Methodology
The study was registered with Clinical Trial Registry of India (CTRI/2016/03/010916). Ethics approval from local institutional review board was obtained by all the 27 participating centres. Consent from the parents and assents from participants as applicable were taken prior to the commencement of treatment.
InPOG-HL-15-01 utilized ABVD chemotherapy regimen as most of the centres in India were familiar with this regimen. It can be easily administered as day care chemotherapy and the need for supportive care is very minimal. RT was reserved for children with bulky disease at diagnosis and those with suboptimal response to chemotherapy. A conservative estimate of event free survival (EFS) of 70% was targeted as this was the maiden attempt of Indian pediatric oncologists to work together on such a large scale. Most of the centres were remotely located and did not even have a long track record of a fully functional pediatric oncology unit.
Primary objective of this study was to prospectively collect epidemiological and outcome data in children and adolescents with early and advanced stage HL which has been reported previously5,6.
Study Population
The patient population comprised of children and adolescents up to 18 years of age with a confirmed diagnosis of HL. For the purpose of this study, patients with stage I and II A were classified as early and those with II B, III and IV were classified as advanced disease. 27 centres across the country participated in the study from August 2015 till February 2018. Children with prior treatment (RT or chemotherapy) or those with a relapse were excluded from the study.
Diagnosis, Staging and Baseline data
Details of data collected and investigations done have been reported elsewhere5,6. Staging was done as per Ann Arbor classification by either contrast enhanced computed tomography (CECT) neck, chest, abdomen and pelvis or PET-CT scan. Choice of staging modality was at the discretion of local treating team based on the availability of PET-CT facility. Financial support was available through partnership with a Non-governmental Organization (NGO) for facilitation of scans, chemotherapy drugs and RT. Bone marrow aspiration and biopsy were done for all patients. Bulky disease was defined as a single node or conglomerate nodal tissue measuring more than 6 cm in the longest diameter or a mediastinal mass with a diameter exceeding one third of the maximum mediastinal width at the level of the dome of the diaphragm or hilum in an upright postero-anterior chest radiograph. Spleen and liver involvement was defined as presence of one or more hypodense lesion on CECT or PET-CT imaging.
Treatment
Treatment for early disease included 4 cycles of ABVD and for advanced disease incorporates 6 cycles of same chemotherapy (doxorubicin-25mg/m2, bleomyicn-10 Units/m2, vinblastine-6mg/m2 and dacarbazine-375 mg/m2 given on days 1 and 15 of a 4-weekly cycle) with interim assessment after two cycles. For patients who did not achieve complete response (CR) or very good partial response (VGPR) after 2 cycles, second interim assessment was done after completion of 4 cycles. Response evaluation was recorded as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) for patients undergoing PET-CT and CR, VGPR, PR, SD or PD was recorded for patients undergoing CECT scan. CR was defined as complete metabolic resolution (Deauville criteria 1-3) of initial demonstrable disease on PET-CT scan or more than 80% reduction in the product of perpendicular diameter (PPD) of each of the nodal masses on CECT scan. VGPR was defined as reduction of at least 60% in nodal masses on conventional imaging. PR was defined as at least 50% reduction in the PPD of each of the areas of measurable disease or presence of metabolically active disease (Deauville criteria 4-5) in one or more of the previously involved sites without evidence of any new lesion. The response of SD was less than PR in the absence of PD. PD was defined as a disease with at least 50% increase in the PPD of any of the involved sites or eruptions of new lesions. For patients, who did not have a complete response after 4 cycles, were offered an option of alternative salvage therapy. Radiological disease assessment at the end of treatment was not necessary but it was recommended for patients not in CR after first and second interim evaluation. RT was reserved for those with initial bulky disease or less than satisfactory response at ERA. Satisfactory response to decide avoidance of RT after ERA (post 2 cycles of ABVD) was defined as CR for patients undergoing PET-CT and CR or VGPR for patients undergoing conventional scanning. RT was administered in once-daily fractions of 1.5 Gy to the afflicted nodal region (site of bulky disease or the sites with residual disease) using anteroposterior/posteroanterior techniques, usually 2-4 weeks following completion of last dose of chemotherapy to a total dose of 21 Gy.
Follow up
After completion of treatment, patients were followed up clinically every three months for the first year, every four months in the second year, every six months from third to fifth year and yearly thereafter. Radiological investigations were done only for clinically suspected cases.
Statistical Analysis
Continuous variables were described using mean with standard deviation or median with range and categorical variables were represented by frequencies with corresponding percentages. Differences in the distribution of individual parameters were analyzed using Fisher’s exact test or chi-square test for categorical variables and t-test for continuous variables. Primary outcome was assessed by EFS which was defined as time from date of start of chemotherapy to relapse, progressive disease during treatment, failure to attain CR or VGPR at the end of treatment or death from any cause. Secondary outcome was assessed by event free survival including abandonment (EFSa) in which abandonment of treatment was also considered as an event and overall survival (OS) which was defined as time from start of chemotherapy to death from any cause. Treatment abandonment was defined as the termination of care by the caregiver or not presenting for scheduled treatment for four weeks or more from the scheduled date of treatment. Various risk factors likely to affect EFS, EFSa and OS were evaluated in the univariate analysis. Kaplan Meier method and log rank test were used for survival analysis. The data was analyzed using IBM SPSS statistics for windows version 21.0 (Armonk, NY, USA). The timeline cut off for data analysis was December 2020.
For the analysis in this paper, the main outcomes of interest were percentage of patients who achieved satisfactory response on
ERA via CECT vs PET-CT. The outcome variable was categorical and Chi-square test was used to test for significance.