Discussion
The success story of Hodgkin lymphoma is attributed to collaborative
efforts of research groups and sets an example for improving outcomes of
childhood cancer by participation in national and international
cooperative clinical trials. LMICs are largely dependent on outcomes
demonstrated by trials conducted in developed countries and that poses
unique challenges in implementation of such protocols. We successfully
demonstrated the execution of a multicentric, prospective clinical trial
in Indian setting where lack of resources and trained manpower (data
managers/clinical trial coordinators), adept pathologists, PET scan
machines etc was substantial and these facilities were available only at
a few centres. We reported excellent outcomes in early-stage HL and
suboptimal outcomes in advanced disease as compared to those reported
from the developed world with a risk stratified and response based
algorithm using ABVD as the backbone of treatment. Although most
high-income countries have moved to a PET based treatment protocol for
management of adult and pediatric HL, it is still not a norm in many
LMICs. Our prospective multicentre trial with 27 centres provided an
opportunity to examine the impact of the modality used assess response
in childhood Hodgkin disease. We attempted to compare the differences in
staging, response assessment, treatment and outcomes in the cohorts that
underwent CECT or PET-CT. Equitable distribution of early and advanced
disease patients made the comparison feasible with minimal bias.
Our study detected more stage IV patients in PET-CT arm as compared to
CECT arm. Notwithstanding the similar baseline characteristics of the
two groups, this discrepancy indicates the ability of PET-CT to identify
more nodal and extra-nodal sites and upstage the disease. The CECT arm
of our study did pick more bulky disease patients as compared to PET-CT.
Nonetheless, we do not anticipate this denotes superiority of one
modality over the other as both CECT and PET-CT have the accurate
ability to obtain two dimensional measurements7. This
difference though significant may be due to the late presentation of
patients in government hospitals where CECT was more often used as
compared to the trust hospitals or private sector where PET-CT was the
preferred modality. Despite a misconstrued perception that PET-CT will
detect more FDG avid lesions in a tropical country like ours where
infectious diseases like tuberculosis are rampant, we did not find any
reports of an inadvertent or missed diagnosis of infection amongst the
trial participants on a reasonably long follow up.
PET upstaged 14% of the patients (159) and down staged 6% (74) in the
Response-Adapted Therapy in HL study (RATHL). Extranodal disease in bone
marrow (92 patients), lungs (11 patients), or multiple sites (12
patients) were left undetected in patients undergoing a conventional
CECT scan8. Another study highlighted better detection
of nodal disease in 62 patients with HL and superiority of PET-CT in
identifying bone and bone marrow disease. Detection of other extra-nodal
sites however did not vary significantly between the two
modalities9. A Spanish randomised multicentric study,
in contrast, showed similar staging outcomes when comparing a PET-CT
with a 64 slice multi-detector row CT among 181 patients with HL,
diffuse large B-cell lymphoma and follicular
lymphoma10.
A satisfactory response in PET-CT was defined as Deauville score 1-3 and
for CECT arm was defined as patients with VGPR/CR based on the published
consensus of the international conference on malignant lymphoma
classification imaging group recommendations11,12. Two
major single centre Indian studies have also used similar criteria to
consider optimum metabolic response in children assessed with PET
scan13,14 while one Indian study has used Deauville
1-2 for early stage and 1-3 for advanced stage HL15.
Some studies from western world also use a more stringent criteria of
Deauville score 1-2 to determine good response post 2 cycles of
chemotherapy especially those contemplating therapy de-escalation.
EURONET-PHL-C1 study defined adequate response as a combination of
partial remission (> 50% volume reduction in any involved
site) and visual category-based PET response (no FDG uptake/activity or
only slight FDG uptake/activity corresponding to Deauville score
1-2)2. Even the AHOD0831 study used Deauville score
1-2 at interim PET to consider omission of radiotherapy. This has
important implication when we compare results and may account for more
relapses in protocols using relatively liberal Deauville criteria for
de-escalation. We performed the response assessment scan after 2 cycles
of chemotherapy in line with the most contemporary protocols. Some of
the older trials have implemented the response scan after 4 cycles of
chemotherapy and it has been ascertained to have an inferior predictive
value 16,17.
We found significantly more satisfactory responses in PET-CT based ERA
(81.2%) as compared to CECT (64.3%). The significance persisted while
evaluating only non-bulky disease patients who would have otherwise not
received radiation had their disease been considered as satisfactory
responder. For the PET-CT arm 84.2% children with non-bulky disease
achieved a satisfactory response as compared to 68.5% patients in the
CECT arm. This led to a 50% lower allocation of patients to
radiotherapy in the PET-CT arm (15.8% in PET-CT arm vs 31.5% in CECT
arm). Evidently, it is exceedingly pivotal to emphasize on the usage of
interim PET-CT scan which distinctly indicates the response of the tumor
cells to the treatment. CECT is less helpful in deciphering the
treatment response due to low specificity and therefore the clinician
may misinterpret the residual node as persistence of disease leading to
inaccurate treatment decisions and unnecessarily exposing the patients
to RT or additional chemotherapy.
The type of imaging modality used at ERA had no impact on outcomes. This
demonstrates that therapy de-escalation and omission of RT was plausible
in our patients if they sustained a satisfactory response after 2 cycles
of chemotherapy. This is one of the largest studies conducted in an LMIC
substantiating a beneficial effect of imaging modality in therapy
de-escalation in pediatric Hodgkin lymphoma patients setting a benchmark
for policy makers to appraise easy and affordable access to nuclear
medicine facilities. Euronet-PHL-C1 study conducted over 186 hospital
sites established that a 5 year EFS of 90.1% in patients who respond
adequately and confirm that omission of RT is possible if one uses an
intensive vincristine, etoposide, prednisolone, doxorubicin (OEPA)
induction followed by consolidation with cyclophosphamide, vincristine,
prednisolone, procarbazine (COPP) or cyclophosphamide, vincristine,
prednisolone and dacarbazine (COPDAC)2. The benefit
has also been documented in other single centre studies from
India13,18. Children’s oncology group trials have also
demonstrated lower usage of radiation and reduction in radiotherapy
volumes as compared to historical controls for children who are deemed
‘rapid early responders’19.
The controversy of therapy de-escalation is eminent in adult studies.
While the importance of outcome prediction has been shown in both
international and Indian studies, the impact on EFS has been
significantly different leading to a lack of
consensus8,18.
Pooled analysis from 4 randomised studies comprising 2267 early stage HL
patients showed that recurrence was 11.2% in patients who did not
receive RT as compared to 4.7% in RT group. The significant difference
in PFS was in favour of RT group (HR= 2.08; 95% CI 1.27-3.43,
p<0.004, RE)1,19,20,21,22,23. Furthermore,
the more recent SWOG S0816 study also showed a poor negative predictive
value of negative PET-CT after 2 courses of ABVD and suggested against
therapy de-escalation24.
Conversely, few research studies affirm that negative PET-CT allows
omission of RT without leading to a dwindled EFS. GHSG HD17 trial
performed PET scan after 4 cycles of chemotherapy (BEACOPP x 2 followed
by ABVD x 2) and successfully omitted RT for PET negative
patients25. Another study on nodular lymphocyte
predominant Hodgkin lymphoma (nLHPL) patients recently demonstrated the
possibility of RT omission for PET negative patients after 2 cycles of
ABVD. These trials have differences in timing and patient population but
they provide grounds for further research in this area. In the light of
above findings, we feel that more studies are needed in pediatric
population, especially in centres using ABVD based chemotherapy but
strongly recommend the imaging modality of choice to be PET-CT. Choosing
CECT in lieu of PET-CT scan leads to gratuitous exposure of RT to the
children. The relatively younger age of presentation of the pediatric HL
patients in developing countries further adds to the burden of delayed
side effects of radiotherapy such as secondary malignancy, endocrine
impairment and cardiorespiratory damage.
Our study has some limitations. The study cohorts are not randomised.
Central review of scan was not done and hence quality control of
reporting could not be established. Despite being cognizant of late
relapses in HL, the follow up data was collected only for 3
years24. Our study mainly relied on Deauville criteria
for response assessment. Biomarkers such as metabolic tumor volume and
total lesion glycolysis are also elicited by PET-CT which elucidate
details regarding tumor burden and disease activity, however data on
these newer parameters was not available for
analysis12.
To conclude, our study reinforces that PET-CT should be the preferred
choice of investigation rather than CECT to preclude the needless
exposure of RT/additional therapy to the patients. Moving ahead, the
study team of InPOG-HL group has proposed only PET-CT based assessment
in future studies with assured support from partner NGO for provision of
at least 2 PET-CT scans per patient to those who are unable to access
free scan at their institution or are unable to bear the costs involved.