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.