Aug 25, 2014
By Shira Klapper, Senior Writer/Editor
Over the past few decades, advances in cancer care have enabled many patients to live for years after a diagnosis and to even be declared “cured.” This great success has paved the way for the field of Survivorship, which addresses the medical, psychological, and financial outcomes that arise from surviving cancer and the effective, yet toxic treatments of chemotherapy and radiation.
Recent research has shown that one of the long-term medical outcomes of cancer treatment is an increased risk of developing diabetes mellitus (DM). Now, a new Journal of Clinical Oncology (JCO) study, “Risk of Diabetes Mellitus in Long-Term Survivors of Hodgkin Lymphoma,” adds to this growing literature linking past cancer treatment to an increased risk of developing DM. The study, published online, ahead of print, August 25 found that five-year survivors of adolescent and adult Hodgkin lymphoma (HL) who received more than 36 gray (Gy) of radiation to the para-aortic lymph nodes and spleen had a significantly higher risk of developing DM. “Gy” defines a unit of radiation.
Prior studies point to HL
|Frederika A. van
According to study coauthor Frederika A. van Nimwegen, MSc, a PhD student at the Netherlands Cancer Institute, there are several reasons the researchers chose specifically to focus on HL when looking at the association between cancer treatments and risk of developing DM. First, HL is a paragon of curable cancer, meaning patients survive for many years and are thus susceptible to the down-the-road effects of cancer treatments. Second, in a 2012 study, a French-British group reported an increased risk of DM among childhood cancer survivors who had received radiation to their total bodies or abdomen, resulting in irradiation of the pancreatic tail.
“We were intrigued by the findings and thought, well, maybe HL survivors are also at increased risk,” said Ms. van Nimwegen. “Most adult and adolescent HL patients are not treated like childhood cancer patients in that HL patients receive bone marrow transplants and total body irradiation less frequently, but they do frequently receive para-aortic radiotherapy, which exposes the pancreas to radiation as well.”
For HL survivors, risk of diabetes 20 years down the line
To uncover any associations between HL and DM, the researchers looked at 2,264 HL survivors from Dutch University hospitals and cancer centers. All patients met three criteria: Survivors of five years or longer, HL diagnosis before age 51, and treatment between 1965 and 1995. Data were collected on such variables as stage, chemotherapy, radiation field and dose, diabetes, and date of death. Data were gathered on patients who were five to 40 years away from their HL diagnosis, with most patients falling between 15 and 30 years.
When the data were analyzed, the researchers found that 30 years down the line, 8.3% of survivors of HL had developed DM. Patients with HL who received 36 Gy or more to the para-aortic nodes and spleen had a 2.3-fold risk of developing DM. Patients who received 36 Gy or more to the para-aortic region alone had a 1.82-fold increased risk of developing HL, compared to patients not treated with radiation below the diaphragm. Overall HL survivors had a 2.6-fold increased risk of developing DM compared to the general population.
No additional risk of developing DM was observed among patients who received radiation of less than 36 Gy.
“Lower radiation doses, up to 35 Gy, were not associated with a significant increase in risk of diabetes,” said Ms. van Nimwegen. “Most patients however, received 36 Gy or more to the para-aortic lymph nodes, with or without the spleen, and it seems that these patients, the high dose radiation groups, are at increased risk. Because the group that received lower radiation doses of up to 35 Gy is rather small in this cohort, it is hard to draw any firm conclusion on the risk of DM in this group.”
Explaining the connection between radiation and DM
According to Ms. van Nimwegen, research has not yet explained why radiation to the spleen and para-aortic lymph nodes, which results in radiation to the pancreas, should be associated with an increased risk for DM.
“The question has not been investigated properly, so we are still guessing,” said Ms. van Nimwegen.
However, several theories have been suggested.
“From studies in primates, we know that low dose fractionated irradiation of the pancreas can cause reduced insulin release as well as glucose intolerance,” said Ms. van Nimwegen. “So not only does irradiation cause damage to the pancreas, which results in reduced insulin release, but there might also be something more systemic going on, causing the body to be less sensitive to insulin.” Diabetes arises when the pancreas does not produce enough insulin, or when the cells of the body do not respond properly to the insulin produced.
In addition, some researchers have speculated that radiation causes damage to the normal abdominal subcutaneous depot of adipose tissue, causing fat to accumulate in the deep viscera, which can lead to insulin resistance.
“Another option is that maybe it’s a combination of both reduced insulin production and also damage to the microvasculature of the pancreas, resulting in reduced insulin release,” said Ms. van Nimwegen.
Educating patients about increased risk
One piece of encouraging news is that these days, radiation fields are becoming smaller and smaller, with the goal of sparing as much normal tissue as possible.
However, while radiotherapy to the spleen is rarely administered nowadays, there are many long-term HL survivors who received splenic or para-aortic irradiation as part of their HL treatment in the past. And for some HL patients, radiotherapy to the para-aortic lymph nodes is still part of treatment. In addition, for patients with other types of cancer, such as testicular and stomach, radiation to the abdomen, and thus the pancreas, cannot be avoided if the goal is cure.
“And cure,” said Ms. van Nimwegen, “is the first thing we want for these patients,”
For now, said Ms. van Nimwegen, doctors can only educate patients about their elevated risk for developing DM and keep track of patients’ blood glucose levels.
“It’s important that treating physicians are aware of the increased risk of diabetes in Hodgkin lymphoma survivors who have been treated with para-aortic and splenic radiotherapy. This awareness enables doctors to properly treat DM at an early stage and to reduce comorbidity due to DM.”
Frederika A. van Nimwegen is a PhD student in the Department of Epidemiology, Netherlands Cancer Institute
Click here to read the abstract.
Click here to read the PDF.
van Nimwegen FA, Schaapveld M, Janus, CPM, et al. Risk of diabetes mellitus in long-term survivors of Hodgkin lymphoma. J Clin Oncol. 2014. Published online ahead of print 8.25.2014.
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@ 2014 American Society of Clinical Oncology