Clinical Outcomes and Long-Term Effects of Consolidative Radiotherapy in Paediatric Hodgkin's Lymphoma

By Syed Muhammad Jawad Zaidi, Rabia Muhammad Wali, Naila Inayat, Sadia Anjum

Affiliations

1. Department of Paediatric Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan

doi: 10.29271/jcpsp.2025.06.778

ABSTRACT
Objective: To evaluate the long-term effects and disease outcomes of consolidative radiotherapy in paediatric Hodgkin’s lymphoma (PHL).
Study Design: Descriptive study.
Place and Duration of the Study: Department of Paediatric Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, from March to November, 2023.
Methodology: This retrospective cohort study was conducted on 91 PHL patients. All patients with the presence of residual disease on interim PET scan received radiation therapy. A standard dose of 19.8 Gy was given as 11 fractions, and boost was given to bulky disease as 10 Gy in 5 fractions. Data regarding patient demographics, disease characteristics, and treatment details were collected from the institutional database.
Results: Out of the 91 patients, 73 (80.2%) were male and 18 (19.8%) were female. The overall mean age at presentation was 7.7 ± 3.3 years. High-risk disease was found in 81 (89%), while 44 (48.4%) had stage IV disease. Complete remission was achieved in 70 (76.9%), loss to follow-up in 11 (12.1%), disease progression/relapse in 4 (4.4%), and death during treatment in 6 (6.6%) patients. The five-year overall survival was 90%, and event-free survival was 76.9%. During treatment, a total of nine patients had moderate-to- severe left ventricular dysfunction, six patients had altered thyroid profiles (hypothyroidism), three developed pulmonary fibrosis, and one patient developed cerebellar ataxia.
Conclusion: There is a good five-year overall and event-free survival. Cardio toxicity, hypothyroidism, and pulmonary fibrosis were common long-term chemotherapy / radiotherapy-related side effects. Prospective randomised controlled trial is needed to reduce dose of radiotherapy by giving it to PET-positive residual disease at the end of treatment rather than at mid-assessment.

Key Words: Paediatric Hodgkin’s lymphoma, Radiotherapy, Clinical outcomes.

INTRODUCTION

The incidence of paediatric Hodgkin’s lymphoma (PHL) is increasing worldwide, especially in developing countries and consists of 5 to 6% of all childhood cancers.¹ Over the decades, there has been significant improvement in treatment modalities and survival of PHL.² Literature shows that the five-year survival rate of PHL has significantly improved to 80- 90%.^2,3 The improvement in survival rates is mainly due to advancements in radiation therapies and the combination of chemotherapeutic agents.⁴ As a result, HL is one of the most curable cancers, especially in the paediatric age group.⁵
 

Radiotherapy has historically played an important role in PHL. However, due to excellent outcomes with systemic chemotherapy, the role of radiotherapy (RT) has evolved over the last three decades. Even though these modalities have proved beneficial, they have long-term treatment-related complications that significantly alter the quality of life of such patients.⁶

Data from the European Network Paediatric Hodgkin Lymphoma Study (Euro Net-PHL) shows that combination chemotherapy and consolidative radiation predispose PHL patients to various secondary malignancies, cardiovascular disease, infertility, neurotoxicity, and pulmonary fibrosis later in life.⁴ Therefore, the focus of paediatric oncologists has shifted to improve these treatment-related long-term complications, minimising chemotherapy-related toxicities, and improving event-free survival (EFS). Hence, the current study is aimed to see the long-term disease outcomes and late effects of consolidative radiotherapy (RT) in PHL. Currently, no data has been published from Pakistan or other low middle-income countries (LMIC) looking at radiotherapy outcomes and late effects in these cohorts of patients.
 

METHODOLOGY

This retrospective descriptive study conducted at the Shaukat Khanum Memorial Cancer Hospital and Research Centre in Lahore, Pakistan. The study included paediatric patients aged 1-18 years diagnosed with PHL, between January 2013 and December 2019. The study followed patients for five years post-treatment, specifically those who received consolidative radiotherapy. Patients who did not receive consolidative radiotherapy as part of their treatment protocol, aged more than 18 years at diagnosis, and had disease remission only with chemotherapy were excluded from the study. Moreover, patients with cardiac, pulmonary, and thyroid dysfunction before the initiation of treatment were also excluded from the analysis. The study was ethically approved by the Institutional Review Board of the Shaukat Khanum Memorial Trust, exemption number (EX-05-10-22-01-A1).

Patient data encompassed demographics, disease stage, histological subtype, B symptoms, treatment specifics (chemotherapy and radiotherapy details), and follow-up information (diagnosis, radiotherapy dates, follow-up duration, and disease status). Long-term effects documented included cardiac toxicity, pulmonary complications, secondary malignancies, and growth concerns. Primary outcomes were overall survival (OS), event-free survival, and relapse rates. Secondary outcomes included treatment toxicity and long-term complications. Patients’ data were retrieved using patient electronic records and files.

PHL diagnosis relied on pathological and radiological assessments, employing morphological and immunophenotyping criteria. Euro Net-PHL guidelines facilitated disease staging and treatment group allocation, utilising clinical, radiological, and pathological parameters. Staging involved baseline CT or PET scans (CT scans were done when PET scan was unavailable). Treatment groups (low, intermediate, and high-risk) were determined based on disease stage, presence of B symptoms, and relevant factors. Low-risk: (stage I/II) without bulky disease or B symptoms. Intermediate risk: Stage I or II with bulky disease or B symptoms, or stage III without B symptoms. High-risk: Stage III with B symptoms and stage IV disease.

All Patients received alternate cycles of COPDAC at day 1 and day 8 (Cyclophosphamide 500 mg/m², Vincristine 1.5 mg/m², Dacarbazine 375 mg/m², and Prednisolone 20 mg/m² for 15 days) and ABVD at day 1 and day 15 (Vinblastine 6 mg/m², Doxorubicin 25 mg/m², Bleomycin 10 mg/m², and Dacarbazine 375 mg/m²). Patients with low-risk received 4 cycles, intermediate-risk 6, and high-risk 8 cycles at intervals of 28 days.

After completion of chemotherapy, an interim PET scan was performed to assess for response to chemotherapy. Patients with residual disease at the interim PET scan were eligible for radiation therapy following completion of chemotherapy. All patients with residual disease at this interim PET evaluation underwent a repeat (third) PET scan to assess the response to radiotherapy.

Radiotherapy, adhering to Euro Net-PHL guidelines,⁴ was commenced 3-4 weeks post-chemotherapy. Modified involved field radiotherapy included a standard 19.8 Gy dose in 11 fractions; bulky disease received a 10 Gy boost in 5 fractions, with dose modifications to minimise normal tissue effects. Reassessment PET scans were done after four cycles of consolidative radiotherapy for partial responders.

The response to treatment was divided into complete resolution, stable disease, or disease progression as per PET scan reports. Complete resolution refers to complete obliteration of disease during/after chemotherapy and radiotherapy sessions, stable disease refers to persistent disease with no downstaging, and disease progression refers to an increase in the number and size of lymph nodes or upstaging of disease despite treatment.⁴

Before the initiation of treatment, all patients underwent a baseline echocardiography and pulmonary function testing. During and after the completion of treatment with radiotherapy, follow-up echocardiography, visit to paediatric cardiologist if any abnormality in echocardiography, and pulmonary function testing were performed to establish the diagnosis of cardiotoxicity and pulmonary toxicity. To assess thyroid function after radiotherapy, all patients who were to receive neck XRT had TSH levels measured. Similarly, patients’ pulmonary function tests were performed at baseline, and patients receiving chest XRT were followed up with regular pulmonary function tests. Follow-up over five years involved chest imaging, targeted ultrasounds, yearly echocardiogram (for cardiac dysfunction), pulmonary function tests, and thyroid/renal profiles.

Descriptive statistics were employed to express categorical variables. Frequencies and percentages were utilised to present key demographic characteristics, disease stage distribution, presence of B symptoms, and treatment specifics, such as chemotherapy and radiotherapy details. This approach allowed for a clear and concise representation of the categorical variables within the study population. Moreover, continuous variables were expressed as mean ± standard deviation. Survival analysis was conducted using Kaplan-Meier curves to visualise and assess the OS, event-free survival, and relapse rates over the five-year follow-up period. A p-value of less than 0.05 was considered statistically significant. All data analysis was completed on SPSS version 25.

RESULTS

A total of 91 patients were included in the study, comprising 73 (80.2%) males and 18 (19.8%) females. The overall mean age at presentation was 7.7 ± 3.3 years. Most of the patients, 81 (89%), were stratified as high-risk patients. Baseline details of the study participants are displayed in Table I.

Following treatment, 65 patients achieved complete metabolic response, 17 exhibited stable disease (neither increasing nor decreasing), and 9 had disease progression. All patients with residual disease received radiation (19.8 Gy, standard dose in 11 fractions; 10 Gy boost for bulky disease in 5 fractions).

Table I: Baseline details of the study participants.

Parameters		Frequencies	Percentages
Gender	Male	73	80.2%
	Female	18	19.8%
Disease stage	Stage II	15	16.5%
	Stage III	32	35.2%
	Stage IV	44	48.4%
Risk stratification	Low	7	7.7%
	Intermediate	3	3.3%
	High	81	89%
Splenic involvement	Yes	23	25.3%
	No	68	74.7%
B symptoms	Yes	38	41.8%
	No	53	58.2%
Baseline scan	CT scan	27	29.7%
	PET scan	64	70.3%

Table II: Disease outcomes.

Parameters		Frequencies	Percentages
Disease status post- treatment	Complete metabolic response	65	72.2%
	Stable disease	17	18.7%
	Disease progression	9	9.8%
Outcomes	Remission	70	76.9%
	Progression	4	4.4%
	Death	6	6.6%
	Loss to follow-up	11	12.4%
Long-term adverse effects	Cardiotoxicity	9	9.9%
	Pulmonary fibrosis	4	4.3%
	Cerebellar ataxia	1	1.1%
	Hypothyroidism	6	6.6%
	Hepatotoxicity	3	3.3%
	Nephrotoxicity	1	1.1%
Cause of death	Multiorgan failure due to disease progression	3	3.3%
	Sepsis	1	1.1%
	Death during radiotherapy related complications (severe oesophagitis and pulmonary fibrosis)	2	2.2%

Figure 1: OS curve for the entire study cohort.

Treatment outcomes: 76.9% achieved complete remission, but 11 (12.1%) were lost to follow-up. All 11 patients with loss to follow-up had disease remission at their last outpatient visit. The median loss to follow-up time was four months after completion of treatment (IQR 2-12). Unfavourable outcomes included 4.4% with progression/relapse and 6.6% succumbed during treatment. Late effects of radiotherapy included left ventricular dysfunction (9.9%), hypothyroidism (6.6%), pulmonary fibrosis (3.3%), and cerebellar ataxia (1.1%).

Figure 2: OS curves based on low, intermediate, and high-risk patients.

Treatment details and long-term adverse effects observed in the study are shown in Table II.

Median duration of follow-up in all patients was sixty-five months. The five-year OS rate was determined to be 90%. The five-year OS for low and intermediate risk patients was 100% while that of the high-risk patients was 85.3% (p = 0.520). The Kaplan-Meier curves for OS are shown in Figure 1, 2.

Five-year EFS for the entire study cohort was determined at 76.9%. The five-year EFS for low, intermediate, and high-risk patients were 75%, 100%, and 78.9%, respectively (p = 0.667). The Kaplan-Meier curves for EFS are shown in Figure 3, 4.

Figure 3: EFS for the entire study cohort.

Figure 4: EFS for low, intermediate, and high-risk patients.

DISCUSSION

The findings demonstrated a five-year OS rate of 90%, which is consistent with other studies that report OS rates between 85-95%.^1,3,5 A study conducted in the United States reported a five-year OS rate of 92% in PHL who underwent a similar treatment approach involving consolidative radiotherapy.⁷ However, Euro-NET recommends omitting radiotherapy in PHL as there is an insignificant difference in overall and event-free survival.⁴ Another study advocates the omission of radiotherapy in PHL and reports an excellent overall five-year survival rate of 92.9% in patients treated only with chemo-therapy.⁸ These findings suggest that even though consolidative radiotherapy plays a vital role in treatment, it can be omitted so that treatment-related toxicities can be prevented.^2,3

The occurrence of treatment-related toxicities is an important consideration in PHL management. In this study, cardiotoxicity was observed in 9.9% of patients, which is consistent with the range reported in other studies.^1,9 For instance, a multicentre study found a similar incidence of cardiac toxicity (8.7%) in paediatric patients treated with chemotherapy and consolidative radiotherapy.¹⁰ However, it is worth noting that the specific cardiac monitoring protocols and definitions of cardiotoxicity may vary across studies, making direct comparisons challenging.

Hypothyroidism was observed in 6.6% of the study population, aligning with the reported incidence rates in previous studies. In a retrospective study, the incidence of hypothyroidism was found to be 5.8%.¹¹ This suggests that the occurrence of hypothyroidism is a recognised long-term consequence of treatment in this patient population. Similarly, pulmonary fibrosis was noted in 3.3% of patients, consistent with the reported incidence rates in other studies.⁶ A study conducted in South Korea reported a similar incidence of pulmonary fibrosis (3.7%).¹² These complications are more pronounced in patients receiving consolidative radiotherapy of mediastinal PHL.¹⁰ These findings emphasise the importance of long-term monitoring for pulmonary complications and the need for proactive management strategies to minimise the impact of treatment-related toxicities on patients' quality of life.

Cerebellar ataxia, a rare neurological complication in paediatric Hodgkin's lymphoma (1.1% in this study), is documented in similar populations. Jones et al. found it in 1.7% of patients receiving chemotherapy and consolidative radiotherapy in a retrospective analysis.¹³ This can be regarded as a treatment-related complication because cerebellar ataxia was not related to the Hodgkin’s disease and was established after the treatment. Neurological surveillance and potential early intervention to address neurological complications in PHL survivors are also essential.

Disease progression, relapse, death, and loss to follow-up were considered as events. Loss to follow-up is considered as an event in paediatric oncology survival analysis studies in developing countries.¹⁴ The five-year OS rate in this study was determined to be 90%. This rate is comparable to or slightly higher than the survival rates reported in other studies conducted in different regions.^14-17 For instance, a study conducted in Chennai reported a five-year OS rate of 92% in a similar patient population.¹⁵ The five-year OS rate aligns with global findings (89%). Notably, a study from India reported that LMIC patients indicate a 90.3% five-year OS rate in a comprehensive retrospective analysis on radiotherapy outcomes.¹⁸

While comparing survival rates based on risk stratification, the five-year OS for low and intermediate-risk patients was 100%, indicating excellent survival outcomes in these groups. The five-year OS rate for high-risk patients was 85.3%, which aligns with the reported survival rates in similar studies. For example, a study conducted in the United States reported a five-year OS rate of 87% for high-risk patients.¹⁹ Similarly, an Indian study reported five-year OS for high-risk patients to be at 86.4%.¹⁸

This study cohort achieved comparable survival rates in high- risk patients. Overall, five-year EFS was 76.9%, with the intermediate-risk group exhibiting the highest rate. An Indian study reported a four-year EFS of 82.4-84.5% for PHL patients on RT.¹⁸ Comparatively, other studies have reported EFS rates ranging from 65 to 85% in paediatric Hodgkin's lymphoma.^8,15,16,19 Thus, this study group shows similar event-free survival outcomes. Same trials advocate for the safe omission of radiotherapy in PHL, even with bulky disease. Emphasising risk-based treatments, specifically COPDAC/ OEPA chemotherapy regimens, these approaches aim to minimise radiation, reduce late effects, and maintain excellent survival outcomes.^18,20 EuroNet-PHL C1 trial endorses safe radiotherapy omission in intermediate and advanced- stage Hodgkin's lymphoma, given a robust response to OEPA induction and COPDAC consolidation. This omission does not compromise event-free or overall survival. The ongoing EuroNet-PHL C2 trial explores the feasibility of administering radiotherapy post-chemotherapy rather than at re-assessment based on late PET-based response.⁴ Exploring advanced radiotherapy techniques such as IMRT or proton therapy can help minimise long-term toxicities.^2,12

Regular cardiac evaluations, thyroid function assessments, pulmonary function tests, and neurologic surveillance should be incorporated into long-term follow-up protocols.¹⁶ Early detection and intervention improve outcomes and quality of life for survivors. However, the study's single-centred, retrospective design, and potential selection bias limit its scope. Furthermore, the studies which were compared to the present study’s results not only included patients who received radiotherapy but were mixed populations. Moreover, comparison of this patient subset with patients who only received chemotherapy would have provided better insight regarding the long-term complications. Larger, multi-centre nationwide studies are essential to validate findings and offer comprehensive data on PHL survival outcomes.

CONCLUSION

The analysis demonstrated favourable five-year overall and event-free survival rates in PHL. However, the occurrence of long-term side effects due to chemoradiotherapy, such as cardiotoxicity, hypothyroidism, and pulmonary fibrosis, highlights the need for prospective research. Trials are crucial to assess benefits of reducing radiotherapy based on PET findings, minimising complications while ensuring effectiveness.

ETHICAL  APPROVAL:
This study was ethically approved by the Institutional Review Board of Shaukat Khanum Memorial Trust Exemption Number (EX-05-10-22-01-A1).

PATIENTS’  CONSENT:
Informed consent was obtained from all the patients included in the study.

COMPETING  INTEREST:
The authors declared no conflict of interest.

AUTHORS’  CONTRIBUTION:
SMJZ, RMW: Conceptualisation, statistical analysis, and writing initial and final draft.
NI, SA: Data Collection, review of initial and final draft.
All authors approved the final version of the manuscript to be published.

REFERENCES

1. Flerlage JE, Hiniker SM, Armenian S, Benya EC, Bobbey AJ, Chang V, et al. Pediatric Hodgkin lymphoma, version 3.2021. J Natl Compr Canc Netw 2021; 19(6):733-54. doi: 10.6004/ jnccn.2021.0027.
2. Gonzalez VJ. Role of radiation therapy in the treatment of Hodgkin lymphoma. Curr Hematol Malig Rep 2017; 12(3): 244-50. doi: 10.1007/s11899-017-0385-y.
3. Totadri S, Radhakrishnan V, Ganesan TS, Ganesan P, Kannan K, Lakshmipathy KM, et al. Can radiotherapy be omitted in children with Hodgkin lymphoma who achieve metabolic remission on interim positron emission tomography? Experience of a tertiary care cancer referral center. J Glob Oncol 2018; 4:1-7. doi: 10.1200/JGO.2017.009340.
4. Korholz CM, Parker JL, Balwierz W, Ammann RA, Anderson RA, Attarbaschi A, et al. Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): A titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial. Lancet Oncol 2022; 23(1):125-37. doi: 10.1016/S1470-2045(21)00 470-8.
5. Lo AC, Dieckmann K, Pelz T, Evans EG, Cabillic RE, Vordermark D, et al. Pediatric classical Hodgkin lymphoma. Pediatr Blood Cancer 2021; 68 (Suppl 2):e28562. doi: 10.1002/pbc. 28562.
6. Venkatramani R, Kamath S, Wong K, Olch AJ, Malvar J, Sposto R, et al. Pulmonary outcomes in patients with Hodgkin lymphoma treated with involved field radiation. Pediatr Blood Cancer 2014; 61(7):1277-81. doi: 10.1002/ pbc.24969.
7. Kelly KM, Cole PD, Pei Q, Bush R, Roberts KB, Hodgson DC, et al. Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): A report from the children's oncology group. Br J Haematol 2019; 187(1):39-48. doi: 10.1111/bjh.16014.
8. Marr KC, Connors JM, Savage KJ, Goddard KJ, Deyell RJ. ABVD chemotherapy with reduced radiation therapy rates in children, adolescents and young adults with all stages of Hodgkin lymphoma. Ann Oncol 2017; 28(4):849-54. doi: 10. 1093/annonc/mdx005.
9. Benetou DR, Stergianos E, Geropeppa M, Ntinopoulou E, Tzanni M, Pourtsidis A, et al. Late-onset cardiomyopathy among survivors of childhood lymphoma treated with anthracyclines: A systematic review. Hellenic J Cardiol 2019; 60(3):152-64. doi: 10.1016/j.hjc.2018.09.004.
10. O'Brien MM, Donaldson SS, Balise RR, Whittemore AS, Link MP. Second malignant neoplasms in survivors of pediatric Hodgkin's lymphoma treated with low-dose radiation and chemotherapy. J Clin Oncol 2010; 28(1):1232-9. doi: 10. 1200/JCO.2009.24.8062.
11. Inskip PD, Veiga LHS, Brenner AV, Sigurdson AJ, Ostroumova E, Chow EJ, et al. Hyperthyroidism after radiation therapy for childhood cancer: A report from the childhood cancer survivor study. Int J Radiat Oncol Biol Phys 2019; 104(2): 415-24. doi: 10.1016/j.ijrobp.2019.02.009.
12. Song KJ, Park JH, Im HJ, Ahn SD. Survival and long-term toxicities of pediatric Hodgkin lymphoma after combined modality treatment: A single institute experience. Radiat Oncol J 2020; 38(3):198-206. doi: 10.3857/roj.2020.00346.
13. Jones LW, Liu Q, Armstrong GT, Ness KK, Yasui Y, Devine K, et al. Exercise and risk of major cardiovascular events in adult survivors of childhood Hodgkin lymphoma: A report from the childhood cancer survivor study. J Clin Oncol 2014; 32(32):3643-50. doi: 10.1200/JCO.2014.56.7511.
14. Adam M, Bekueretsion Y, Abubeker A, Tadesse F, Kwiecinska A, Howe R, et al. Clinical characteristics and histopathologicalp Patterns of Hodgkin lymphoma and treatment outcomes at a tertiary cancer center in Ethiopia. JCO Glob Oncol 2021; 7:277-88. doi: 10.1200/GO.20.00391.
15. Radhakrishnan V, Dhanushkodi M, Ganesan TS, Ganesan P, Sundersingh S, Selvaluxmy G, et al. Pediatric Hodgkin lymphoma treated at cancer institute, Chennai, India: Long-term outcome. J Glob Oncol 2016; 3(5):545-54. doi: 10. 1200/JGO.2016.005314.
16. Belgaumi A, Al-Kofide AA, Khafaga Y, Joseph N, Malik RJ, Siddiqui KS, et al. Clinical characteristics and outcome of pediatric patients with stage IV Hodgkin lymphoma. Hematol Oncol Stem Cell Ther 2009; 2(1):278-84. doi: 10.1016/ s1658-3876(09)50038-6.
17. Hazarika M, Sutnga C, Raj DN, Roy PS, Sarangi SS, Reddy R, et al. Pediatric Hodgkin’s lymphoma: Experience from a tertiary cancer center in North East India. Int J Contemp Pediatrics 2023; 10(2):204-10. doi: 10.18203/2349-3291.ijcp 20230085.
18. Palayullakandi A, Trehan A, Jain R, Kumar R, Mittal BR, Kapoor R, et al. Retrospective single-center experience with OEPA/COPDAC and PET-CT based strategy for pediatric Hodgkin lymphoma in a LMIC setting. Pediatr Hematol Oncol 2022; 39(7):587-99. doi: 10.1080/08880018.2022.2044418.
19. Kahn JM, Pei Q, Friedman DL, Kaplan J, Keller FG, Hodgson D, et al. Survival by age in paediatric and adolescent patients with Hodgkin lymphoma: A retrospective pooled analysis of children’s oncology group trials. Lancet Haematol 2022; 9(1):e49-57. doi: 10.1016/S2352-3026(21)00349-5.
20. Parambil BC, Narula G, Prasad M, Shah S, Shet T, Shridhar E, et al. Clinical profile and outcome of classical Hodgkin lymphoma treated with a risk-adapted approach in a tertiary cancer center in India. Pediatr Blood Cancer 2020; 67(2): e28058. doi: 10.1002/pbc.28058.