Doxorubicin treatment of Hodgkin lymphoma increases the risk of breast cancer many years later, regardless of age at exposure and in addition to the known risk from radiotherapy, a study has shown.

While the effects of radiotherapy on second cancer risk have been known for many years,  the new findings from a 20-year follow up study of almost 2000 people treated for HL indicate that exposure to doxorubicin should now also be factored in when it comes to risk mitigation and long term follow up of adolescent and adults patients with Hodgkin lymphoma, researchers say.

In a paper published in Journal of Clinical Oncology (link here), clinicians from the Netherlands said previous studies in childhood survivors of Hodgkin lymphoma have reported an increased risk of breast cancer in those exposed to chemotherapy with doxorubicin.

However, until now this effect has not been described in an older population where doxorubicin-containing regimens, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) are the mainstay of first-line treatment.

Their new study followed 1964 females aged 15-50 when first treated for Hodgkin lymphoma between 1975 and 2008 and who subsequently survived at least five years.

After a median of 21.6 years follow-up the key finding was that patients who received a total cumulative dose of doxorubicin 200mg/m² had a 1.5-fold increased risk of breast cancer compared with those not exposed to doxorubicin, reported Dr Suzanne Neppelenbroek and colleagues from the Netherlands Cancer Institute, Amsterdam.

Moreover, each additional cumulative dose of 100mg/m² was associated with a further 1.18- fold increase in risk (Ptrend =0.004) and the risk increase associated with doxorubicin was not modified by age at first treatment or chest radiotherapy.

The association of doxorubicin with breast cancer risk appeared to be present only after 20 years following treatment for Hodgkin lymphoma, and not in the five-19 years interval after treatment, possibly reflecting an anthracycline-associated induction period for breast cancer.

The study authors noted that doxorubicin chemotherapy had become more widely used in recent years as an alternative to gonadotoxic chemotherapy regimens. It could potentially cause second cancers, they suggested, because it causes DNA damage by inducing double-strand breaks, and chromatin damage through histone eviction in the genome.

“Our study shows that it remains of great importance to follow patients for more than 20 years after their treatment has been completed,” the authors said.

“Our findings confirm the importance of risk-based long-term follow-up care for lymphoma survivors and possibly survivors of other cancers treated with doxorubicin.

“Our results are also relevant for treatment strategies for patients with newly diagnosed HL, when balancing the risks and benefits of systemic therapy and RT. Since effective novel agents (eg, antibody-drug conjugates and immune checkpoint inhibitors) have been introduced in the treatment for patients with HL, future clinical trials should also aim at reducing the dose of doxorubicin,” they concluded.

Implications for follow up care

In an accompanying commentary (link here), Professor John Radford, a medical oncologist at Manchester University, UK, said the results had implications for those who have already undergone treatment for Hodgkin lymphoma and been exposed to doxorubicin, such as recommendations for breast cancer screening.

“Patients need to be clearly informed of their individual risks, and the lifestyle and screening interventions recommended to mitigate these,” he wrote.

“A long-term management plan for staying healthy after cancer provided to each patient seems a good first step,” he suggested.

The new results would likely prompt a review of breast screening guidelines for survivors of Hodgkin lymphoma exposed to doxorubicin and also possible inclusion in emerging lung cancer screening programs, said Professor Radford.

The risks and benefits of doxorubicin exposure would now also  “have to be carefully weighed” for a newly diagnosed Hodgkin lymphoma patient,  he added.

“Clearly a choice of treatment needs to be made from the various options available for the patient presenting today with newly diagnosed Hodgkin lymphoma,” he said.

“ Making the most appropriate decision depends on a knowledge of the individual concerned and the treatment itself, not only in terms of efficacy but also late consequences and how these might interact with the sex and age of the patient, the presence or absence of comorbidity, and whether radiotherapy is also being considered.”

While this requires a highly complex decision making process, “it is highly likely that there is no completely risk-free option but minimising risk should be within our grasp,” he concluded.