Long-term Fatigue Plagues Hodgkin's Lymphoma Survivors

Fran Lowry

September 29, 2016

The disease might be cured, but the fatigue associated with Hodgkin's lymphoma (HL) continues for many patients, according to new research.

In a longitudinal study of the German Hodgkin Study Group, there was a high incidence of severe acute and persistent fatigue in Hodgkin's lymphoma survivors that was largely independent of tumor stage and treatment.

"Long-term fatigue is a major problem in HL survivors," lead author Stefanie Kreissl, MD, University Hospital of Cologne, Germany, told Medscape Medical News.

"In our study, around 15% to 25% throughout all stages suffered from severe fatigue, which means that they are not able to handle their everyday life activities. Further, 30% to 40% suffered from less severe, but still clinically relevant, fatigue. Cancer-related fatigue, therefore, should be considered a distinct diagnosis and not only a symptom, and intervention strategies are urgently needed," Dr Kreissl said.

The study was published in The Lancet Oncology.

However, editorialists writing in an accompanying comment question whether persistent fatigue in HL survivors relates to cancer. The editorialists are Michel Henry-Amar, MD, PhD, and Raphaël Busson, from the Centre de Traitement des Données du Cancéropôle Nord-Ouest, Caen, France.

They write: "Before tertiary prevention interventions are undertaken to manage or prevent the development of persistent fatigue, among which exercise-programmes and cognitive behavioural therapy have been proposed, there is a need to understand the mechanisms by which individuals who develop a cancer are also susceptible to develop abnormal fatigue."

Looking at the Course of Cancer-Related Fatigue

For Dr. Kreissl and her colleagues in the German Hodgkin Study Group (GHSG), the fact that so many patients with HL survive means an increasing number of patients who are successfully treated will go on to have debilitating fatigue that adversely affects their quality of life.

"Today, Hodgkin's lymphoma is a curable malignancy for the majority of our patients. Therefore, we face a continuously growing number of predominantly young survivors at high risk for long-term sequelae and impairments in their quality of life," she said.

"We know from previous studies that cancer-related fatigue is one of the most frequent patient-reported outcomes in HL survivors, but our knowledge on the complete course of fatigue as well as prognostic risk factors has long been limited, due to a lack of large, prospective clinical trials," Dr Kreissl said.

In their study, Dr. Kreissl and her colleagues analyzed cancer-related fatigue in 4215 patients aged 18 to 60 years who were enrolled in 3 prospective randomized controlled clinical trials conducted by the GHSG from 2003 to 2009.

The trials included early-stage favorable (HD13 trial), early-stage unfavorable (HD14 trial), and advanced-stage (HD15 trial) HL.

The researchers assessed fatigue with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 self-administered questionnaire at diagnosis, during chemotherapy, at end of treatment, and every year thereafter for 5 years.

"Fatigue scores on the QLQ-C30 range from 0 to 100, with higher scores indicating worse fatigue," Dr Kreissl explained.

Patients and survivors received the questionnaires from their treating physicians or by mail and were asked to send them back to the GHSG by mail.

The scores were matched for age and sex and compared with scores of the general German population, which served as controls.

Compared with scores in healthy German controls, fatigue scores in patients at all stages of disease and at all time points were substantially increased, even at baseline before the start of treatment.

Patients with a higher tumor burden at diagnosis had more fatigue at study entry.

The mean fatigue score at baseline was lowest in patients with early-stage favorable HL (HD13 trial), at 30.8 (standard deviation [SD], 28.0).

In patients with early-stage unfavorable disease (HD14 trial), the score was 39.8 (SD, 29.4), and in patients with advanced-stage disease (HD15 trial), it was 49.0 (SD, 30.2).

In the second year after treatment ended, fatigue persisted, although mean fatigue scores were similar among patients in all the trials.

In HD13, the mean fatigue score was 28.5 (SD, 24.7); in HD14, it was 28.8 (SD, 24.4); and in HD15, it was 30.7 (SD, 24.4).

In the fifth year after treatment, fatigue was still present. The mean fatigue score was 30.8 (SD, 26.0) in HD13, 27.1 (SD, 24.8) in HD14, and 28.2 (SD, 24.9) in HD15.

The proportion of patients with severe fatigue, as indicated by a fatigue score of 50 or greater, increased according to stage. In the HD13 trial, 172 (24%) of 728 patients had severe fatigue compared with 481 (37%) of 1307 patients in the HD14 trial and 654 (48%) of 1357 patients in the HD15 trial.

Baseline fatigue and increasing age were significant predictors of persistent fatigue (P < .0001 for both) at 2 and 5 years after treatment. However, treatment had no significant effect on fatigue scores.

The fact that the baseline fatigue scores were different in the three HD trials is relevant to the study findings, Dr Kreissl said.

"Our study is the first analysis of fatigue in HL, including all stages. Assessment of fatigue started at the time of diagnosis, before the onset of chemotherapy. Previous studies only reported about early stages and assessment of fatigue started during or after therapy, so no firm conclusions could be drawn about the complete course of fatigue and its relation to disease stage. It is essential to know that fatigue is already prevalent at the time of diagnosis, especially because baseline fatigue was shown to be the most important prognostic factor for long-term fatigue," she said.

It is essential to know that fatigue is already prevalent at the time of diagnosis. Dr Stefanie Kreissl

The editorialists note that the method the researchers used to determine fatigue trajectories in their study has an important limitation because "it cannot provide any information about which patients will belong to which category because it is based on a posteriori data."

They also point out other limitations of the study, including the researchers' use of a one-dimensional method to assess fatigue, "which is a multidimension entity," they point out. Another limitation they highlight is the use of clinical trials data only for understanding the pathogenesis of persistent fatigue 'because potential relevant information is missing," they suggest.

The editorialists conclude: "No medical explanation exists for why fatigue develops or persists in some patients, and the findings of Kreissl and colleagues suggest that persistent fatigue is not related to disease or treatment. Therefore, psychological factors (eg, susceptibility to anxiety or depression) or biological factors such as immunocompetence or heritable genetic variations (eg, chemotherapy drug metabolism genetic polymorphisms) might be playing a part."

Approached for comment on this study, George Canellos, MD, from Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, noted that psychological factors that are as yet unclear may play a role in the persistent fatigue in HL.

"The data are primarily European and have been previously published from the German group as well as the EORTC/GELA [Groupe d’É tude de Lymphomes de l’Adulte], which is predominantly French. The Germans have focused on this and yet few data exist from North America," Dr Canellos told Medscape Medical News.

"It is also said that Hodgkin survivors have a higher rate of suicide than expected. One can speculate that some of the metabolic effects of active HL can lead to fatigue, but they were noted even in early favorable patients. The fact that it [chronic fatigue] persists after cure suggests that there may be an emotional reaction to the diagnosis which persists despite cure, whereas other populations may be more confident and trusting," he said.

"I have to admit that it has not been a major factor in my experience, but again, we have not given quality-of-life tests as a matter of routine. The editorial states the case well. Since there is no psychological explanation, it remains in the speculative realm to this day," Dr Canellos said.

Also approached for comment, John Leonard, MD, a medical oncologist at Weill Cornell Medicine and New York-Presbyterian Hospital, New York City, said the study is important because it demonstrates that fatigue is a major symptom for patients with HL even several years after treatment.

"Quality of life is undoubtedly adversely affected by this phenomenon. This detailed measurement of fatigue-related issues provides important benchmark information for researchers to now go on to develop and assess potential interventions that can improve fatigue-related symptoms for patients following completion of treatment," Dr Leonard said.

The study was funded by Deutsche Krebshilfe. Dr Kreissl, Dr Henry-Amar, Mr Busson, Dr Canellos, and Dr Leonard have disclosed no relevant financial relationships.

Lancet Oncol. Published online September 6, 2016. Abstract, Comment

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