, 77.6% and 36% of patients at baseline. These results were similar to the other two extensive retrospective studies on the outcome of HL in the pediatric population from India, where the incidence of B symptoms, bulky disease and high-risk disease was seen in 54%, 46% and 70% of the patients, respectively. Also, anaemia and elevated ESR incidence were seen in 58% of the patient population. This also corresponds to figures from other resource-poor nations. Most reports from North America and Europe have shown nodular sclerosis (60–70%) as the most frequent subtype in the pediatric age group. In countries with suboptimal socioeconomic conditions, histologic subtypes associated with poor prognosis are predominant. Histologic differences are considered to be largely dependent on variable host immunologic response, which is influenced by genetic and environmental factors. Distribution of HL cases over age, gender, geographical areas and socioeconomic settings have long suggested multiple etiologically distinct entities for HL, rather than a single disease. The prevalent type in developing countries, as discussed earlier, is the MC histological subtype, which predominates in young children, particularly in males, and mainly presents as an advanced-stage disease. The hypothesis of an etiologic role of EBV in the pathogenesis of HL could partly explain these features. Studies have shown a causal relationship between infectious mononucleosis and subsequent Epstein-Barr virus (EBV)-positive HL [ 19 ]. Çavdar et al. showed a high frequency of EBV-related LMP-1 positivity (73.6%) in pediatric HL. Cases. Childhood HL in developed countries affects mainly older children, mostly presenting as NS histological subtype and might be explained by 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. Most of the data coming from the other centres, as well as the Turkish pediatric oncology group (TPOG) data, including 1823 children from 22 different centres 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 [ 20 ]. Our data, reflecting the figures from our country's mixed population, was more consistent with the data from other developing countries. The lower socioeconomic status may be a contributing factor to this striking resemblance. Prognostic Factors: In our study, prognostic factors evaluated for OS and EFS were the stage of disease, histological subtype, risk group, presence or absence of bulky disease, B symptoms, anaemia and elevated ESR, LDH & β2 macroglobulin levels. Factors found significant in the multivariate analysis for EFS were risk group and haemoglobin levels, while none were found statistically significant for OS in the multivariate analysis. Abnormalities in haemoglobin levels reflect cytokine activation, which may have a wide range of effects, from gene expression and influence on apoptotic potential to expression of adhesion molecules, which may influence metastatic capability [ 21 ]. Prognostic factors evaluated from other retrospective studies in India associated with a poor outcome and termed unfavourable include male sex, B symptoms, bulky mediastinal or peripheral lymphadenopathy, an extranodal extension of disease, and stage IIIb and stage IV disease. They found that the presence of B symptoms and advanced-stage disease were significantly associated with inferior outcomes and relapse, with advanced-stage disease being the only factor independently associated with an inferior outcome in their analysis [ 22 , 23 ]. Prognostic factor analysis has been reported in two studies of children with advanced HL from the Western world. The Pediatric Oncology Group (POG) found stage IV and male sex prognostic for inferior event-free survival [ 13 ]. In contrast, the Children's Cancer Group found stage, ESR, liver size, and mediastinal bulk among stage III patients as prognostic for inferior event-free survival [ 24 ]. Recently, in pediatric advanced Hodgkins lymphoma patients, a study by Schwartz et al [ 9 ] identified four factors prognostic for event-free survival: fever; stage IV lymphoma, bulky mediastinal lymphadenopathy and serum albumin less than 3.5 g/dL commonly identified as CHIP (Childhood Hodgkins lymphoma International Prognostic Score) score. Our study incorporated these four factors into a prognostic index and stratified patients into three groups with significantly different survival outcomes. EFS was 92% for patients with a CHIPS score of 0 or 1, 82% for those with a CHIPS score of 2, and 70% & 61% for those with a CHIPS score of 3 or 4 (EFS: p = 0.065). Table 5 Response rates in various advanced stage hodgkins lymphoma trial Study Group/Trial Sample Size Treatment EFS/DFS (%) OS (%) Follow-up (Years) St. Jude Children’s Research Hospital 25 30 (CS III) 5 COP(P)/4 ABVD + 20 Gy IFRT 97 100 5 27 (CS IV) 85 86 Stanford 15 13 (CS/PS IV) 3 MOPP/3 ABVD + 15-25.5 Gy IFRT 69 85 10 German Multi-Centre HD-90 17 124 (IR) 2 OEPA/OPPA + 2 COPP + 20–35 Gy IFRT 93 97 5 179 (HR) 2 OEPA/OPPA + 4 COPP + 20–35 Gy IFRT 86 94 5 Pediatric Oncology Group 26 179 4 MOPP/4 ABVD ± 21 Gy TNI 79 92 5 U.S. Children’s Cancer Group 12 394 6 COPP/ABV ± 21 Gy IFRT (intermediate risk) 88 (IFRT) 95 3 141 COPP/ABV + CHOP + Ara-C/VP-16 ± 21 Gy IFRT (high risk) 91 (IFRT) 100 3 German Multi-center HD-95 27,28 224 (IR) 2 OPPA/OEPA + 2 COPP + 20–35 Gy IFRT 91 97% (all) 3 280 (HR) 2 OPPA/OEPA + 4 COPP + 20–35 Gy IFRT 84 3 Stanford/St. Jude/Dana Farber 25 159 3 VAMP/3 COP + 15-25.5 Gy IFRT 75.5 92.7 5 PGIMER 22 206 (all stages) (4–6 cycles) ABVD/COPP MOPP/COPP VAEP/ABVD ABVD 77.75 92.7 5 AIIMS 23 148 (all stages) COPP(4)/ABVD(4) 87.9 91.5 5 TMH* 152 ( CS-IIB,III &IV) ABVD + 20–36 Gy IFRT 78 84 3 As seen from Table 5 , combined modality therapy with different chemotherapy regimens used in the West resulted in an EFS and OS in the range of 85–90% and 95%, respectively. Our study showed an EFS and OS at a median followup of 37 months of only 73% and 83%, respectively. Given the poor outcome of ABVD, associated toxicity and also the increased risk of subclinical dysfunction of the heart, lungs, and thyroid [ 10 ] in combination with involved-field radiotherapy (IFRT), there is a need to improve the results and decrease the toxicity in advanced stage hodgkins lymphoma. Two retrospective studies from India demonstrated the EFS and OS benefit in the range of 80–85% and 90–92%, respectively, but both the studies used hybrid regimens (MOPP/ABVD; COPP/ABV, VEEP) and involved all-stage patients [ 25 – 28 ]. Early Response and Outcome: Prior to treatment completion, early identification of chemoresistant disease would facilitate an individualized, risk-adapted strategy. Mid-treatment (interim) metabolic imaging via FDG-PET has strong potential. In HL and aggressive B-cell non-HL (NHL), it has been repeatedly recognized that PET performed after only 2 or 3 cycles of chemotherapy provides valuable prognostic information. Early achievement of a negative PET (absence of abnormal FDG uptake concerning for tumour) is prognostically favourable, whereas persistent abnormal FDG uptake on early PET, even in the context of a CT response, raises concern for treatment failure. PET performed after only one cycle also appears to have prognostic significance. Interim response evaluation by PET-CT scan in our study also showed a better EFS and OS for patients who achieved CR versus non-CR (94% & 94% versus 72% & 62% respectively, p = 0.001).This is further supported by a study in an adult population, which showed that Interim PET was the only significant prognostic factor. The 3-y EFS was 53.4% for PET-positive patients and 90.5% for PET-negative ones (P < 0.001). When patients were categorized according to low or high IPS risk and according to the early or advanced stage of disease, PET was also significantly associated with treatment outcome [ 29 ]. Thus, our first study has shown PET-CT-based early response as an accurate and independent predictor of EFS and OS in HL. A negative interim 18F-FDG PET result is highly predictive of treatment success in overall HL patients, as well as in subgroups with early or advanced-stage disease. Conclusions Our study has confirmed that the biology of HL is different as compared to west as evidenced by slightly older age of presentation, male preponderance, increased mixed cellularity histology. The OS and EFS of 83% and 78% with ABVD based therapy in our study is inferior to that of dose-intense regimens from west where OS and EFS approaches 94% and 90% respectively. CHIPS score has prognostic value in advanced HL in Indian patients in the context of ADVD based therapy but should be validated in prospective large clinical trial. Early PET based response is an important prognostic factor and may be used in tailoring therapy. This study suggests the need for employing combined modality therapy using aggressive dose-intense regimens with less overall chemotoxicity and addition of early metabolic response adapted treatment tailoring for optimizing outcome in children This study also highlights the need for large scale national multicentric trials to understand local biology of HL, define local risk factors, and test regionally relevant treatment strategies Abbreviations HL – HL RT – Radiotherapy IFRT – Involved Field Radiotherapy GDP – Gemcitabine, Dexamethasone, Cisplatin ICE – Ifosfamide, Carboplatin, Etoposide MINE – Mesna, Ifosfamide, Vinorelbine, Etoposide CR – Complete Remission OS – Overall Survival EFS – Event-Free Survival CHIPS – Childhood Hodgkin's International Prognostic Score TMH – Tata Memorial Hospital RF – Risk Factors COG – Children’s Oncology Group PR – Partial Response SD – Stable Disease PD – Progressive Disease RER – Rapid Early Response SER – Slow Early Response LDH – Lactate Dehydrogenase β2 microglobulin – Beta-2 Microglobulin ESR – Erythrocyte Sedimentation Rate ABVD – Adriamycin, Bleomycin, Vinblastine, Dacarbazine ABVE-PC – Adriamycin, Bleomycin, Vinblastine, Etoposide, Prednisone, Cyclophosphamide OEPA – Vincristine, Etoposide, Prednisone, Adriamycin OPPA – Vincristine, Procarbazine, Prednisone, Adriamycin BEACOPP – Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone COPP – Cyclophosphamide, Vincristine, Procarbazine, Prednisone ABV – Adriamycin, Bleomycin, Vinblastine MOPP – Mechlorethamine, Oncovin (Vincristine), Procarbazine, Prednisone G-CSF – Granulocyte-Colony Stimulating Factor PET – Positron Emission Tomography FDG – Fluorodeoxyglucose ABMT – Autologous Bone Marrow Transplant NS – Nodular Sclerosis MC – Mixed Cellularity LP – Lymphocyte Predominant LD – Lymphocyte Depleted IPS – International Prognostic Score Declarations Ethics approval and consent to participate : This retrospective study on prospectively collected data was approved by the Institutional Ethics Committee, TMH. Written informed consent was obtained from all patients at the time of primary diagnosis. Consent for publication : Not applicable. Availability of data and materials : The datasets generated and analyzed during the current study are not publicly available due to privacy restrictions but are available from the corresponding author upon reasonable request. Competing interests : The authors declare no competing interests. Funding : None Authors' contributions: All authors contributed equally Acknowledgements : We would like to thank Tata Memorial Hospital. Author Information : Amol Dongre : Medical Oncology, Jawaharlal Nehru Medical College, Wardha, India Karan Sood: Medical Oncology, Jawaharlal Nehru Medical College, Wardha, India Trupti Dongre : Pathology, N.K.P Salve Institute of Medical Sciences and Research Centre and Lata Mangeshkar Hospital, Nagpur, India Brijesh Arora : Pediatric Oncology, Tata Memorial Hospital, Mumbai, India References Hudson MM, Donaldson SS: HL: Principles and Practice of Pediatric Oncology Pizzo PA, Poplack DG (Eds). Lippincott Williams & Wilkins, Philadelphia; 2006. RuHL U, Albrecht MR, Lueders H, et al.: The German Multinational GPOH-HL 95 trial: Treatment results and analysis of failures in pediatric Hodgkins lymphoma using combination chemotherapy with and without radiation (abstract). Int J Radiat Oncol Biol Phys. 2004, 60:131. 10.1016/j.ijrobp.2004.06.029 Smith R, Chen Q, Melissa M, et al.: Prognostic Factors for Children With HLTreated With Combined-Modality Therapy. J Clin Oncol. 2003, 21:2026. 10.1200/JCO.2003.07.124 Ferraris AM, Racchi O, Rapezzi D, et al.: Familial HL: a lymphoma of young adulthood?. Ann Hematol. 1997, 74:131. 10.1007/s002770050270 Correa P, O'Conor GT: Epidemiologic patterns of HL. Int J Cancer. 1971, 8:192. 10.1002/ijc.2910080203 Arora RS, Eden T,Kapoor G: Epidemiology of childhood cancer in India.. Indian journal of cancer. 2009, 46:264-73. 10.4103/0019-509X.55546 Foltz LM, Song KW, Connors JM: HL in adolescents. J Clin Oncol. 2006, 24:2520. 10.1200/JCO.2005.04.5823 Dinand V, Arya L.S: Epidemiology of Childhood HL: Is it Different in DevelopingCountries?. Indian Pediatrics. 2006:141-7. Scwartz C, Lu Chen, Louis Constine, et al.: The Childhood Hodgkin International Prognostic Score (CHIPS) for Predicting Event Free. Survival in Pediatric. 2010, 10.1002/pbc.26278 Donaldson SS, Link MP, Weinstein HJ, et al.: Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk HL. J Clin Oncol. 2007, 25:332. 10.1200/JCO.2006.08.4772 Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with HL who achieve a complete response to chemotherapy. J Clin Oncol. 2002, 20:3765. 10.1200/JCO.2002.12.007 Tebbi CK, Mendenhall N, London WB, et al.: Treatment of stage I, IIA, IIIA1 pediatric HL with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: a Pediatric Oncology Group (POG) study. Pediatr Blood Cancer. 2006, 46:198. 10.1002/pbc.20546 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. 9:1591-1598. 10.1200/JCO.1991.9.9.1591 Bonadonna G, Zucali R, Monfardini S, et al.: Combination chemotherapy of Hodgkin’s disease with Adriamycin, Bleomycin, Vinblastin and Imidazole Carboxamide versus MOPP. Cancer. 1975, 36:252-259. 10.1002/1097-0142(197507)36:13.0.co;2-7 S.P. Hunger, M.P. Link and S.S. Donaldson: ABVD/MOPP and low-dose involved-field radiotherapy in pediatric Hodgkin’s disease: The Stanford experience. J Clin Oncol. 12:2160-2166. 10.1200/JCO.1994.12.10.2160 Kelly KM, Sposto R, Hutchinson R, et al.: BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk HL: a report from the Children's Oncology Group. Blood . 2011, 9:2596-603. 10.1182/blood-2010-05-285379 Schellong G, Pötter R, Brämswig J, et al.: High cure rates and reduced long-term toxicity in pediatric Hodgkin's disease: the German-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric Hodgkin's Disease Study Group. J Clin Oncol . 1999, 12:3736-44. 10.1200/JCO.1999.17.12.3736 Schwartz CL, Constine LS, Villaluna D, et al.: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk HL: the results of P9425. Blood. 2009, 114:2051. 10.1182/blood-2008-10-184143 C¸ avdar AO, Pamir A, Go¨zdasoglu S, et al.: Hodgkin’s disease in children: Clinicoepidemiologic and viral (Epstein-Barr virus) analyses. Med Pediatr Oncol. 1999, 32:18-24. 10.1002/(sici)1096-911x(199901)32:13.0.co;2-s Mutafoglu K U, Çetingoz R, Gunes D, et al.: Clinical characteristics and therapy outcome of pediatric Hodgkin’slymphoma - a single centre experience from the west part of Turkey. Turkish Journal of Cancer Volume 37, No. 3. 2007: Kadin ME, Leibowitz DN : Cytokines and cytokine receptors in Hodgkin’s disease.. Philadelphia, PA, Lippincott; 1999. pp:139-157. Amita Trehan, Shaveta Singla, Ram K. Marwaha, et al.: HL in Children: Experience in a Tertiary Care Centre in India. J Pediatr Hematol Oncol. 2012, 000-000. 10.1097/MPH.0b013e318271f587 Arya LS, Dinand V, Thavaraj V, et al.: HL in Indian children: outcome with chemotherapy alone. Pediatr Blood Cancer. 2006, 46:26-34. 10.1002/pbc.20157 Hutchinson RJ, Fryer CJH, 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. 16:897-906. 10.1200/JCO.1998.16.3.897 M.M. Hudson, M. Krasin, M.P. Link, 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. 22:4541-4550. 10.1200/JCO.2004.02.139 Weiner M, 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, 15:2769-2779. 10.1200/JCO.1997.15.8.2769 U. Ruhl, M. Albrecht, K. Dieckmann, 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. 51:1209-1218. 10.1016/s0360-3016(01)01798-9 W. Dorffel, H. Luders, U. Ruhl, et al.: Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin’s disease in children and adolescents: Analysis and outlook. Klin Padiatr. 2003, 215:139-145. 10.1055/s-2003-39372 Juliano J. Cerci1, Luı´s F. Pracchia, Camila C.G, et al.: 18F-FDG PET After 2 Cycles of ABVDPredicts Event-Free Survival in Earlyand Advanced HL. J Nucl Med . 2010, 51:1337-43. 10.2967/jnumed.109.073197 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5990461","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":414181798,"identity":"5d50bd04-792f-4ca0-bba7-c9d804dc63f6","order_by":0,"name":"Amol Dongre","email":"","orcid":"","institution":"Datta Meghe Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Amol","middleName":"","lastName":"Dongre","suffix":""},{"id":414181799,"identity":"89b86c09-f446-460d-b56b-bd63ce8c17a4","order_by":1,"name":"Karan Sood","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYBACCTiLvQFIGFiQooXnAEiLBE6VWLRIJKDycQLJ9rMPPxcw2OTxz3x+dcOPAgkG/vbuBLxapHnSjaVnMKQVS9zOKbvZA3SYxJmzG/BqkWNIA2pjOJy4QTon7QYPUIuBRC4BLfzPmH+DtUieSbv5hxgt0hJpbBBbJNiP3SbKFskZz9iseQzSEmecyWG7LWMgwUPQLxLn05hv81TYJPa3H392880fGzn+9l78WiDAAETwQEgilMMB+wNSVI+CUTAKRsEIAgA+7D8DMbkPNgAAAABJRU5ErkJggg==","orcid":"","institution":"Datta Meghe Institute of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Karan","middleName":"","lastName":"Sood","suffix":""},{"id":414181800,"identity":"205d9720-93d4-4a86-bd68-e45c724d048c","order_by":2,"name":"Trupti Dongare","email":"","orcid":"","institution":"NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital","correspondingAuthor":false,"prefix":"","firstName":"Trupti","middleName":"","lastName":"Dongare","suffix":""},{"id":414181801,"identity":"b09b234b-6d5b-4df4-88a3-f894a1a167ef","order_by":3,"name":"Brijesh Arora","email":"","orcid":"","institution":"Tata Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Brijesh","middleName":"","lastName":"Arora","suffix":""}],"badges":[],"createdAt":"2025-02-09 04:23:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5990461/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5990461/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":76108552,"identity":"10769907-e91e-429d-b491-b5709c8346e7","added_by":"auto","created_at":"2025-02-12 11:37:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65027,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier Curves for OS and EFS according to interim PET-CT evaluation\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5990461/v1/761de22342d3df24517c74f8.png"},{"id":76109624,"identity":"a2fed9a7-628f-45df-933e-ee8d7f6e1d7e","added_by":"auto","created_at":"2025-02-12 11:45:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24301,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan Meier curves for OS and EF\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5990461/v1/bff1b43f8d2583d9bffa4623.png"},{"id":76108521,"identity":"92893adb-4b65-4af8-99ee-2d3789a2e327","added_by":"auto","created_at":"2025-02-12 11:37:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":77125,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curves for EFS according to CHIPS score\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5990461/v1/1c36dfeccf3e02f62f005527.png"},{"id":78802348,"identity":"b2c43cea-abc5-4b63-a902-e2662deafa9c","added_by":"auto","created_at":"2025-03-19 06:53:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2109234,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5990461/v1/23012f8c-766e-47ec-b826-1b43556f09f7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Presentation and Outcome of Hodgkin's Lymphoma in Children: A Retrospective Study","fulltext":[{"header":"Background","content":"\u003cp\u003eHL (HL) comprises 6% of all childhood cancers. It is a rare cancer before the age of 5 years, with the highest incidence occurring between years 15\u0026ndash;30. It has a bimodal presentation peak, with the second peak occurring after age 55 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Childhood HL is defined as affecting those less than 15 years of age. There is an inverse relationship between the incidence of HL in children and young adults within countries according to their economic development. Based on limited data from India, HL is more common than NHL, has a lower age peak, and is more common in males with a predominance of mixed cellularity phenotype and a significant association with EBV. Although many Western studies have identified prognostic factors, in local studies, there is limited data from India or validation of Western factors in Indian studies.\u003c/p\u003e \u003cp\u003eThe treatment of HL in the West is different from that in India. Most centres in India use 2\u0026ndash;6 cycles of ABVD chemotherapy followed by IFRT for bulky and residual lymphoma, unlike the alkylator and anthracycline-free regimens like OEPA/OPPA, VAMP, ABVE for low-risk HL, and dose-intensive regimens like ABVE-PC, BEACOPP for high-risk HL. In India, there is limited published data on outcome, which shows variable 5-year survival ranging from 65\u0026ndash;94%, which seems lower than 85\u0026ndash;95% survival in the west [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Modern strategies focus on reducing late effects while maintaining excellent cure rates using response-adapted therapies. FDG PET avidity after two cycles of chemotherapy is a good predictor of treatment failure in adults but has been evaluated in children. There is limited data on the clinical presentation and outcome of HL in children from India. Tata Memorial Hospital is the largest pediatric oncology centre in the country, treating more than 1500 children with cancer per year, including approximately 100 children with HL. This study has helped us understand the clinical-biological differences from the West, dissecting the local prognostic factors, assessing the outcome and toxicity with current therapy, and optimizing the future treatment for this highly curable disease while minimizing the acute and late toxicities.\u003c/p\u003e"},{"header":"Materials \u0026 Methods","content":"\u003cp\u003eThe primary aim was to assess event-free survival, overall survival and tumour response. The secondary aim was to assess the local clinic-biological features and compare them with the west, evaluate the local prognostic factors with the current therapy, examine the value of CHIPS score in predicting outcomes in advanced lymphoma at TMH, and evaluate for acute toxicity of therapy.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003eMethodology\u003c/b\u003e:\u003c/h2\u003e \u003cp\u003eThis retrospective observational study includes pediatric patients (up to 15 years) with HL who had registered at the pediatric oncology OPD at our hospital from January 2005 to December 2010. This study was approved by the Hospital Ethics Committee, and a waiver of consent was granted since the patients had received treatment before initiating the retrospective analysis. The medical records of these patients are available from our medical record department. Medical records and lymphoma clinic charts were reviewed for presenting symptoms, examination findings, laboratory investigations and treatment done outside, if any, prior to our hospital presentation. The investigations done at our hospital to confirm the diagnosis, stage of the disease, and risk stratification of the patients were collected. Treatment at our hospital was recorded, including chemotherapy regimen, number of chemotherapy cycles, and second and subsequent lines of treatment. Radiation therapy charts for field, volumes and dose were obtained. The response and toxicity to each line of treatment were recorded from the charts as per the guidelines. The investigations done for interim response assessment and end-of-treatment response were recorded. The restaging and response assessment investigations were recorded in case of a relapse, along with the treatment given. The patient\u0026rsquo;s disease status till the last followup was recorded. Here, we report our results of advanced-stage HL patients.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCurrent therapy of HL:\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly favourable HL: Stage I \u0026amp; II without RF: 2\u0026ndash;4 cycles of ABVD \u0026amp; low dose IFRT.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly Unfavourable HL: Stage I \u0026amp; II with RF, IIIA: Four cycles of ABVD \u0026amp; low dose IFRT to bulky/residual sites.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdvanced HL Stage III \u0026amp; IV: Six cycles of ABVD with low dose IFRT to bulky/residual sites.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRF (Risk factors): Bulky disease lymphoma, B-symptoms and \u0026gt;\u0026thinsp;three nodal sites.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInclusion Criteria:\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll consecutive newly diagnosed children up to 15 years with HL who have registered in Pediatric oncology OPD from January 2005 till December 2010 were included in the study protocol.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eExclusion criteria:\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Any prior chemotherapy or radiotherapy.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Incomplete treatment details.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. Nodular lymphocyte predominant HL.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section4\"\u003e \u003ch2\u003e\u003cb\u003eAnalysis of the variables\u003c/b\u003e:\u003c/h2\u003e \u003cp\u003eTumor responses were classified according to the COG response criteria based on CT and PET-CT scans.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eComplete Response (CR)\u003c/strong\u003e \u003cp\u003eAll of the criteria must be fulfilled in order to achieve CR.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabd\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Resolution of pathologic palpable lymphadenopathy. At least 80% reduction in the PPD of each nodal mass, or return to normal size. No residual nodal mass, except the mediastinal mass, may be greater than 2.0 cm in maximal transverse diameter. A mediastinal mass may be larger than 2 cm, provided it has demonstrated at least 80% reduction in the PPD. Individual nodes that were previously confluent must have regressed by more than 80% of the sum of the products of their perpendicular diameters (SPPD) compared with the size of the original mass.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Nodal masses that have not regressed at least 80% in their PPD or returned to normal size may reflect residual disease or fibrotic changes, and biopsy should be considered.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. No residual disease in non-measurable assessable lesion sites.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. No new lesion(s).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5. FDG-PET or Gallium negative.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePartial Response (PR):\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabe\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. At least a 50% reduction in the PPD of each area of measurable disease, or return to normal nodal size, but not constituting a CR.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Individual nodes that were previously confluent must have regressed by more than 50% in their SPPD compared to the size of the original mass.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. No progression of non-measurable assessable disease sites.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. No new lesion(s).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5. FDG-PET or Gallium may be positive or negative.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eStable disease (SD):\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabf\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Less than a partial response but not progressive disease.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive disease (PD): (any of the following)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. At least a 50% increase in the PPD of any involved nodes or nodal masses.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. New lesion(s).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. Progression of a non-measurable assessable disease site.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section4\"\u003e \u003ch2\u003eRER and SER Definitions:\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabg\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Rapid Early Response (RER):\u0026nbsp;Complete Response (CR) or very good partial response (VGPR) following two cycles of chemotherapy.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Slow Early Response (SER):\u0026nbsp;Less than CR following two cycles of chemotherapy.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis:\u003c/h2\u003e \u003cp\u003eDescriptive variables were used to include numbers, tables, charts, and graphs to describe, organize, summarize and present raw data. Progression-free survival and Overall survival were calculated from the date of diagnosis to the date of relapse/progression and the date of the last follow-up, respectively. Event-free survival was calculated from the date of diagnosis to the date of any event, i.e. relapse, progression or death due to any cause. Kaplan-Meier graphs were plotted for survival curves. The Cox- proportional hazards model was used to determine variables affecting the above outcomes.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWe enrolled 355 HL patients from January 2005 to December 2010. One hundred sixty-five patients had advanced stage HL (stage IIBX, III \u0026amp; IV). One hundred fifty-two patients were included in the final analysis of advanced-stage HL. Thirteen patients were excluded due to the following reasons: patients who had no treatment after diagnosis (n:10), patients with diagnoses other than classical HL (n:1) or patients who had to complete part of their treatment in different centres (n:2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Characteristics:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable \u003cem\u003e1\u003c/em\u003e shows the characteristics of 152 advanced-stage HL patients in this study. The median age was 9.27 years (range 3-15 years). Eighty-five per cent (130/152) of the patients were males. The M: F ratio was 5.9:1. The most common histologic subtype was mixed cellularity (49.3%) followed by nodular sclerosis (30%), Classical-NOS (not otherwise specified) (11.2%), Lymphocyte predominant (8%) and others (3%). Fifty-three per cent (81/152) had B symptoms at presentation. Stage IIBx, III and stage IV lymphomas were seen in 3% (5/152), 72% (109/152), and 25% (38/152) patients, respectively. Bone marrow involvement was seen in 9% (20/223) of patients. Twenty-five per cent of patients (38/152) had one or more areas of extra-nodal participation at diagnosis. Anatomical locations mostly involved were marrow (n: 15), liver (n: 11), lung (n: 11), skeletal (n: 3), peritoneal (n: 2) and gonadal (n:1). Twenty per cent of patient (31/152) had intermediate-risk disease while 80% (121/152) had high-risk disease. Bulky disease was seen in 46% (69/152) patients. Fifty per cent of patients (74/152) had anaemia at baseline presentation as defined by haemoglobin level of less than 10.0gm%, raised ESR, LDH \u0026amp; \u0026beta;2 microglobulin levels were present in 44.7%, 77.6% and 36% of patients at baseline.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1: Baseline characteristics of all patients\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOTAL (n=152)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWestern data 8,17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e130 (85.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e49 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e22 (14.5%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e49 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale: Female\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e5.9:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e1:1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian Age (years): \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e9.27 (3-15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e14 (4-20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage: IIB \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e5 \u0026nbsp;(03%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e23 (23%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage: III \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e109 (72%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e17 (17%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage: \u0026nbsp;IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e38 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e58 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBulky disease*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e69 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e64 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Grouping: Intermediate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e31 (20%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e30 (30%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Grouping: High \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e121 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e68 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCHIPS score: \u0026nbsp;0,1 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e70 (46%) \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e589 (76.4%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCHIPS score: \u0026nbsp;2 \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e57 (37.5%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e141(18.3%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCHIPS score: \u0026nbsp;3,4 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e25 (16.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e32 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB symptoms:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e81 (53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e69 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNote: *Bulky disease is defined as a nodal mass whose greatest dimension is \u0026gt; 7 cm in size and/or a widening of the mediastinum (middle chest by \u0026gt; 1/3rd)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment response:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForty-five per cent of patients (68/152) received radiation therapy with doses ranging from 19.8 Gy to 30.6 Gy to the residual and bulky disease sites. CR and PR rates observed were 84% (127/152) and 8% (12/152), respectively, for the whole group, while thirteen patients (9%) had PD at the end of completion of first-line chemotherapy \u0026plusmn; IFRT. Median number of treatment cycles received was six (range 4 to 8). Mid-cycle evaluation was done in 110 patients (73%). Fifty-seven per cent of patients (63/110) were in CR, thirty-nine per cent (43/110) in PR, and three per cent of patients (4/110) had progressive disease at interim response evaluation. Fifty-three per cent of patients (81/152) had an interim response evaluation done by PET-CT scan, which showed a CR, PR and progressive disease of 66.7%, 28.4% \u0026amp; 5.1%, respectively. The OS and EFS were 94% and 94% for rapid early responders, whereas OS and EFS were 72% and 68% for slow early responders, with statistically significant differences in OS and EFS. (for OS: p =0.002; EFS:p = 0.001) for CR versus non-CR patients at a median followup of 37 months when evaluated by interim PET-CT scan, as shown in Figure 1. Out of the 54 patients who achieved CR at interim PET-CT scan, one patient expired due to treatment complication (Bleomycin toxicity), while three patients relapsed. All three patients received salvage chemotherapy and were alive at the last followup. A total of six patients (4%) underwent autologous bone marrow transplant (ABMT). Two patients were in PR, and the remaining four were in CR at the time of ABMT. Two patients received MINE, while four received GDP as a salvage chemotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eToxicity\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHematological\u003c/strong\u003e: Only three patients developed febrile neutropenia while on chemotherapy. None of the patients required ICU. Admission during chemotherapy. None of the patients developed grade 4 thrombocytopenia or anaemia due to chemotherapy requiring transfusions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNon-haematological\u003c/strong\u003e:\u0026nbsp;Five per cent of patients (8/152) developed clinical bleomycin-induced lung toxicity requiring stoppage of bleomycin, as evidenced by a decline in pulmonary functions and radiological confirmation. Baseline echocardiography was done in 141 (92%) patients. None of the patients developed clinical cardiotoxicity with anthracycline-based chemotherapy till the last followup.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome \u0026amp; Survival Rates:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up time was 37 months (2-80 months). Twenty-one per cent of patients (32/152) progressed or relapsed in the cohort. Eleven patients (7%) had primary progressive disease, while eight (5%) and thirteen patients (8.6%) had early and late relapses, respectively. Relapses were more frequent in patients with a bulky disease than in non-bulky patients. Of the 21 relapsed patients, 11 (52%) received RT during\u0026nbsp;the course of\u0026nbsp;initial treatment. Ninety per cent (19/21) of patients had relapsed at their primary site, while only two patients relapsed at sites other than primary. (1 patient relapses in the liver; 1 in skeletal tissue and spleen). None of them had received RT for primary disease.\u003c/p\u003e\n\u003cp\u003eThe study group\u0026apos;s 3-year EFS and OS rates were 77% and 83%, respectively, as shown in Figure \u003cem\u003e2\u003c/em\u003e. A total of 18 patients died in the studied cohort, of which two patients died during ongoing chemotherapy (2 died of bleomycin-induced lung toxicity), 4 had progressive disease \u0026amp; remaining 12 patients had disease relapsed, which was refractory. No patients died during followup. At the last followup (median 37 months), 88% (134/152) of patients were alive. Three patients were still on treatment for relapse.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe factor that was statistically significant on univariate analysis, as shown in Table \u003cem\u003e2\u003c/em\u003e for OS, was \u0026beta;2 microglobulin levels, while for EFS, \u0026beta;2 microglobulin levels, stage of the disease and haemoglobin levels were substantial. Factors analyzed in multivariate analysis, as shown in Table \u003cem\u003e3\u003c/em\u003e for OS, were a stage, bulky disease, B symptoms, haemoglobin, \u0026beta;2 microglobulin, risk group, and histology (mixed cellularity versus non-MC). None of the factors were statistically significant for overall survival. For EFS, factors evaluated on multivariate analysis, as shown in Table \u003cem\u003e4\u003c/em\u003e, were B symptoms, bulky disease, risk group, haemoglobin level, \u0026beta;2 microglobulin, and histology, and the factors that were found statistically significant for EFS were risk group and haemoglobin levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Univariate analysis for prognostic factors\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSr.No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrognostic factors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS (P value)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEFS (P value)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHistology : MC versus non MC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.202\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBulky disease : yes/no\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eB symptoms; presence or absence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eStage: II/III/IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.008*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRisk group: Intermediate vs High\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSerum LDH; \u0026lt;190 vs.\u0026gt;191\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBeta 2 microglobulin\u0026lt;2.4 vs. \u0026gt;2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.01*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.002*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eESR: \u0026lt;20 vs. \u0026gt;20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHemoglobin: \u0026lt;10 vs. \u0026gt;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.005*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSerum albumin:\u0026lt;3.5 vs. \u0026gt;3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.988\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Multivariate analysis for OS\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"641\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 135px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWald\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003edf\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSig.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eH.R\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95.0% CI for Exp(B)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLower\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSTAGE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-1.110\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.095\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.028\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.311\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.330\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.039\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB-Symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-.111\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.613\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.856\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.895\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.269\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBulky disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-.260\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.659\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.156\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.693\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.771\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.212\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-1.032\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.203\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.736\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.391\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.356\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.034\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHemoglobin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-.624\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.653\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.914\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.339\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.536\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.149\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003csub\u003e2\u003c/sub\u003emicroglobulin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-.462\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.604\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.584\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.445\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.630\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.193\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-.764\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.618\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.528\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.216\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.466\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.139\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAccording to Childhood Hodgkin\u0026apos;s International Prognostic Score (CHIPS), 46% (70/152) patients had a score of 0-1, 37.5% (57/152) patients had a score of 2 and 16.4% (25/152) patients had a score of 3-4. We evaluated the CHIPS score as a prognostic factor for event-free survival rate; EFS, as depicted in Figure 3, was 92% for patients with a CHIPS score of 0 or 1, 82% for those with a CHIPS score of 2, and 70% \u0026amp; 61% for those with a CHIPS score of 3 or 4 (EFS: p = 0.065).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Multivariate analysis for EFS\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 131px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWald\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003edf\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSig.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eH.R\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 149px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95.0% CI for Exp(B)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLower\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUpper\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB-Symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.325\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.502\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.420\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.517\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.384\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.518\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.702\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBulky-disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.350\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.530\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.436\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.509\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.419\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.502\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk-Group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-2.212\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.126\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.858\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.050\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.110\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.995\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHemoglobin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-1.874\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.636\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.674\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.154\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.044\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.534\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003csub\u003e2\u003c/sub\u003emicroglobulin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-.485\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.566\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.734\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.392\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.616\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.203\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.866\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-.348\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.495\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.495\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.482\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.706\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.268\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.862\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eHL treatment is one of the success stories of modern medicine. There is a unified pathologic classification schema, a noninvasive staging evaluation, and an increasingly sophisticated approach to therapy with risk and response-adapted therapies in pediatric and adult patients. Survival rates have continued to improve while treatment modifications to decrease late effects are studied across all populations. However, a strong age gradient exists with respect to patient outcomes, with younger patients faring somewhat better than their adult counterparts and older adults faring significantly worse. There has been a growing appreciation for the differences in epidemiology across age groups and the potential differences in lymphoma biology. Novel approaches to prognostic stratification and therapy based on these differences may be necessary to maximize cure and minimize late effects across the ages.\u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eEpidemiology of HL in India:\u003c/h2\u003e \u003cp\u003eIn India, HL exceeds non-HL, a pattern opposite to the West. This is due to the result of a higher incidence of HL in male children. A study by Arora et al. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] has shown a remarkable 12-fold increase in the incidence of HL in males in Delhi. The incidence of HL in India ranges from 8.2\u0026ndash;19.6 per million children per year compared to 5.7 in the USA and 6.4 in Britain [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In developing countries, it occurs predominantly during childhood, with its incidence decreasing. In contrast, it occurs more commonly in industrialized countries in adolescents or young adults than young children. The patterns are similar to the occurrences of Epstein-Barr virus (EBV), tuberculosis and poliomyelitis infections. Childhood HL also shows a predilection for the male gender, with the M: F ratio being 1.5:1 in the West compared to adult HL, which occurs equally in both sexes. India shows a significant male predominance in HL, much higher than in any other type of childhood cancer. Various studies have shown different sex distributions from M: F of 1.8:1 in Bangalore to 7.4:1 in Delhi and 6:1 in Mumbai [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The sex distribution discrepancy is not yet fully understood. In the case of India, it could also be due to poor healthcare access for females, reflecting the cultural disinterest in the female child. EBV's association with HL has been shown by various epidemiological, serological and pathological studies. EBV infection is more commonly associated with mixed cellularity histology in childhood HL (\u0026lt;\u0026thinsp;10 years) and less developed regions. In India, EBV was found in 78% of all ages HL cases and 91\u0026ndash;98% of children. This leads to an earlier incidence peak in India compared to 16\u0026ndash;30 years in the West. HL could be caused by a genetically determined abnormal immune response to a childhood infection. This hypothesis is supported by the increased incidence of HL among patients with immune deficiency states, such as ataxia telangiectasia or HIV infection. There is a threefold to sevenfold increased risk of HL for the siblings of young adults with HL, and siblings of the same sex as the affected person have a risk double that of siblings of the opposite sex [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe WHO classification of lymphomas divides HL into classical HL and nodular lymphocyte predominant HL. Classical HL occurs more commonly (90 to 95 per cent of cases) than nodular lymphocyte-predominant HL and is subdivided into four subtypes: Nodular sclerosis (NS), Mixed cellularity (MC), Lymphocyte predominant(LP) and Lymphocyte depleted(LD). In the West, NS is the most common form of pediatric HL, representing 70 to 80 per cent of cases in adolescents and 40 to 50 per cent of cases in children younger than ten years of age. However, in India, mixed cellularity represents the most common form of HL. The incidence of MC decreases with age, from 30 to 35 per cent in younger children to 10 to 15 per cent in adolescents. LD and LR are rare events, accounting for fewer than 5% of all HL cases. Advanced HL (Stage IIBX, III \u0026amp; IV) in children requires more aggressive therapy. The data from various international study groups show that outcomes can be improved significantly by increasing the dose intensity of treatment. Modern CMT trials report 5-year EFS rates greater than 80% in advanced lymphoma [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Hybrid regimens using ABVD/ABV alternating with MOPP/COPP provide disease control in about 75% of stage IIB-IV patients without RT [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Still, stage IV patients do poorly with such conventional therapy, whether additional IFRT is administered or not.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003ePrognostic factors in Pediatric HL:\u003c/h2\u003e \u003cp\u003ePrognostic factors have been identified in adult patients with HL, and several prognostic indices have been developed to guide therapy decisions. However, these indices may not be relevant for children with HL. Prognostic factor analysis has been reported in two studies of children with advanced HL. The Pediatric Oncology Group (POG) found stage IV lymphoma and male sex as prognostic for inferior event-free survival. In contrast, the Children's Cancer Group found stage, ESR, liver size, and mediastinal bulk among stage III patients as prognostic for inferior event-free survival [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recently, CHIPS scores, like the IPSS score (Hesenclever index) for adult HL, have been found to be a useful tool to prognosticate pediatric HL in the West, and it may be a valuable tool to predict outcomes in advanced HL in India, but it needs validation due to different lymphoma biology and therapeutic strategy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eTreatment of Pediatric HL:\u003c/h2\u003e \u003cp\u003eHL in children is one of the most curable malignancies of childhood. Chemotherapy alone or in combination with radiotherapy (RT) is the preferred mode of treatment, both being associated with significant acute and late toxicities. Combining chemotherapy and radiotherapy broadens the spectrum of toxicity while reducing the incidence and severity of individual drug and radiation toxicity. Therapy at TMH includes 2\u0026ndash;6 cycles of ABVD chemotherapy followed by IFRT to bulky and residual lymphoma. ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) developed in the 1970s made long-term survival possible for patients with advanced and unfavourable (e.g., bulky, symptomatic) HL [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The response rate and outcome of advanced-stage HL with an ABVD regimen is around 80\u0026ndash;84%. ABVD-related sequelae include a dose-related risk of cardiopulmonary toxicity related to doxorubicin and bleomycin. The cumulative dose of these agents is proactively restricted in pediatric patients to reduce this risk. Commonly used regimens in the West for early stages include four cycles of VAMP plus LD-IFRT or four cycles of COPP/ABV plus LD-IFRT or ABVE administered for two to four courses depending on the response, followed by LD-IFRT or OEPA for males or OPPA for females followed by LD-IFRT, depending upon the initial response to chemotherapy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Similarly, commonly used dose-intense regimens in advanced lymphoma include BEACOPP, ABVE-PC or COPP/ABV without IFRT. Efforts have also been made to try to eliminate RT from the treatment strategy. However, the survival advantage was noted with combined modality therapy over chemotherapy alone. Intensification of therapy using dose-intense hybrid regimens has improved the outcomes in advanced-stage HL and patients having unfavourable factors. The role of IFRT in this group of patients has been studied with mixed results. Some studies showed EFS and OS advantages with the addition of IFRT to chemotherapy, while the POG 8725 study showed no difference in EFS or OS. The various dose-intensified chemotherapy protocols, such as Stanford V (nitrogen mustard, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisolone) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone) along with G-CSF improved the outcome of adults with advanced HL with acceptable toxicity [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The first attempt to treat children with stage IIB, IIIB or IV with four doses of escalated BEACOPP [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] as induction therapy has shown feasibility and good tolerance in children. The rapid early responders received either four cycles of COPP/ABV (girls) or 2 ABVD plus IFRT (boys), while slow early responders received four more BEACOPP cycles plus IFRT. The results show a significant improvement in EFS (91%) and OS (98%), but further follow-up is necessary to evaluate the effectiveness and long-term toxicity of dose-intensive chemotherapy in children. The role of additional RT in involved sites in stage III or IV disease remains controversial. The overall consensus is that the use of IFRT improves the event-free survival by 5\u0026ndash;15% across various studies but not the overall survival.\u003c/p\u003e \u003cp\u003eRecent studies indicate that the outcome of patients with unfavourable risk factors has improved with the intensification of chemotherapy. In the German HL-DAL 90 protocol [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], after two cycles of OPPA or OEPA, for intermediate- and high-risk HL, an additional 2 or 4 cycles of COPP (cyclophosphamide, vincristine, procarbazine, and prednisone) were given. All patients received 20- to 35 Gy IFRT, including those with stage III and IV disease. Five-year EFS in the intermediate- and high-risk groups was 93% and 86%, respectively. The EFS in these groups was comparable to that seen in the low-risk group, with all three risk groups experiencing 5-year OS rates\u0026thinsp;\u0026ge;\u0026thinsp;94%. In the HD-95 trial, which used the same chemotherapy, but IFRT was omitted in complete responders, the EFS for intermediate- and high-risk patients was 91% and 84%, respectively [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Substitution of dacarbazine for procarbazine (OEPA-COPDAC) in boys produces comparable results to standard OPPA-COPP in girls when used in combination with IFRT for intermediate- and high-risk patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In the CCG 5942 protocol children with intermediate-risk disease received six cycles of COPP/ABV; those with high-risk disease received two courses of intensive multidrug chemotherapy with cytarabine/etoposide, COPP/ABV, and cyclophosphamide, vincristine, doxorubicin, and methylprednisolone/prednisone with granulocyte colony-stimulating factor support. The children who achieved complete remission were randomly assigned to 21 Gy IFRT or no further therapy. Three-year EFS rates for patients receiving IFRT were 93% vs 85% for those not receive IFRT [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Other studies have also used low-dose IFRT after chemotherapy in intermediate-risk with good disease control. The Pediatric Oncology Group trial has used response-based, risk-adapted therapy utilizing dose-dense ABVE-PC (prednisone and cyclophosphamide) for unfavourable advanced-stage patients in combination with 21 Gy IFRT. A dose-dense, early response-based treatment approach with ABVE-PC permitted a reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response after three ABVE-PC cycles. Five-year EFS was comparable for rapid early responders (86%) and slow early responders (83%) treated with three and five cycles of ABVE-PC, respectively, followed by 21 Gy radiation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on the above studies, intensification of chemotherapy can overcome the adverse features of many patients with intermediate and high-risk diseases. Treatment with 4 to 6 cycles of multiagent chemotherapy followed by low-dose IFRT can produce good results, although achieving EFS\u0026thinsp;\u0026gt;\u0026thinsp;90% in high-risk patients remains challenging. Notably, the use of RT in the management of advanced-stage pediatric HL differs considerably from the usual practice for adult HL. In both the GPOH HD-9520 and CCG 5942, the benefit of IFRT in reducing relapse rates was most pronounced among high-risk patients. In the HD-95 study, intermediate- and high-risk patients who received IFRT had significantly better EFS than those who did not, despite the latter group achieving a better response to chemotherapy. In the CCG 5942, IFRT was associated with an 11%, 5%, and 12% improvement in 3-year EFS among low-, intermediate-, and high-risk patients, respectively [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Accordingly, IFRT remains an important component of treatment in intermediate- and high-risk diseases in most multi-institutional pediatric protocols. There is limited data on the clinical presentation and outcome of HL in children from India. This study at Tata Memorial Hospital was our attempt to understand the clinicobiological differences from the West, dissecting the local prognostic factors, assessing the outcome \u0026amp; toxicity with current therapy and optimizing the future treatment for this highly curable lymphoma while minimizing the acute \u0026amp; late toxicities.\u003c/p\u003e \u003cp\u003eRisk-adapted treatment in children with HL based on pretreatment factors attempts to spare patients with favourable lymphoma presentations from the potential toxicity of aggressive treatment while reserving this therapy for those with a high risk of relapse after conventional treatment. However, many pretreatment factors must be systematically analyzed to determine their relationship to the outcome. We undertook this study to understand the local biology of HL, identify pretreatment characteristics prognostic for outcome, validate the western prognostic subgroups in our cohort, analyze the outcome with ABVD-based chemotherapy and incorporate them into a prognostic index that could stratify pediatric patients into risk groups on which to base treatment decisions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eBiology:\u003c/h2\u003e \u003cp\u003eThe median age of our patients was 9.7 years. We had only 21 patients (13%) younger than five during the initial diagnosis. In our study group, the M: F ratio was 5.9:1, which is similar to studies published by AIIMS and PGIMER Chandigarh, where the median age of presentation was eight years and 7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6 years, whereas the M: F ratio of 8:1 and 10.6:1 respectively. We had only 21 patients (13%) younger than five during the initial diagnosis. 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 five years of age, against some 5% in developed countries 4,16,17 Pediatric HL also 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 8:1 and 10:1. Similar to the general national figures as well as the data from other developing countries, MC histopathologic subtype (50%) was the most common in our study population which was very similar to other published studies from India. However, 30% of our cases had NS histology, a proportion lower than those observed in developed countries. Fifty-three percent (81/152) had B symptoms at presentation. Stage III and stage IV diseases were seen in 72% (109/152) and 25% (38/152) patients, respectively, with 80% percent of patients being high risk. Bulky disease was seen in 46% (69/152) patients. Fifty per cent of patients (74/152) had anaemia at baseline presentation as defined by haemoglobin level of less than 10.0gm%, raised ESR, LDH \u0026amp; β2 microglobulin levels were present in 44.7%, 77.6% and 36% of patients at baseline. These results were similar to the other two extensive retrospective studies on the outcome of HL in the pediatric population from India, where the incidence of B symptoms, bulky disease and high-risk disease was seen in 54%, 46% and 70% of the patients, respectively. Also, anaemia and elevated ESR incidence were seen in 58% of the patient population. This also corresponds to figures from other resource-poor nations. Most reports from North America and Europe have shown nodular sclerosis (60\u0026ndash;70%) as the most frequent subtype in the pediatric age group. In countries with suboptimal socioeconomic conditions, histologic subtypes associated with poor prognosis are predominant. Histologic differences are considered to be largely dependent on variable host immunologic response, which is influenced by genetic and environmental factors.\u003c/p\u003e \u003cp\u003eDistribution of HL cases over age, gender, geographical areas and socioeconomic settings have long suggested multiple etiologically distinct entities for HL, rather than a single disease. The prevalent type in developing countries, as discussed earlier, is the MC histological subtype, which predominates in young children, particularly in males, and mainly presents as an advanced-stage disease. The hypothesis of an etiologic role of EBV in the pathogenesis of HL could partly explain these features. Studies have shown a causal relationship between infectious mononucleosis and subsequent Epstein-Barr virus (EBV)-positive HL [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. \u0026Ccedil;avdar et al. showed a high frequency of EBV-related LMP-1 positivity (73.6%) in pediatric HL. Cases. Childhood HL in developed countries affects mainly older children, mostly presenting as NS histological subtype and might be explained by 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. Most of the data coming from the other centres, as well as the Turkish pediatric oncology group (TPOG) data, including 1823 children from 22 different centres 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 [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Our data, reflecting the figures from our country's mixed population, was more consistent with the data from other developing countries. The lower socioeconomic status may be a contributing factor to this striking resemblance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003ePrognostic Factors:\u003c/h2\u003e \u003cp\u003eIn our study, prognostic factors evaluated for OS and EFS were the stage of disease, histological subtype, risk group, presence or absence of bulky disease, B symptoms, anaemia and elevated ESR, LDH \u0026amp; β2 macroglobulin levels. Factors found significant in the multivariate analysis for EFS were risk group and haemoglobin levels, while none were found statistically significant for OS in the multivariate analysis. Abnormalities in haemoglobin levels reflect cytokine activation, which may have a wide range of effects, from gene expression and influence on apoptotic potential to expression of adhesion molecules, which may influence metastatic capability [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Prognostic factors evaluated from other retrospective studies in India associated with a poor outcome and termed unfavourable include male sex, B symptoms, bulky mediastinal or peripheral lymphadenopathy, an extranodal extension of disease, and stage IIIb and stage IV disease. They found that the presence of B symptoms and advanced-stage disease were significantly associated with inferior outcomes and relapse, with advanced-stage disease being the only factor independently associated with an inferior outcome in their analysis [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Prognostic factor analysis has been reported in two studies of children with advanced HL from the Western world. The Pediatric Oncology Group (POG) found stage IV and male sex prognostic for inferior event-free survival [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In contrast, the Children's Cancer Group found stage, ESR, liver size, and mediastinal bulk among stage III patients as prognostic for inferior event-free survival [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Recently, in pediatric advanced Hodgkins lymphoma patients, a study by Schwartz et al [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] identified four factors prognostic for event-free survival: fever; stage IV lymphoma, bulky mediastinal lymphadenopathy and serum albumin less than 3.5 g/dL commonly identified as CHIP (Childhood Hodgkins lymphoma International Prognostic Score) score. Our study incorporated these four factors into a prognostic index and stratified patients into three groups with significantly different survival outcomes. EFS was 92% for patients with a CHIPS score of 0 or 1, 82% for those with a CHIPS score of 2, and 70% \u0026amp; 61% for those with a CHIPS score of 3 or 4 (EFS: p\u0026thinsp;=\u0026thinsp;0.065).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResponse rates in various advanced stage hodgkins lymphoma trial\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy Group/Trial\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSample Size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEFS/DFS (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOS (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFollow-up (Years)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSt. Jude Children\u0026rsquo;s Research Hospital\u0026nbsp;\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (CS III)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 COP(P)/4 ABVD\u0026thinsp;+\u0026thinsp;20 Gy IFRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (CS IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStanford\u0026nbsp;\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (CS/PS IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 MOPP/3 ABVD\u0026thinsp;+\u0026thinsp;15-25.5 Gy IFRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGerman Multi-Centre HD-90\u0026nbsp;\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124 (IR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 OEPA/OPPA\u0026thinsp;+\u0026thinsp;2 COPP\u0026thinsp;+\u0026thinsp;20\u0026ndash;35 Gy IFRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e179 (HR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 OEPA/OPPA\u0026thinsp;+\u0026thinsp;4 COPP\u0026thinsp;+\u0026thinsp;20\u0026ndash;35 Gy IFRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePediatric Oncology Group \u003csup\u003e26\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 MOPP/4 ABVD\u0026thinsp;\u0026plusmn;\u0026thinsp;21 Gy TNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eU.S. Children\u0026rsquo;s Cancer Group\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e394\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 COPP/ABV\u0026thinsp;\u0026plusmn;\u0026thinsp;21 Gy IFRT (intermediate risk)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88 (IFRT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCOPP/ABV\u0026thinsp;+\u0026thinsp;CHOP\u0026thinsp;+\u0026thinsp;Ara-C/VP-16\u0026thinsp;\u0026plusmn;\u0026thinsp;21 Gy IFRT (high risk)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91 (IFRT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGerman Multi-center HD-95\u0026nbsp;\u003csup\u003e27,28\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e224 (IR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 OPPA/OEPA\u0026thinsp;+\u0026thinsp;2 COPP\u0026thinsp;+\u0026thinsp;20\u0026ndash;35 Gy IFRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e97% (all)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e280 (HR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 OPPA/OEPA\u0026thinsp;+\u0026thinsp;4 COPP\u0026thinsp;+\u0026thinsp;20\u0026ndash;35 Gy IFRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStanford/St. Jude/Dana Farber\u0026nbsp;\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 VAMP/3 COP\u0026thinsp;+\u0026thinsp;15-25.5 Gy IFRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e92.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePGIMER\u0026nbsp;\u003csup\u003e22\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e206 (all stages)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(4\u0026ndash;6 cycles) ABVD/COPP\u0026nbsp; MOPP/COPP VAEP/ABVD ABVD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e92.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAIIMS\u0026nbsp;\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e148 (all stages)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCOPP(4)/ABVD(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e91.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMH*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e152 ( CS-IIB,III \u0026amp;IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eABVD\u0026thinsp;+\u0026thinsp;20\u0026ndash;36 Gy IFRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs seen from Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, combined modality therapy with different chemotherapy regimens used in the West resulted in an EFS and OS in the range of 85\u0026ndash;90% and 95%, respectively. Our study showed an EFS and OS at a median followup of 37 months of only 73% and 83%, respectively. Given the poor outcome of ABVD, associated toxicity and also the increased risk of subclinical dysfunction of the heart, lungs, and thyroid [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] in combination with involved-field radiotherapy (IFRT), there is a need to improve the results and decrease the toxicity in advanced stage hodgkins lymphoma. Two retrospective studies from India demonstrated the EFS and OS benefit in the range of 80\u0026ndash;85% and 90\u0026ndash;92%, respectively, but both the studies used hybrid regimens (MOPP/ABVD; COPP/ABV, VEEP) and involved all-stage patients [\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eEarly Response and Outcome:\u003c/h2\u003e \u003cp\u003ePrior to treatment completion, early identification of chemoresistant disease would facilitate an individualized, risk-adapted strategy. Mid-treatment (interim) metabolic imaging via FDG-PET has strong potential. In HL and aggressive B-cell non-HL (NHL), it has been repeatedly recognized that PET performed after only 2 or 3 cycles of chemotherapy provides valuable prognostic information. Early achievement of a negative PET (absence of abnormal FDG uptake concerning for tumour) is prognostically favourable, whereas persistent abnormal FDG uptake on early PET, even in the context of a CT response, raises concern for treatment failure. PET performed after only one cycle also appears to have prognostic significance. Interim response evaluation by PET-CT scan in our study also showed a better EFS and OS for patients who achieved CR versus non-CR (94% \u0026amp; 94% versus 72% \u0026amp; 62% respectively, p\u0026thinsp;=\u0026thinsp;0.001).This is further supported by a study in an adult population, which showed that Interim PET was the only significant prognostic factor. The 3-y EFS was 53.4% for PET-positive patients and 90.5% for PET-negative ones (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). When patients were categorized according to low or high IPS risk and according to the early or advanced stage of disease, PET was also significantly associated with treatment outcome [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThus, our first study has shown PET-CT-based early response as an accurate and independent predictor of EFS and OS in HL. A negative interim 18F-FDG PET result is highly predictive of treatment success in overall HL patients, as well as in subgroups with early or advanced-stage disease.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study has confirmed that the biology of HL is different as compared to west as evidenced by slightly older age of presentation, male preponderance, increased mixed cellularity histology. The OS and EFS of 83% and 78% with ABVD based therapy in our study is inferior to that of dose-intense regimens from west where OS and EFS approaches 94% and 90% respectively. CHIPS score has prognostic value in advanced HL in Indian patients in the context of ADVD based therapy but should be validated in prospective large clinical trial. Early PET based response is an important prognostic factor and may be used in tailoring therapy. This study suggests the need for employing combined modality therapy using aggressive dose-intense regimens with less overall chemotoxicity and addition of early metabolic response adapted treatment tailoring for optimizing outcome in children This study also highlights the need for large scale national multicentric trials to understand local biology of HL, define local risk factors, and test regionally relevant treatment strategies\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003col\u003e\n \u003cli\u003eHL \u0026ndash; HL\u003c/li\u003e\n \u003cli\u003eRT \u0026ndash; Radiotherapy\u003c/li\u003e\n \u003cli\u003eIFRT \u0026ndash; Involved Field Radiotherapy\u003c/li\u003e\n \u003cli\u003eGDP \u0026ndash; Gemcitabine, Dexamethasone, Cisplatin\u003c/li\u003e\n \u003cli\u003eICE \u0026ndash; Ifosfamide, Carboplatin, Etoposide\u003c/li\u003e\n \u003cli\u003eMINE \u0026ndash; Mesna, Ifosfamide, Vinorelbine, Etoposide\u003c/li\u003e\n \u003cli\u003eCR \u0026ndash; Complete Remission\u003c/li\u003e\n \u003cli\u003eOS \u0026ndash; Overall Survival\u003c/li\u003e\n \u003cli\u003eEFS \u0026ndash; Event-Free Survival\u003c/li\u003e\n \u003cli\u003eCHIPS \u0026ndash; Childhood Hodgkin\u0026apos;s International Prognostic Score\u003c/li\u003e\n \u003cli\u003eTMH \u0026ndash; Tata Memorial Hospital\u003c/li\u003e\n \u003cli\u003eRF \u0026ndash; Risk Factors\u003c/li\u003e\n \u003cli\u003eCOG \u0026ndash; Children\u0026rsquo;s Oncology Group\u003c/li\u003e\n \u003cli\u003ePR \u0026ndash; Partial Response\u003c/li\u003e\n \u003cli\u003eSD \u0026ndash; Stable Disease\u003c/li\u003e\n \u003cli\u003ePD \u0026ndash; Progressive Disease\u003c/li\u003e\n \u003cli\u003eRER \u0026ndash; Rapid Early Response\u003c/li\u003e\n \u003cli\u003eSER \u0026ndash; Slow Early Response\u003c/li\u003e\n \u003cli\u003eLDH \u0026ndash; Lactate Dehydrogenase\u003c/li\u003e\n \u003cli\u003e\u0026beta;2 microglobulin \u0026ndash; Beta-2 Microglobulin\u003c/li\u003e\n \u003cli\u003eESR \u0026ndash; Erythrocyte Sedimentation Rate\u003c/li\u003e\n \u003cli\u003eABVD \u0026ndash; Adriamycin, Bleomycin, Vinblastine, Dacarbazine\u003c/li\u003e\n \u003cli\u003eABVE-PC \u0026ndash; Adriamycin, Bleomycin, Vinblastine, Etoposide, Prednisone, Cyclophosphamide\u003c/li\u003e\n \u003cli\u003eOEPA \u0026ndash; Vincristine, Etoposide, Prednisone, Adriamycin\u003c/li\u003e\n \u003cli\u003eOPPA \u0026ndash; Vincristine, Procarbazine, Prednisone, Adriamycin\u003c/li\u003e\n \u003cli\u003eBEACOPP \u0026ndash; Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone\u003c/li\u003e\n \u003cli\u003eCOPP \u0026ndash; Cyclophosphamide, Vincristine, Procarbazine, Prednisone\u003c/li\u003e\n \u003cli\u003eABV \u0026ndash; Adriamycin, Bleomycin, Vinblastine\u003c/li\u003e\n \u003cli\u003eMOPP \u0026ndash; Mechlorethamine, Oncovin (Vincristine), Procarbazine, Prednisone\u003c/li\u003e\n \u003cli\u003eG-CSF \u0026ndash; Granulocyte-Colony Stimulating Factor\u003c/li\u003e\n \u003cli\u003ePET \u0026ndash; Positron Emission Tomography\u003c/li\u003e\n \u003cli\u003eFDG \u0026ndash; Fluorodeoxyglucose\u003c/li\u003e\n \u003cli\u003eABMT \u0026ndash; Autologous Bone Marrow Transplant\u003c/li\u003e\n \u003cli\u003eNS \u0026ndash; Nodular Sclerosis\u003c/li\u003e\n \u003cli\u003eMC \u0026ndash; Mixed Cellularity\u003c/li\u003e\n \u003cli\u003eLP \u0026ndash; Lymphocyte Predominant\u003c/li\u003e\n \u003cli\u003eLD \u0026ndash; Lymphocyte Depleted\u003c/li\u003e\n \u003cli\u003eIPS \u0026ndash; International Prognostic Score\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Declarations","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: This retrospective study on prospectively collected data was approved by the Institutional Ethics Committee, TMH. Written informed consent was obtained from all patients at the time of primary diagnosis.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: The datasets generated and analyzed during the current study are not publicly available due to privacy restrictions but are available from the corresponding author upon reasonable request.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare no competing interests.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: None\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e All authors contributed equally\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: We would like to thank Tata Memorial Hospital.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAuthor Information\u003c/strong\u003e:\u003c/li\u003e\n\u003c/ul\u003e\n\u003col start=\"5\"\u003e\n \u003cli\u003e\u003cstrong\u003eAmol Dongre\u003c/strong\u003e: Medical Oncology, Jawaharlal Nehru Medical College, Wardha, India\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eKaran Sood:\u003c/strong\u003e Medical Oncology, Jawaharlal Nehru Medical College, Wardha, India\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTrupti Dongre\u003c/strong\u003e: Pathology, N.K.P Salve Institute of Medical Sciences and Research Centre and Lata Mangeshkar Hospital, Nagpur, India\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eBrijesh Arora\u003c/strong\u003e: Pediatric Oncology, Tata Memorial Hospital, Mumbai, India\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHudson MM, Donaldson SS: HL: Principles and Practice of Pediatric Oncology Pizzo PA, Poplack DG (Eds). Lippincott Williams \u0026amp; Wilkins, Philadelphia; 2006.\u003c/li\u003e\n\u003cli\u003eRuHL U, Albrecht MR, Lueders H, et al.: The German Multinational GPOH-HL 95 trial: Treatment results and analysis of failures in pediatric Hodgkins lymphoma using combination chemotherapy with and without radiation (abstract). Int J Radiat Oncol Biol Phys. 2004, 60:131. 10.1016/j.ijrobp.2004.06.029\u003c/li\u003e\n\u003cli\u003eSmith R, Chen Q, Melissa M, et al.: Prognostic Factors for Children With HLTreated With Combined-Modality Therapy. J Clin Oncol. 2003, 21:2026. 10.1200/JCO.2003.07.124\u003c/li\u003e\n\u003cli\u003eFerraris AM, Racchi O, Rapezzi D, et al.: Familial HL: a lymphoma of young adulthood?. Ann Hematol. 1997, 74:131. 10.1007/s002770050270\u003c/li\u003e\n\u003cli\u003eCorrea P, O\u0026apos;Conor GT: Epidemiologic patterns of HL. Int J Cancer. 1971, 8:192. 10.1002/ijc.2910080203\u003c/li\u003e\n\u003cli\u003eArora RS, Eden T,Kapoor G: Epidemiology of childhood cancer in India.. Indian journal of cancer. 2009, 46:264-73. 10.4103/0019-509X.55546\u003c/li\u003e\n\u003cli\u003eFoltz LM, Song KW, Connors JM: HL in adolescents. J Clin Oncol. 2006, 24:2520. 10.1200/JCO.2005.04.5823\u003c/li\u003e\n\u003cli\u003eDinand V, Arya L.S: Epidemiology of Childhood HL: Is it Different in DevelopingCountries?. Indian Pediatrics. 2006:141-7.\u003c/li\u003e\n\u003cli\u003eScwartz C, Lu Chen, Louis Constine, et al.: The Childhood Hodgkin International Prognostic Score (CHIPS) for Predicting Event Free. Survival in Pediatric. 2010, 10.1002/pbc.26278\u003c/li\u003e\n\u003cli\u003eDonaldson SS, Link MP, Weinstein HJ, et al.: Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk HL. J Clin Oncol. 2007, 25:332. 10.1200/JCO.2006.08.4772\u003c/li\u003e\n\u003cli\u003eNachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with HL who achieve a complete response to chemotherapy. J Clin Oncol. 2002, 20:3765. 10.1200/JCO.2002.12.007\u003c/li\u003e\n\u003cli\u003eTebbi CK, Mendenhall N, London WB, et al.: Treatment of stage I, IIA, IIIA1 pediatric HL with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: a Pediatric Oncology Group (POG) study. Pediatr Blood Cancer. 2006, 46:198. 10.1002/pbc.20546\u003c/li\u003e\n\u003cli\u003eWeiner MA, Leventhal BG, Marcus R, et al.: Intensive chemotherapy and low-dose radiotherapy for the treatment of advanced-stage Hodgkin\u0026rsquo;s disease in pediatric patients: A Pediatric Oncology Group study. J Clin Oncol. 9:1591-1598. 10.1200/JCO.1991.9.9.1591\u003c/li\u003e\n\u003cli\u003eBonadonna G, Zucali R, Monfardini S, et al.: Combination chemotherapy of Hodgkin\u0026rsquo;s disease with Adriamycin, Bleomycin, Vinblastin and Imidazole Carboxamide versus MOPP. Cancer. 1975, 36:252-259. 10.1002/1097-0142(197507)36:1\u0026lt;252::aid-cncr2820360128\u0026gt;3.0.co;2-7\u003c/li\u003e\n\u003cli\u003eS.P. Hunger, M.P. Link and S.S. Donaldson: ABVD/MOPP and low-dose involved-field radiotherapy in pediatric Hodgkin\u0026rsquo;s disease: The Stanford experience. J Clin Oncol. 12:2160-2166. 10.1200/JCO.1994.12.10.2160\u003c/li\u003e\n\u003cli\u003eKelly KM, Sposto R, Hutchinson R, et al.: BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk HL: a report from the Children\u0026apos;s Oncology Group. Blood . 2011, 9:2596-603. 10.1182/blood-2010-05-285379\u003c/li\u003e\n\u003cli\u003eSchellong G, P\u0026ouml;tter R, Br\u0026auml;mswig J, et al.: High cure rates and reduced long-term toxicity in pediatric Hodgkin\u0026apos;s disease: the German-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric Hodgkin\u0026apos;s Disease Study Group. J Clin Oncol . 1999, 12:3736-44. 10.1200/JCO.1999.17.12.3736\u003c/li\u003e\n\u003cli\u003eSchwartz CL, Constine LS, Villaluna D, et al.: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk HL: the results of P9425. Blood. 2009, 114:2051. 10.1182/blood-2008-10-184143\u003c/li\u003e\n\u003cli\u003eC\u0026cedil; avdar AO, Pamir A, Go\u0026uml;zdasoglu S, et al.: Hodgkin\u0026rsquo;s disease in children: Clinicoepidemiologic and viral (Epstein-Barr virus) analyses. Med Pediatr Oncol. 1999, 32:18-24. 10.1002/(sici)1096-911x(199901)32:1\u0026lt;18::aid-mpo5\u0026gt;3.0.co;2-s\u003c/li\u003e\n\u003cli\u003eMutafoglu K U, \u0026Ccedil;etingoz R, Gunes D, et al.: Clinical characteristics and therapy outcome of pediatric Hodgkin\u0026rsquo;slymphoma - a single centre experience from the west part of Turkey. Turkish Journal of Cancer Volume 37, No. 3. 2007:\u003c/li\u003e\n\u003cli\u003eKadin ME, Leibowitz DN : Cytokines and cytokine receptors in Hodgkin\u0026rsquo;s disease.. Philadelphia, PA, Lippincott; 1999. pp:139-157.\u003c/li\u003e\n\u003cli\u003eAmita Trehan, Shaveta Singla, Ram K. Marwaha, et al.: HL in Children: Experience in a Tertiary Care Centre in India. J Pediatr Hematol Oncol. 2012, 000-000. 10.1097/MPH.0b013e318271f587\u003c/li\u003e\n\u003cli\u003eArya LS, Dinand V, Thavaraj V, et al.: HL in Indian children: outcome with chemotherapy alone. Pediatr Blood Cancer. 2006, 46:26-34. 10.1002/pbc.20157\u003c/li\u003e\n\u003cli\u003eHutchinson RJ, Fryer CJH, Davis PC, et al.: MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin\u0026rsquo;s disease in children: Results of the Children\u0026rsquo;s Cancer Group phase III trial. J Clin Oncol. 16:897-906. 10.1200/JCO.1998.16.3.897\u003c/li\u003e\n\u003cli\u003eM.M. Hudson, M. Krasin, M.P. Link, et al.: Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin\u0026rsquo;s disease. J Clin Oncol. 22:4541-4550. 10.1200/JCO.2004.02.139\u003c/li\u003e\n\u003cli\u003eWeiner M, 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\u0026rsquo;s disease in pediatric patients: a Pediatric Oncology Group study. J Clin Oncol. 1997, 15:2769-2779. 10.1200/JCO.1997.15.8.2769\u003c/li\u003e\n\u003cli\u003eU. Ruhl, M. Albrecht, K. Dieckmann, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin\u0026rsquo;s disease: An interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys. 51:1209-1218. 10.1016/s0360-3016(01)01798-9\u003c/li\u003e\n\u003cli\u003eW. Dorffel, H. Luders, U. Ruhl, et al.: Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin\u0026rsquo;s disease in children and adolescents: Analysis and outlook. Klin Padiatr. 2003, 215:139-145. 10.1055/s-2003-39372\u003c/li\u003e\n\u003cli\u003eJuliano J. Cerci1, Luı\u0026acute;s F. Pracchia, Camila C.G, et al.: 18F-FDG PET After 2 Cycles of ABVDPredicts Event-Free Survival in Earlyand Advanced HL. J Nucl Med . 2010, 51:1337-43. 10.2967/jnumed.109.073197\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HL chips score, clinical presentation, clinico-biological differences, therapy-outcome","lastPublishedDoi":"10.21203/rs.3.rs-5990461/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5990461/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHodgkin\u0026rsquo;s Lymphoma (HL) is one of the most curable malignancies of childhood, with chemotherapy alone or in combination with radiotherapy (RT) being the preferred treatment modality, albeit associated with significant acute and late toxicities. Therefore, this retrospective study aims to comprehend clinical-biological differences from the west, analyse local prognostic factors, and evaluate outcomes and toxicity with current therapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study included 355 treatment-naive patients with classical HL. All patients received 4\u0026ndash;8 cycles of upfront ABVD-based chemotherapy followed by involved field radiotherapy (IFRT) to the bulky/residual sites. Relapsed patients received one of the commonly used salvage regimens (GDP, ICE, or MINE). Analyses were conducted for interim response assessment and end-of-treatment response.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOut of the 355 patients evaluated, 167 presented with advanced-HL (Stage IIBX, III \u0026amp; IV), and 15 of these 167 were ineligible for the final analysis due to various reasons. The median age was 9.7 years, and the male-to-female ratio was 5.9:1. The primary histologic subtype was mixed cellularity. The majority (73%) had stage III disease, with 80 out of 152 (53%) presenting 'B' symptoms and 69 out of 152 (45%) having bulky disease. Extranodal involvement was observed in 26% of patients. The first-line treatment regimen was ABVD for all patients, with IFRT in 68 (44.7%) cases. At the end of therapy, 83% of patients achieved complete remission (CR), while 32 (21%) progressed or relapsed. The median follow-up was 37 months, and the overall survival (OS) and event-free survival (EFS) rates were 83.6% and 78% at three years, respectively. These survival rates were lower than those reported in studies from the west. The CHIPS score was a prognostic factor that evaluated four of the mentioned factors (Stage IV, bulky mediastinal disease, serum albumin, and fever). The event-free survival rate was 83% for patients with a CHIPS score of 0 or 1, 70% for those with a CHIPS score of 2, and 61% for those with a CHIPS score of 3 or 4.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe CHIPS score can predict the outcome of children with advanced HL treated with ABVD-based therapy but requires prospective validation.\u003c/p\u003e","manuscriptTitle":"Clinical Presentation and Outcome of Hodgkin's Lymphoma in Children: A Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-12 11:37:15","doi":"10.21203/rs.3.rs-5990461/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b11bdde5-e8fc-4f4e-8343-e52f00582272","owner":[],"postedDate":"February 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-19T06:53:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-12 11:37:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5990461","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5990461","identity":"rs-5990461","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}