Survival rates of adult patients with Hodgkin lymphoma who underwent ABVD versus escalated BEACOPP in a resource‐limited country: An observational study

Abstract Background The survival rate of adult patients with Hodgkin lymphoma (HL) depends on the responses to standard chemotherapy, radiotherapy, or combined therapy. Resource‐limited countries face numerous obstacles in supporting patients with HL who undergo chemotherapy, especially in advanced stages. Aim To analyze the survival outcomes of adult patients with HL after combined‐modality treatment (CMT) with involved‐field or non‐involved‐field radiotherapy. Methods and Results We retrospectively reviewed the medical records of 90 adult patients with HL who received CMT at Rajavithi Hospital, Bangkok between 2007 and 2021. Patients with stage I‐IV disease received different therapies depending on their risk group. The risk groups were evaluated according to initial response, bulky disease, and B symptoms. Patients (n = 90) who underwent CMT were followed up for 34.7 months (range, 1–141 months). The median follow‐up periods of early and advanced‐stage patients were 53.1 months and 23.5 months, respectively. The estimated 5‐year overall survival (OS) and progression‐free survival (PFS) rates of patients with advanced‐stage diseases were 85% and 62%, respectively. There was a difference in the 3‐year overall survival among advance‐stage patients who underwent ABVD (94%) compared to those administered BEACOPPesc (50%), and the 3‐year PFS (84%) among patients who underwent ABVD was higher than that among those administered BEACOPPesc (66%). Radiotherapy increased toxicity but did not improve the survival rate. Conclusion Chemotherapy administered to patients with advanced‐stage adult HL was more effective than BEACOPPesc when ABVD was administered. Our findings are relevant for hospitals with limited resources.


| INTRODUCTION
Adult Hodgkin lymphoma (adult HL) is an uncommon hematological malignancy with an estimated incidence of 3.5 per 100 000 people. [1][2][3] In Southeast Asia, adult HL represents approximately 5% of adult lymphoma. 4,5 The clinicopathological findings of adult HL in Southeast Asia differs from those of patients residing in Western countries. 6 The survival rate of adult HL patients depends on treatment responses to standard chemotherapy, radiotherapy, or combined therapy. Achieving a longer overall survival (OS) must balance the disease-response to treatment and treatment-associated toxicity. Patients with earlystage adult HL experience higher OS rates than those with advancedstage HL. Bulky disease adversely influences disease-response-treatment. 7 The ideal first-line treatment for advance-stage adult HL is controversial because of response rates and clinical toxicities. 4,8,9 For example, there is debate concerning the ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and escalated BEACOPP (BEACOPPesc; escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, dacarbazine, and dexamethasone) regimens with respect to their tumor control activities and clinical toxicities. 8 Five clinical trials of patients residing in Western countries, which compared the ABVD and BEACOPP-base regimens, found that the relapse rate of the BEACOPP group was lower, although the survival rates between the groups were not significantly different. [8][9][10][11][12] Unfortunately, resource-limited countries face numerous obstacles to the support of patients with adult HL who undergo chemotherapy. 2 Moreover, we are unaware of any report on the long-term survival or treatment-related clinical toxicities of patients with early-and advance-stage adult HL at a tertiary hospital with limited resources. Interim evaluation is employed to optimize personalized chemotherapy and radiation therapy (RT). 3,13 However, diagnostic tools are unavailable in many countries, particularly in resource-limited countries or countries most affected by the COVID-19 pandemic. 14

| MATERIALS AND METHODS
We reviewed the medical records of patients with HL, aged at least 18 years, between 2007 and 2022. All patients were pathologically diagnosed using a surgical lymph node or percutaneous lymph node biopsy. We enrolled patient (n = 90) with tissue pathologies consistent with HL, and excluded those with unavailable medical records, and those who did not undergo CMT. This retrospective and prospective observational study was approved by the Ethical Committee of Rajavithi Hospital (IRB No.159/2564).
Patients were examined according to the hospital protocol, which included bone marrow aspiration/biopsy, and computed tomography (CT) of the neck, chest, and whole abdomen. Patients with sufficient economic resource underwent PET-CT. Patients were classified according to the Ann Arbor Staging (AAS) system which defines a bulky mass as that of a lymph node >10 cm in diameter or a mediastinal mass size > one-third of the maximal thoracic diameter. 4   After the completion of CMT, clinical evaluation was conducted by two independent physicians who identified LN on diagnostic imaging. Complete remission (CR) was defined a decrease in the mass/LNs size >70% on CT or ultrasonography, 21,22 absence of the disease as determined by gallium scans based on gallium uptake at tumor site, 23 or Deauville Criteria score ranging from 1 to 3 for PET-CT. 4 A partial response (PR) characterized using CT, was indicated by 50-70% smaller LNs and Deauville Criteria 4 without new LNs according to PET-CT findings. A stable response (SR) or progressive response was defined as similar or increasing LNs pre-and post-CMT. In these groups, the patients continuously underwent additional CMT. Regular clinical evaluations were performed every 6 months until 2 years after the last CMT, and every year thereafter until loss to follow-up or death. 4,20 Toxicities were defined as acute-and last-stages which were evaluated between pre-and post-CMT according to available laboratory tests, imaging, pulmonary function tests, and echocardiography. Acute toxicities, which were evaluated during CMT and 1 month thereafter, were classified as chemotherapy-and RT-related toxicities. Patients who underwent the anthracycline based regimen were evaluated using echocardiography at least once after the completion of CMT. The Common Terminology Criteria were used to classify the severity of toxicities. 24 Data were collected from electronic medical records, and all parameters were analyzed. OS was calculated from the first diagnosis to any cause of death and was censored if patients were lost to follow-up or information for >12 months. Progression free survival (PFS) was calculated as the time form the first diagnosis to disease progression, relapse, or death. We used the Kaplan-Meier method and log-rank test to evaluate the significance of the differences in OS rates and PFS between the groups. Hazard ratios (HRs) with 95% confidence intervals (CI) associated with 5-years survival were calculated using Cox regression models. Statistical analyses were performed using SPSS software for Windows (version 18; IBM: NY; USA). Statistical significance is defined by p-value ≤.05.

| Patients' characteristics
We analyzed the records of 90 patients with HL treated with CMT (Table 1)

| Treatment outcomes
The median follow-up time for all patients was 34.7 months (range, 1-    Table 2).

The 5-year OS and PFS rates of all patients with HLs were 95%
and 81%, respectively. The 5-year OS rates of patients with AAS III and IV were 94% and 73%, respectively. The OS did not significantly differ among AAS stages ( p = .06). In contrast, the 5-year PFS rates of patients with AAS II (90%) and AAS IV (31%) were significantly different ( p = .04) (Figure 2A,B). There were significant differences in the significantly different from that in the advanced (62%) (Figure 2C,D).
The estimated 5-year OS and PFS rates of the high-risk group were 85% ( p = .069) and 62% ( p = .08), respectively ( Figure 2E,F). All patients who responded to chemotherapy had significantly longer 5-year OS and PFS than those with an incomplete response (OS = 78%, p = .003; PFS = 91%, p < .001) ( Figure 2G,H). Patients' records of advance adult HL patients were collected for only 3 years; 3-year OS rates of those who underwent treatment with ABVD (94%) and BEACOPPesc (50%), and 3-year PFS rates of those who underwent treatment with ABVD (84%), and BEACOPPesc (66%). There were no significant differences in 5-year OS and PFS rate between patients with advanced disease who underwent radiotherapy and those who did not (data not shown). Moreover, 3 patients died (one each of pneumonia, secondary lymphoma, and sudden cardiac arrest).
Two adult patients with HL treated with CMT developed cardiotoxicity. As shown in Table 3 The median follow-up of patients with AAS III and IV was 34 months (range, 14-68 months), which is shorter than that of patients with other stages. The PFS and OS rates of patients with stage IV AAS were significantly lower than those of patients with other AAS stages. These findings are similar to those of other studies of patients with AAS IV. 28 Here, we found that the 5-year OS differed according to favorable classification (advanced stage), and that risk-stratification (high-risk group) revealed significantly shorter rates compared with the low-intermediate risk groups. Furthermore, our patients received a radiation dose of 40 Gy, equal to that employed by van Nimwegen and colleague. 29 The early-stage groups significantly treat chemotherapy with RT than advance-stage. An advanced stage may comprise numerous metastatic LNs that are incurable using local radiotherapy. 30 In contrast, this finding is associated with an increased risk of mortality in patients who undergo RT. For example, van Nimwegan et al., (2016) and Schaapveld et al., (2015) found that cardiac toxicity and the risk of secondary tumors increased among such patients. 29,31 The main unanswered question is: What is the optimal regimen to improve survival among advanced stage adult HL patients?
Therefore, we focused our analyses on adult patients with advanced stage HL. To our knowledge, there is a lack of evidence indicating the efficacy of the bleomycin-based regimen (ABVD) and the intensive regimen (BEACOPPesc) when applied in limited-resource countries. Our findings revealed differences in the 3-year OS rates between patients with advanced HL treated with ABVD (94%) and BEACOPPesc (50%). However, inferior 3-year PFS was experienced by patients in the BEACOPPesc group (66%), which is inconsistent with other studies, including the EORTC 20012 and HD2000 studies. 8,9,12,32 Our present analysis of data in a resource-limited country shows that ABVD is more suitable, although there were a small number of patients in the BEACOPPesc group. We noted a slight decrease in In conclusion, our study supports ABVD as a well-tolerated chemotherapy regimen that is effective in controlling advance-stage tumors with higher survival rates than BEACOPPesc. These findings highlight its role as a first-line treatment for advance-stage adult patients with HL in resource-limited countries.