Today, more than 80% of all patients with Hodgkin lymphoma can be cured, and in early stages even more than 90%. Nevertheless, the disease and its therapy have a significant impact on the life expectancy of those affected. Radiation therapy in particular seems to have taken its toll over the years.
The adverse long-term effects of chemotherapy and radiotherapy have long been known, but few systematic studies of the precise effects of cancer therapies on long-term survivors exist. A study published in the Journal of the National Cancer Institute now analyzed the association of different therapies for Hodgkin’s disease with life expectancy. Especially from the point of view of the often young age of onset of the disease with the first peak of incidence between the age of 20 and 30, the longer-term therapy and disease consequences are of great importance for the management of patients with Hodgkin’s disease. Their life expectancy is significantly lower compared to the general population, even after surviving Hodgkin lymphoma.
Excess mortality under the microscope
The authors of the Dutch study observed a 5.1-fold increased risk of dying from causes other than their lymphoma among Hodgkin survivors compared with the general population. Or, to put it another way, 123 additional deaths occurred per 10,000 person-years. Even in patients whose initial diagnosis was 40 years earlier, this effect persisted (standardized mortality rate 5.2; 95% CI 4.2-6.5; absolute excess mortality 619). The cumulative mortality of 54-year-old Hodgkin survivors was comparable to that of 71-year-olds from the general population and was 20%. Causes of death were – apart from Hodgkin lymphoma itself – mainly second malignancies, cardiovascular diseases, respiratory diseases and severe infections (tab. 1) . The latter represented a relevant risk not only after splenectomy, but also after irradiation of the spleen.
The analysis included 4919 Hodgkin’s lymphoma sufferers whose disease had been diagnosed between 1965 and 2000 when they were under 51 years of age. While 23.9% of patients had received radiotherapy alone and 14% had received chemotherapy alone, 62.1% had been treated with combined radio-chemotherapy. The median follow-up was 20.2 years. The authors selected standardized mortality rates, absolute excess mortality, and cause-specific cumulative mortality by disease stage and primary treatment modality as endpoints. They were able to demonstrate that even 40 years after primary treatment of Hodgkin lymphoma, mortality – especially from therapy-associated sequelae – is significantly higher than in the general population.
What’s the reason?
Depending on the therapy the patients had received, differences in the risk of death were found – immediately and decades later. In stages I and II, chemotherapy alone was associated with higher Hodgkin lymphoma mortality (p<0.001 for chemotherapy vs. radiotherapy; p=0.04 for chemotherapy vs. radio-chemotherapy). However, those patients who received chemotherapy alone had a lower probability of dying from another cause within 30 years (Tab. 2) . The statistical analysis showed that the use of radiotherapy – and in particular supradiaphragmatic radiotherapy – increased mortality in the long term. Mortality due to second malignancies (HR 2.02, 95% CI 1.54-2.65), cardiovascular disease (HR 4.36, 95% CI 2.74-6.94), and infections (HR 2.17, 95% CI 0.99-4.79) was significantly increased in those who received radiotherapy above the diaphragm. These results were also somewhat less pronounced for infradiaphragmatic radiotherapy.
Also, the choice of chemotherapy appears to be relevant to long-term outcomes and life expectancy. Thus, mortality from second cancers was significantly increased after high doses of procarbazine (HR 1.53, 95% CI 1.26-1.85), an effect that has not been described previously. Splenectomy, unsurprisingly, increased the likelihood of dying from infection. However, the authors concluded that irradiation of the spleen resulted in even higher infection-associated mortality. This may be due to the fact that vaccination is better established in splenectomy than in radiotherapy of the spleen.
The bottom line
While mortality from Hodgkin’s lymphoma is greatest in the first few years after diagnosis, the likelihood of dying from long-term adverse effects of therapy increases steadily. After about 25 years, absolute excess mortality from non-Morbus Hodgkin-related causes such as second malignancies, cardiovascular disease, and infections exceeds excess mortality caused by Hodgkin lymphoma. It is imperative that this fact be taken into account given the young patient population. On the one hand, the results of the study underscore the importance of lifelong prevention. On the other hand, the authors also emphasize the importance of careful patient selection – an option that hopefully can be better applied in the future with the increasing personalization of oncological therapies and technical advances in the field of radiation. However, even if this does indeed reduce long-term damage, of which there are only faint signs today, the Hodgkin lymphoma patients of yesterday must not be forgotten.
Source: de Vries S, et al: Long-term cause-specific mortality in hodgkin lymphoma patients. J Natl Cancer Inst. 2020. doi: 10.1093/jnci/djaa194. Epub ahead of print.
Literature:
- German Hodgkin Study Group website: www.ghsg.org/ (last accessed 05/13/2021).
InFo ONCOLOGY & HEMATOLOGY 2021; 9(3): 32-33.