Long-term clinical outcomes of combined modality therapy for advanced-stage Hodgkin lymphoma in the PET era: A retrospective study

Hodgkin lymphoma (HL) is still one of the few cancers that can still be cured with contemporary treatment modalities. Evolving treatment strategies are now being influenced by the ultimate goal of curing individuals without inducing long-term toxicities1. In advanced-stage HL, expected cure rates with the current treatment modalities, range between 80 to 90 per cent2. Radiotherapy (RT) and combination chemotherapy are both proven treatment modalities. However, what becomes the optimal choice of treatment remains debatable.

ABVD (Anthracycline-based chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine) still remain the standard of care in HL because of favourable clinical outcomes and toxicity profile compared to a hybrid regimen utilizing ABVD alternating with MOPP [mechlorethamine, vincristine (Oncovin), procarbazine, and prednisone]3. Intense regimens such as escalated BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) used by the German Hodgkin Study Group (GHSG) have demonstrated its efficacy in the post-PET (positron emission tomography) era456. Given the excellent results of escalated BEACOPP, the GHSG presently advocates the omission of consolidation RT (CRT) in complete metabolic responders (CMRs) and adding RT only for partial responders (PR)5. However, excessive and unwanted toxicities of escalated BEACOPP4 preclude it from being commonly used due to constraints in supportive measures required for administering such intensive chemotherapy even in well-equipped tertiary care centres. Therefore, ABVD regimen with consolidation RT is still considered a standard of care the world over and especially in low- and middle-income countries (LMICs) due to its unmatched efficacy and safety profile for the past two decades78.

The controversy regarding CRT in advanced-stage HL is not only due to conflicting results from randomized studies256910 but also is linked with the concerns around increased late effects of therapy, especially second malignancies and cardiac toxicities. The ambiguity regarding the use of CRT has further increased in the contemporary era, where the response is assessed with more sensitive functional imaging, such as the PET scan56. However, omitting RT in the management paradigm of advanced HL may be detrimental as studies have shown the benefit of adding CRT in terms of reducing relapse rates at the initial bulky sites of the disease and in residual disease1112. Moreover, the patterns of recurrences have demonstrated that omitting RT to sites where CRT should be given can result in increased relapse rates1314. Further, the advent of novel RT delivery techniques and the evolution in treatment strategies to smaller RT volumes and lesser doses have contributed to the reduction in radiation doses to organs at risk without compromising tumour control and may have a future impact on reducing late sequelae1516. The current RT techniques and field preferences may also reduce the need for intensive chemotherapy, leading to subsequent reductions in related toxicities and prolonging disease control. Therefore, ABVD with CRT was still the preferred regimen in this study particularly among those individuals who achieved objective metabolic response (CMR or PR) on interim PET-CT (iPET-CT) even in the post-PET era.

We conducted a retrospective chart review to study the outcome of participants with advanced-stage HL who were treated with chemotherapy and subsequently received CRT at the study hospital, a leading cancer care centre in India. We primarily looked at survival outcomes and the patterns of failure. In addition, we also studied the various clinical predictors affecting long-term outcomes.

Material & Methods

Participant selection: A retrospective chart review of adults (age >15 yr) who were diagnosed with stages III or IV HL was conducted between 2012 and 2016 and treated at Tata Memorial Hospital, Mumbai, Maharashtra. Prior approval of the Institutional Ethics Committee was taken.

Inclusion/Exclusion Criteria: Individuals who completed the planned course of 6 cycles of chemotherapy followed by CRT either as involved field RT (IFRT) or involved site RT (ISRT) were consecutively included in the study. Individuals who were HIV-positive were excluded from the analysis.

Study plan: All study participants had baseline and iPET/CT for staging and response evaluation PET-CT post 2-4 cycles of ABVD or AEVD (Adriamycin, etoposide, vinblatine, and dacarbazine) chemotherapy and/or RT. Individuals who had an objective metabolic response [either CMR (complete metabolic response) or PMR (partial metabolic response)] on iPET scan formed the study cohort and the response was recorded as per Deauville’s 5-point criteria17. Data were collected from the hospital medical records. All sites of disease were carefully mapped and recorded. The bulky disease was considered when the maximum diameter of the nodes was ≥7 cm. Extranodal disease was considered when bone marrow was involved either on a PET scan or on bone marrow biopsy and/or visceral involvement on PET according to the updated Lugano classification18. Responders were further classified as early responders (CMR after two cycles of chemotherapy) and late responders (CMR after 4 or 6 cycles of chemotherapy).

Chemotherapy treatment details: All the study participants were treated with six cycles of either ABVD or AEVD regimen. Bleomycin was replaced by etoposide in individuals whose pulmonary functions were compromised based on the pulmonary function test and diffusion capacity for carbon monoxide findings. Participants who had a partial response to first-line chemotherapy were treated with second-line chemotherapy with GDP (gemcitabine, carboplatin and dexamethasone) regimen19. None of the study participants had chemotherapy dose escalation. All the study participants received six cycles of either the ABVD regimen or the AEVD regimen. Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis was not used in any of the participants. The use of therapeutic G-CSF during chemotherapy for individuals with febrile neutropenia was based on the discretion of the treating oncologist. Blood and blood components were used when clinically indicated for anaemia (usually when haemoglobin was below 8 g/dl) or thrombocytopenia (platelet counts were below 20,000/mm³). Erythropoietin was not used in any of the study participants. It is to note that it is not a standard practice in the study hospital to use G-CSF in individuals undergoing RT.

Radiotherapy treatment details: Indications for CRT included bulky disease at presentation, extranodal disease and residual disease in iPET. Study participants who had bulky nodal disease and/or extranodal involvement received CRT even after CMR to induction chemotherapy to reduce local relapse rates. Pre-RT complete blood count was done before starting RT. In concordance to the treatment protocol followed at the study hospital, it was ensured that Hb above 10 g/dl, TLC above 3000, an absolute neutrophil count was above 1000 and a platelet count was above one lakh before starting RT. RT was delivered by IFRT. Since 2017, we have adopted the practice of ISRT. RT was delivered by conventional radiation portals using cobalt-60 or 6 MV X-rays, three-dimensional conformal RT (3D-CRT), intensity-modulated RT (IMRT) or volumetric intensity-modulated arc therapy (VMAT) based on the proximity of the disease to critical structures and where it appeared that the threshold doses of critical organs would be compromised. The planned dose of RT was 25.2 Gy/14 fractions at 1.8 Gy per fraction for CMRs (Deauvelle’s:1-2) on iPET, while study participants who had PR (Deauvelle’s: 3-4) on iPET received 34.2 Gy/19 fractions at 1.8 Gy per fraction as per the institutional protocol.

Follow up methodology and evaluation: The study hospital has a robust system for ensuring follow up and data retrieval. The follow up data were retrieved from the hospital’s EMRs. Case data are linked to the in-house picture archival and communication systems which store the individual imaging data and can be retrieved by the file number. Study participants who did not follow up were called telephonically to attend the RT department, where their disease status was ascertained either through clinical examination and/or imaging (PET/CT or CT or ultrasound) and documented in the EMR. Despite the above data retrieval systems in place, being a retrospective study, there was at least 10 per cent attrition in the follow up of study participants and consequently loss of treatment-related data, clinical/historical/case data, and late toxicity data that precluded a comprehensive analysis of clinical outcomes.

After completion of the planned treatment, study participants were followed up clinically at regular intervals according to the institutional protocol. The clinical follow up consisted of detailed history and physical examination and complete blood count. The follow up data of study participants were obtained through the institutional EMR system. During follow up, study participants with clinical suspicion of relapse underwent restaging studies with PET/CT. All relapses were confirmed with a biopsy of the suspected site of recurrence. Relapses were categorized into either local (within the irradiated site) or systemic (at unirradiated sites) relapses. Study participants who had relapsed at both the distant (unirradiated) and irradiated sites were designated as having local and systemic relapses.

Statistical analysis: Demographic, tumour and treatment parameters were analyzed using descriptive statistics. The primary objective of the study was local failure-free survival (LFFS); which was calculated from the date of diagnosis to failure to achieve remission at the local site of CRT, detection of local progression/date of death or date of last follow up. The secondary objectives were event-free survival, overall survival (OS) and patterns of relapses. Event-free survival (EFS) was calculated from the date of diagnosis to detection of failure to achieve complete remission on iPET and at the end of four cycles of chemotherapy, local failure/distant failure/development of secondary malignancy, date of last follow up or death whichever occurred first. The OS rate was estimated from the time of diagnosis to the time of death or last follow-up. Relapses were defined only for individuals who had failed after achieving complete responses. PRs on PET with an increase in local disease or development of new lesions at distant sites were defined as progressive disease. The study participants status was censored as of 31 December 2019. The survival outcomes were estimated using the Kaplan–Meier method. Univariate analysis was done to assess the association of various prognostic factors such as age, sex, stage (III vs. IV), presence or absence of ‘B’ symptoms, extranodal involvement, Hasenclever index (HI), early versus late responders and haemoglobin was assessed for prognostic significance for EFS, LFFS and OS. Multivariate analysis using the cox-proportional hazards model was performed to select disease characteristics that contributed significantly to prognosis on univariate analysis.

Since the OS events were rare and the events per variable were <10, Firth’s penalized cox regression was used. Multivariate Firth’s cox regression was used to analyze the factors affecting the OS of the study participants. Statistical significance was assumed at P<0.05. All statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS) version 25, (IBM, Chicago, Illinois, USA) and R Studio™ Software Version 1.1.15 (Boston, MA, USA).

Results

Participant characteristics: A total of 203 study participants were analyzed. The median age was 32 yr [interquartile range (IQR): 26-46]. Bone marrow involvement at presentation was observed in 21.7 per cent (n=44) of study participants. One hundred and fifty-one (74.4%) participants had CMR, while 52 (24.6%) had PR on iPET following induction chemotherapy. Study participants baseline demographic characteristics are represented in Table I.

Treatment details: ABVD regimen was given to 178 study participants (88%) while 25 (12%) received upfront AEVD regimen due to poor pulmonary functions. Of the 178 study participants who received ABVD chemotherapy, three developed febrile neutropenia, while in six, bleomycin was omitted after four cycles due to pulmonary toxicity, and in one participant bleomycin was omitted due to onycholysis of the nails. Indication of CRT included only baseline bulky disease in 140 (69%) study participants, baseline bulky plus post-chemotherapy residual disease in 23 (11%) participants, post-chemotherapy residual disease in five (2.5%) cases, baseline bulky plus extranodal disease in 20 (10%) cases, extranodal disease in 14 (7%) cases and, extranodal and post-chemotherapy residual disease in one (0.5%) individual only.

Disease control and survival outcomes: The median follow up was 52 months (IQR: 40-67) and range (7.2-94.7 months). For the entire analyzed population, the five-year EFS was 83.2 per cent (95% CI: 78-89%), five-year OS was 94.6 per cent (95% CI: 91-98%) and five-year LFFS was 95.1 per cent (95% CI: 92-98%). The Kaplan–Maier survival curves are depicted in Figure 1 and Table II.

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Fig. 1

Kaplan–Maier survival curves showing the EFS, OS and LFFS. EFS, event-free survival; OS, overall survival; LFFS, local failure-free survival.

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Factors affecting event-free survival (EFS), local failure-free survival (LFFS) and overall survival (OS): On univariate analysis, we observed that the presence of extranodal disease was a significant predictor of EFS (P=0.043) (Fig. 2A and Table III). However, univariate analysis revealed no significant clinical prognostic factor for LFFS (Table III). Both the early and late responders had similar LFFS (five-year LFFS was 96.4 vs. 93.3%; P=0.16) (Table III). The trend was also similar to the International Prognostic Score (IPS) where participants with HI ≤ 3 had similar LFFS compared to the participants with HI >3 (five-year LFFS was 95.6 vs. 93.8%; P =0.58). Study participants with HI > 3 had an inferior OS as opposed to individuals with HI <3 (P=0.00047), while participants with median haemoglobin levels ≤10.5 g/dl had poorer survival (P =0.0021) (Fig. 2B and 2C). Multivariate analysis did not reveal any independent prognostic factor that predicted EFS, LFFS, or OS (Table III).

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Fig. 2

(A-C) Kaplan–Maier survival curves showing various prognostic factors associated with survival outcomes. Impact of extranodal disease on EFS (A), show the impact of Hasenclever index (IPS) (B) and median haemoglobin (g/dl) levels on OS (C).

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Patterns of disease failure: Only 28/203 (13.8%) study participants relapsed; nine of the 28 (32.1%) participants had systemic dissemination in addition to local relapse, five (17.9%) had local relapse alone while 14 (50%) had both local and systemic relapse. The median time to relapse was 19.4 months (IQR 13.24-33.48 months). Among the relapsed study participants, presenting stage in the majority was stage IV (n=19; 67.9%). Eighty-five per cent of the participants, who had relapsed presented with the extranodal disease during initial staging. The majority of the study participants (60%; n=17) who had relapsed had HI >3. The bulky disease was present in 71per cent of participants (n=20).

Salvage therapy and outcome: Twenty-six participants received salvage therapy, while two individuals although planned but defaulted before the start of salvage therapy. Salvage chemotherapy alone was given in 16 study participants (57%), while eight (28%) received salvage chemotherapy followed by autologous stem cell transplant (ASCT). Only one participant received salvage chemotherapy followed by IFRT and one received total lymphoid irradiation (TLI). Post ASCT, 5/8 (63%) participants were alive and in remission and the rest three individuals had disease progression. The most common salvage regimen in our relapsed cohort was the GDP regimen (n=20). Lenalidomide, either alone or in combination with other drugs, was given to three participants. One participant received an ICE regimen. Participants who had failed the first salvage regimen and were not candidates for transplant received bendamustine as a second salvage regimen (n=4). Nivolumab as a second salvage therapy was given to two individuals. Two participants (12.5%) post-salvage chemotherapy alone were in remission at the last follow up and the rest 14/16 (87%) had disease progression. One of the study participants who received salvage chemotherapy followed by IFRT died due to disease progression after 31 months, while the participant who received salvage TLI also died of disease progression at 32 months. Of the 28 relapses, 10 died (9 due to HL and 1 due to tuberculosis). Eight participants were successfully salvaged (either transplant or salvage CT) and are free of disease, whereas nine participants are alive with disease at the last follow up.

The median survival after salvage therapy was 23 months (IQR: 8.23-35.31). The five-year OS and LFFS in relapsed study participants after salvage therapy were 66.9 per cent (95% CI: 47.9-85.9%) and 54.5 per cent (95% CI: 27.5-81.5%), respectively (Fig. 3 and Supplementary Table I). On multivariate analysis, only the HI was found to be a significant prediction of OS (P=0.004). Study participants with HI ≥4, had a higher risk (HR 8.54, 95% CI:1.84-81.83) of having deaths as compared to participants with HI ≤2. There were no significant predictiors of EFS.

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Fig. 3

OS and LFFS in relapsed patients after salvage therapy.

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Predictors of disease relapse: We studied the association of various prognostic factors for disease relapse and found that bulky disease (P=0.005) and haemoglobin ≤10.5 g/dl (P =0.036) were significant predictors for relapse (Supplementary Table II).

Radiation toxicity: Acute RT toxicities were studied during RT and at the conclusion of RT. RT-induced dermatitis was recorded in 185 study participants. Grade-I skin reactions were seen in 146 (78.9%) participants, grade-II dermatitis in seven (3.8%) and 32 (17.3%) participants did not have any RT-induced dermatitis. Mucositis was recorded in 108 participants, of which 41.7 per cent had grade-I mucositis, and 2.8 per cent had grade-II mucositis. Dysphagia was recorded in 73 participants, grade-I dysphagia was observed in 23.3 per cent and grade-II dysphagia in 1.4 per cent of participants. All the acute reactions resolved within 4-6 weeks of RT completion. None of the study participants had any acute grade-III radiation-induced reactions. Two individuals who received CRT to neck nodes developed second malignancies (carcinoma lower oesophagus and periampullary carcinoma) which were not associated with radiation therapy. However, clinical hypothyroidism was observed in 12 participants who received radiation to the neck region.

Discussion

The conflicting results of CRT have led to its role being debated in the entire management paradigm of advanced stage HL, especially in the post-PET era where oncologists are moving away from CRT due to concerns of late toxicities20. However, the controversies associated with the use of RT stem from the lack of properly designed trials and their implementation. Historical trials questioning the role of RT in advanced-stage HL were fraught with confounding factors such as heterogeneity in the usage of chemotherapy protocols, poor compliance to allotted treatment, or even response assessment21. In addition, earlier studies used archaic two-dimensional RT delivery techniques where large volumes were treated (extended-field RT, e.g. mantle-field RT, inverted-field RT, subtotal nodal irradiation or total nodal irradiation)29 with excessive RT doses (~50 Gy), resulting in late RT-induced toxicities22. Due to the above limitations, such historical trials may not stand as a good piece of evidence in the contemporary era where there has been a trend towards de-escalation in the RT doses (20-35 Gy) and RT volumes (involved site or involved node RT). This has been possible due to continuous evolution in the RT delivery techniques with a shift from 2D planning to 3D planning, wherein the radiation delivery could be precisely delivered to the tumour sparing the surrounding normal tissues with a possible reduction in the early and late complications, which we normally observe in long-term survivors of Hodgkin’s lymphoma. Therefore, it is not surprising that oncologists have been designing trials wherein either RT is being omitted or limiting its use in certain situations (bulky disease, extranodal sites and PRs)5611.

Although a majority of the studies questioning the role of CRT were done in the pre-PET era9112324 emerging studies have now started reporting the outcomes in the post-PET era5612252627. With the advent of PET scans, there is a paradigm shift in the treatment protocols in HL, especially in advanced-stage disease, where the controversy persists with diverse opinions among haemato-oncologists and radiation oncologists. At present, the push is towards optimizing the role of CRT rather than completely omitting it by exploiting the ability of functional imaging to distinguish the viable residual disease from non-viable fibro-necrotic tissue along with the use of modern RT techniques to enable more conformal treatment, thereby addressing the concerns of late sequelae15.

This retrospective study included 203 participants of advanced stage HL (stage III and IV) treated uniformly, consisting of ABVD or AEVD regimen followed by PET-based response adapted RT to a dose of 25.2 Gy in CMR and a dose of 34.2 Gy in PRs (partial responders) on iPET. This strategy resulted in favourable five-year survival outcomes in our study cohort (EFS: 83.2%, LFFS: 95.1% and OS: 94.6%) comparable to prior single-institution studies and randomized clinical trials112324. The improved outcome from additional CRT in advance stage classical HL was observed when administered to individuals with initial bulky disease and residual disease after a full course of chemotherapy. Given the excellent survival outcomes with the addition of CRT either with moderately intense ABVD or with a more intense Stanford regimen22242526 it is pertinent to revisit its role for advanced stage HL in the contemporary era; therefore, this modality should be considered in the context of an initial bulk and/or residual disease after the full course of chemotherapy based on two pertinent randomized trials done in an ethnically diverse population1123. The UK study showed an improved progression-free survival (PFS) among individuals who received CRT (five-years PFS: 86%) as opposed to those who received chemotherapy alone (five years PFS: 71%) and this translated to improved OS in the participants who received CRT after chemotherapy11. The randomized trial from Tata Memorial Hospital demonstrated a superior eight-year EFS and OS in participants who received CRT (89 and 100%) compared to the individuals not receiving any consolidation radiotherapy (76 and 88%), respectively, P=0.00223.

A significant number of advanced-stage HL participants are not cured with ABVD alone (~25-30%). Therefore, recent trials by the GHSG group have started utilizing very aggressive regimens like escalated BEACOPP with the intent to limit the use of CRT in PET-negative individuals56. However, undue acute toxicities such as infections and excessive marrow suppression requiring supportive measures have subdued such enthusiasm not only in resource-constrained countries but also in certain developed countries. Moreover, late sequelae particularly higher incidence of myelodysplasia and secondary acute myelogenous leukaemia has resulted in hemato-oncologists opting for a moderate approach of ABVD regimen and CRT exploiting modern RT delivery techniques to keep the toxicities to manageable levels without compromising tumour control. In advance stage HL, more than 75 per cent of the affected individuals go into complete remission with ABVD chemotherapy alone when compared to MOPP/ABV regimen. This may be better but not good enough27. The cure rates can therefore be pushed up further by either utilizing aggressive regimens like the escalated BEACOPP or by consolidating with RT after a moderately intense regimen like ABVD. Therefore, the need is to have better predictors of residual disease to tailor the treatment. Metabolic response to chemotherapy is considered an important predictor for relapse of disease282930. Although insignificant, participants with late PET response (after 4 or 6 cycles of chemotherapy) had higher incidence of relapses (early responders: 11% vs. late responders 21%; P=0.07). The lack of statistical significance could be attributed to lesser relapses in our cohort of study participants.

Recent studies have utilized iPET response to escalate or de-escalate chemotherapy in advanced HL with some success313233. However, the same cannot be vouched for RT as PET has not been as helpful in identifying the subgroup of participants that do not benefit from CRT as both iPET and post-chemotherapy PET could not select out this group of individuals343536. This is because PET has a very low negative predictive value meaning a negative PET does not necessarily mean the absence of disease. The lower limit of PET detection in lymphoma is a mass of approximately 0.5–1 cm depending on tumour avidity3738 which translates roughly into 10⁸ to 10⁹ tumour cells. As such, one could have either no, or many millions, of viable tumour cells remaining in the context of a negative PET scan3738. Therefore, for individuals with negative mid-treatment PET, early truncation of therapy is typically not advised outside of a clinical trial, as negative PET does not necessarily mean disease eradication37. Unfortunately, there have been only a few studies on PET-based treatment in advanced-stage disease56. The GHSG HD15 and HD18 trials done in German HL cases, utilized CRT selectively in individuals who had residual PET-positive disease of 2.5 cm after induction with escalated BEACOPP and omitted CRT in PET-negative cases with morphological disease <2.5 cm^5,6. The four-year and three-year PFS was 92 per cent in both the studies for those achieving CMR by PET and CR or CRu on CT56. Although the results of GHSG studies showed promising survival with escalated BEACOPP even without CRT, increased toxicities, prolonged hospital stay and the requirement of supportive measures preclude it from being used in the Indian context where supportive measures are a scarcity for adopting such aggressive regimens. Hence such regimens have not found favour in resource-constrained LMICs as giving ABVD regimens and CRT is a simple outpatient procedure. On the other hand, escalated BEACOPP requires admission for its administration and supportive care.

With our results, we have shown that ABVD with CRT has equivalent results to escalated BEACOPP without the added burden of hospital admissions and financial burden on the affected individuals, caregivers and the hospital. This is important in LMICs where the hospitals in fringe areas may not be geared to administer such regimens where acute complications are very common39. Results from the present study, therefore, represent a real-world scenario where individuals are treated with ABVD or AEVD regimen and CRT. A previous study conducted in the adolescents and young adults (AYA) population at the study hospital corroborated the findings of the present study and demonstrated that ABVD was an effective and safe regimen in AYA individuals of HL. However, the earlier study had a mixed population of early and advanced-stage disease in the AYA population, while our study included adults only and approximately 70 per cent of participants received CRT40. The favourable clinical outcomes of our treatment strategy have led us to believe that the combined modality (six cycles of ABVD with CRT in selective situations) should still be the standard approach for individuals with advanced stage HL achieving objective metabolic response to chemotherapy.

We observed relapses in only 28/203 (13.8%) participants which was a lower rate reported in literature441. Distant relapses were more common in our cohort. Ten participants (35.7%) had died post-salvage therapy, while eight (28.5%) were successfully salvaged and became free of disease. Nine participants are still alive with stable disease despite salvage (32%). The overall five-year OS after various salvage therapies was 66 per cent (median: 23 months). The cure rates of relapsed HL vary with the type of salvage regimens used, best salvage rates being with transplant (50%), with salvage chemotherapy (20%), and with salvage RT (28-40%) reported in various studies42.

Strengths of the present study include a large number of participants data that have been analyzed (n=203), and a consistent treatment policy. This is one of the few studies, which used metabolic imaging (PET) to determine the response to chemotherapy and utilize it for response-adapted radiation doses. The major limitations include the retrospective nature of the study with its unavoidable inherent bias. Since all the participants received combined modality, there was obvious selection bias, although we tried to correct for these factors by multivariate analysis; at the same time, we do accept the fact that all the confounding factors may not have been accounted for in our analysis. We were not able to capture the data for chemotherapy dose modifications as well as chemotherapy-associated infections from our EMRs. Moreover, being a retrospective study, about 10 per cent of the participants were lost to follow up (Supplementary Table III). This attrition rate could be attributed to multiple factors such as lack of awareness among the participants and their caregivers, geographical distance and poor education and financial constraints as the majority of the individuals belonged to the lower strata of the socio-economic structure of our society.

CRT, with moderate doses (~25-34 Gy) in individuals with the bulky or extranodal disease and partial metabolic responders, is associated with favourable clinical outcomes in participants with advanced HL, achieving objective metabolic response with ABVD chemotherapy. CRT following ABVD chemotherapy may obviate the need for more intensified regimens like the escalated BEACOPP, which is associated with not only escalating costs but also increased acute and delayed toxicities, thereby limiting its widespread utility. In the contemporary era, the optimal approach to manage advanced-stage HL may comprise a combination of risk- and response-adapted treatment approaches using chemotherapy and RT based on functional imaging response.