Higher CVD Risks Reported for Hodgkin's Lymphoma Survivors

Alexander M. Castellino, PhD

April 27, 2015

Hodgkin's lymphoma (HL) is a curable disease with 10-year survival rates of greater than 80%. However, patients reaching adulthood show an increased incidence of cardiovascular disease (CVD) as a result of the therapy they received, and they are likely to turn to primary care physicians for treatment.

The extent of the problem is illustrated by a new study published online April 27 in JAMA Internal Medicine, which found that HL survivors from the Netherlands who were followed for longer than 40 years are at a four- to sixfold increased risk for CVD compared with the general population. This is the longest follow-up of such patients to date; previous studies have had follow-up periods of 15 to 25 years.

Corresponding author Flora E. van Leeuwen, PhD, of the Netherlands Cancer Institute, Amsterdam, told Medscape Medical News: "The results of our study are in line with most literature. However, we are the first study with such a long follow-up in adult HL survivors, and we were able to estimate long-term anthracycline-associated effects in HL survivors."

"This study is important because it adds to the increasing body of evidence regarding risk factors in cancer survivorship that do not fit into traditional cardiovascular risk models," write Emily Tonorezos, MD, MPH, and Linda Overholser, MD, MPH, in an accompanying commentary.

"It highlights a population (individuals living with a history of HL) for whom the natural history of cardiovascular disease is only beginning to be understood," they add.

Dr Tonorezos is from the Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York City; Dr Overholser is from the Division of General Internal Medicine, University of Colorado Denver School of Medicine, Aurora.

The Dutch Cohort

CVD risk was studied in 2524 Dutch HL survivors from across five Dutch university hospitals or cancer centers. HL was diagnosed in patients younger than 51 years (median age, 27.3 years; range, 3 - 50). Patients were treated from 1965 through 1995 and had survived for 5 years following diagnosis. Of 2524 patients, 81.3% had received mediastinal radiotherapy, and 30.6% had received anthracycline-containing chemotherapy.

"For the interpretation of our data, it is important to realize that all patients in this study who received mediastinal radiotherapy were treated with radiation techniques that are nowadays considered outdated. However, we are currently working on derivation of a radiation dose-response relationship for CVD based on these data," Dr van van Leeuwen told Medscape Medical News.

"This curve can also be used to predict risk for new patients treated with lower doses, she added.

Although radiation doses have been reduced in recent years, there is a body of experts who question whether radiotherapy is needed at all in the treatment of Hodgkin's lymphoma, as previously reported by Medscape Medical News.

The Dutch team write that after a median follow-up of 20.3 years, 1713 cardiovascular events were reported in 797 HL (30.6%) survivors, with 410 (51.4%) developing two or more events.

The most frequent events reported were coronary heart disease (CHD) — 401 patients developed it as the first event ― followed by 374 events of valvular heart disease (VHD) and 374 events of heart failure (HF).

Median times between HL treatment and first event of CHD, VHD, and HF were 18, 24, and 19 years, respectively.

Compared with the general population, Dr van Leeuwen and colleagues calculated a 3.2- to 6.8-fold higher risk for CHD or HF in HL survivors — 857 more CV events per 10,000 person years.

At 40 years after HL diagnosis, cumulative risk for any CVD was 49.5%, with risk being higher in those diagnosed at a younger age.

Dr van Leeuwen and colleagues also examined treatment factors associated with CVD risk.

Forty-year cumulative incidence of CVD was 54.6% for survivors treated with mediastinal radiotherapy and 24.7% for those who did not receive radiation.

Survivors treated with anthracycline-containing chemotherapy for HL were at a 1.5-fold and 3.0-fold increased risk for VHD and HF, respectively, compared with those who did not receive this treatment.

Generalizing CVD Risk Observations

Medscape Medical News asked Dr van Leeuwen: "How applicable are these observations to HL survivors across times of changing therapeutic choices?"

"This study is relevant for both new HL patients and HL survivors," she said.

For patients treated nowadays, the radiation-related risks of CHD, VHD, and HF are expected to be lower than in patients described in the current article, because radiation target volumes are smaller and radiation doses are lower than before (because of improved chemotherapy), Dr van Leeuwen indicated.

Although radiation techniques have improved significantly, enabling sparing of the heart, radiotherapy is still indicated in substantial numbers of patients with mediastinal involvement, which may lead to substantial incidental cardiac exposure, she elaborated.

Dr van Leeuwen also stressed that anthracyclines are still a key component of systemic treatment in HL.

"For HL survivors, it is important to realize that the increased risks of CVD remain over time. Because of increase of the background risk of heart disease with ageing, this will lead to increasing excess numbers of CVD," she told Medscape Medical News.

Dr van Leeuwen and colleagues conclude: "Treating physicians and patients should be aware of the persistently increased risk of cardiovascular diseases throughout life, and the results of our study may direct guidelines for follow-up of patients with HL."

"For patients treated nowadays, the risks of CVD, VHD, and HF can still be increased if a part of the heart is still included in the radiation target volume, which is sometimes inevitable in case of mediastinal masses," Dr van Leeuwen told Medscape Medical News.

Furthermore, the use of anthracyclines may increase the risk for VHD as well as HF in patients treated nowadays, she added.

Caring for HL Survivors

In light of the observations from this and previous reports, there is a need for identifying and appropriately managing HL survivors who may be at risk for late effects of their therapy, say the editorialists. When these individuals develop CVD, most are typically in the care of primary care physicians; indeed, they rarely report to a clinician in the oncology setting after they are considered to be cured of their HL.

"Primary care physicians may not be comfortable caring for adult survivors of childhood cancer and have gaps in knowledge regarding what additional screening and surveillance this population may require," write Dr Tonorezos and Dr Overholser.

They also emphasize that "the oncology field has not increased to match demand, such that ongoing care in an oncologic setting will not be possible for most survivors."

"It is clear that, although the best models for follow-up care for cancer survivors may vary with the context of individual care settings and local resources, there is a role for specialists involved in cancer care and primary care to address the comprehensive needs of cancer survivors," they write in their commentary.

"It is a matter of providing the right care at the right time. In this context, it is necessary for primary care physicians to rise to the challenge of health promotion in cancer survivors," they add.

Dr van Leeuwen told Medscape Medical News: "We are currently setting up survivorship clinics for adult lymphoma survivors in the Netherlands. These survivors will be screened according to national guidelines."

She added that their draft screening guideline for CVD has not yet been approved by all professional societies but will include screening for general risk factors for CVD and screening for VHD and (subclinical) HF in predefined high risk groups by echocardiography.

"Survivors will receive lifestyle advice," she said.

"The future of good care for cancer survivors will require establishment of the evidence-based best practices for this population," Dr Tonorezos and Dr Overholser conclude in their commentary.

They indicate that large, long-term, prospective studies and randomized clinical trials are needed to guide evidence-based practice.

In the meantime, they suggest that clinicians encountering long-term cancer survivors should take the initiative to ask questions related to patients' cancer diagnosis — the type of cancer, age at diagnosis, and whether they received chest radiation and/or anthracyclines.

"Our clinical experience has been that patients typically know the answers to these basic questions, and these responses will go a long way toward identifying at-risk patients," they add.

Dr van Leeuwen has reported no relevant financial relationships.

JAMA Intern Med. Published online April 27, 2015. Abstract, Commentary


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