Written by | Wang Peilu
According to U.S. epidemiological data, Hodgkin lymphoma accounts for 6% of malignant neoplasms in children, and the incidence in children is highest among adolescents aged 15 to 19 years. To improve efficacy and reduce side effects, treatment options have undergone many evolutions over the past half-century.
A quick look at the chemotherapy regimen for Hodgkin lymphoma
ABVD: doxorubicin A, bleomycin B, vinblastine V, dacarbazine D
MOPP: Mechlorethamine M, Vincristine O, Methylbenzhydrazine P, Prednisone P
ABVE/PC: doxorubicin A, bleomycin B, vincristine V, etoposide E+, prednisone P, cyclophosphamide C
OEPA: Vincristine O, Etoposide E, Prednisone P, Doxorubicin A
COPDAC: Cyclophosphamide C, Vincristine O, Prednisone P, Dacarbazine DAC
COPP: Cyclophosphamide C, Vincristine O, Methylbenzhydrazine P, Prednisone P
COPP/ABV: Cyclophosphamide C, Vincristine O, Methylbenzhydrazine P, Prednisone P+, Doxorubicin A, Bleomycin B, Vinblastine V
Chemotherapy is one of the main treatments for Hodgkin lymphoma, and its regimen is often based on ABVD and MOPP. To reduce reproductive toxicity and other long-term side effects, children with Hodgkin lymphoma often opt for alkylating-free regimens such as the ABVE/PC regimen (North America), OEPA, and COPDAC regimen (Europe). Due to Hodgkin lymphoma's high cell division activity and sensitivity to radiation therapy, expanded wild radiotherapy (EFRT) has been used clinically since the 1970s, and the 5-year survival rate of Hodgkin lymphoma in American children has now exceeded 95%. In recent years, the improvement of treatment protocols has mainly aimed at reducing long-term adverse reactions, and the overall trend is that high-dose, wide-irradiated radiotherapy has gradually decreased, and the comprehensive treatment of precision stratification has gradually increased.
Hodgkin lymphoma survivors are at higher risk of advanced death and serious complications, such as secondary malignancies, cardiovascular disease, lung lesions, sexual dysfunction, diabetes, and other endocrine abnormalities, compared to other tumor patient populations. Risk-adapted therapy was first used in children with Hodgkin lymphoma in the 1990s to avoid overtreatment in patients with low risk of disease progression and recurrence, while providing higher-intensity pre-treatment for high-risk patients. The so-called risk stratified treatment refers to the decision of the treatment plan according to the patient's prognosis-related indicators such as tumor staging, B symptoms, and extranodular involvement. Although a small number of studies suggest that there are fewer long-term complications in stratified treatment of hodgkin lymphoma in children, this conclusion still lacks sufficient evidence to support it.
On July 10, 2021, the joint team was published in the Journal of Clinical Oncology titled Impact of risk-adapted therapy for pediatric Hodgkin lymphoma on risk of long-term morbidity: a report from the Children Cancer Survivor In the Study article, the researchers used data from Hodgkin lymphoma survivors diagnosed from 1970 to 1999 in the North American Child Cancer Survivors Study (CCSS) cohort to compare the incidence of serious complications in survivors who received different treatments in the past three decades to analyze the effect of risk stratified treatment on long-term side effects.
According to CCAE v4.03, the NCI's Common Adverse Events Evaluation Criteria, the study considered only chronic health conditions of grade 3 (severe or disabling), grade 4 (life-threatening, requiring emergency treatment), and grade 5 (death), and focused on three major types of complications: cardiopulmonary disease, secondary malignancy, and endocrine lesions. The researchers tested the following hypothesis:
(1) The risk of complications was lower among the survivors diagnosed from 1990 to 1999 than among the survivors diagnosed from 1970 to 1979;
(2) Compared with survivors who received single cloaked wild radiotherapy (irradiation of affected fields and most of the supradiastinal lymph nodes), survivors who received comprehensive therapy, such as COPP/ABV regimen, ABVE/PC and affected field radiotherapy (IFRT, irradiation of affected wild and surrounding lymph nodes), had a lower risk of complications;
(3) Compared with other survivors, survivors who did not receive radiotherapy and adopted multi-drug chemotherapy regimens had a lower risk of complications.
The researchers also estimated the risk of serious complications for Hodgkin lymphoma survivors treated in a stratified manner according to typical risk levels.
The researchers divided 2996 child survivors who were followed up for ≥5 years after diagnosis into three groups according to the year of diagnosis: 1970-1979 (n=1097), 1980-1989 (n=1057), and 1990-1999 (n=842). There was no significant difference in the rate of disease recurrence among the three groups of survivors, and a gradual decrease in the dose and range of radiotherapy could be observed, while the use of medium-dose alkylating agents and anthracyclines increased gradually (as shown in the figure below).
Therapeutic dose distribution over different periods: (A) chest radiotherapy, (B) abdominal radiotherapy, (C) anthracyclines, (D) alkylating agents.
The study found that the cumulative incidence of chronic health conditions of grade 3 to 5 in these survivors at the age of 35 was 31.4%, and the incidence of central lung disease (10.1%), endocrine disease (13.3%) and secondary malignancy (9.4%) was similar (as shown in the figure below). The risk of serious complications was twice that of female survivors (41.3%) than among male survivors (23.1%), a difference due to endocrine lesions and secondary malignancy. Survivors diagnosed and treated in the 1990s had a 20% lower risk of grade 3-5 complications than those in the 1970s, with the risk of secondary malignancy being the most pronounced (from 10.9% in the 1970s to 5.7%).
Cumulative incidence of serious complications (chronic health conditions of grades 3-5): (A) overall and three major categories of complications, (B) sex differences, and (C) chronological differences in diagnosis.
Survivors receiving high-dose cloaked wild radiotherapy limited to chest and neck were 50% less likely to have secondary malignancy than high-dose (≥35 Gy) expanded wild radiotherapy, but overall chronic health status of grades 3 to 5 did not improve much (as shown in the figure below). In addition to high-dose chest radiotherapy, the addition of alkylating agents or anthracyclines (e.g., MOPP, COPP, or ABVD regimens) did not significantly increase the risk of developing grade 3 to 5 chronic health conditions. Compared with people receiving a single high dose of cloaked wild radiotherapy, receiving a lower dose of radiation therapy (
Cumulative incidence of serious complications (chronic health conditions of grade 3-5) in different treatment groups
After controlling for factors such as age of diagnosis, sex, and age at diagnosis, the researchers found that survivors who received anthracyclines had a higher risk of cardiopulmonary disease, while those treated from 1990 to 1999 had a lower overall risk of serious complications, secondary malignancies, and cardiopulmonary disease. Survivors receiving high doses of alkylating agents were at higher risk of serious complications than those who did not use alkylating agents, while those who received low-dose cloaked wild radiotherapy had a lower risk of complications than those who received high-dose cloaked wild radiotherapy. According to the low-risk, medium-risk treatment regimen of the Children's Oncology Collaborative Group, the cumulative incidence of serious complications at age 30 years (14.5%) was lower than that of survivors receiving high-dose chest radiotherapy (25.1%).
Cumulative incidence of chronic health conditions of grade 3-5 at age 30 years in survivors receiving different treatments
Overall, the study notes that risk stratification of children with Hodgkin lymphoma helps reduce long-term side effects, that when radiation therapy is not included in the treatment regimen, survivors have the lowest risk of long-term cardiopulmonary disease and secondary malignancy, while stratified treatment regimens further reduce the risk of long-term complications. Studies have also shown that women are more likely to experience side effects from Hodgkin lymphoma treatment in childhood, particularly secondary malignancies and endocrine lesions associated with radiation therapy, while salvage therapy for progressive or recurrent tumors has long-term side effects comparable to that of expanded wild radiotherapy in the 1970s.
While the study has limitations, such as including survivors with a survival > = 5 years, does not fully reveal the pros and cons of hodgkin treatment in children, it provides direction for further improving treatment options, improving the quality of life of childhood HL survivors, and long-term care.
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