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.