Introduction
Radiotherapy (RT) is a treatment method that aims
to destroy cancer cells using ionizing radiation.
However, normal tissue around the tumor is also exposed
to some side effects, depending on the type
of tissue. The toxicity of RT is affected not just by
factors of treatment (such as radiation dose, fraction scheme, and duration of treatment) but also patient
factors (such as age and presence of comorbidity),
and the incidence or duration of occurrence varies
from patient to patient.[] Completing the RT
course without interruption is important in terms of
providing local control of the disease. For this reason,
it is important to isolate the factors that can potentialize
the side effects of RT. []
Diabetes mellitus (DM) is a systemic metabolic
disease that causes impairment in glucose metabolism
and has the potential to affect multiple organ systems.
[] DM can cause retinopathy, nephropathy, neuropathy,
and cardiovascular disease as well as problems with
platelet aggregation, leukocyte function, protein metabolism,
and disorders in microvascular circulation.
[,] DM patients have an increased susceptibility to
infection as a result of weak macrophage activity, decreased
chemotaxis and phagocytic activity, decreased
cell proliferation and collagen production, decreased fibroblast
and growth factors, increased apoptosis in cells
in the scar tissue, angiogenesis, and granulation tissue
formation.[,,] Post-operative studies have also highlighted
delayed wound healing in patients with DM
compared to the general population.[-] Tissue damage
due to RT may, therefore, be slow to heal because of
overall impaired wound healing, and so acute RT toxicity
may increase in patients with DM. A number of
researchers have investigated this issue, but most of the
studies investigating the toxicity of RT in DM patients
have tended to investigate late-RT toxicity.[-]
In this study, the effects of DM on acute toxicities
of treatment in cancer patients receiving RT or cardiac
resynchronization therapy (CRT) were investigated.
Methods
This study was performed in accordance with the principles
of the Declaration of Helsinki and approved by
the local ethical committee (Sivas Cumhuriyet University
Ethical Committee).
The data of 1892 cancer patients who were treated
at the Department of Radiation Oncology at Cumhuriyet
University Medical Faculty Hospital between
January 2010 and December 2018 were retrospectively
evaluated. Patients without distant metastases who
received curative/definitive RT or CRT were included
in the study. Patients receiving palliative RT were excluded
from the study. The patients were divided into
two groups: Group 1 comprised patients without a DM
diagnosis, and Group 2 included patients with DM.
DM
• Hypertension
• Heart disease
• Chronic renal failure.
The performance status of the patients was assessed
according to the Eastern Cooperative Oncology Group
performance scale. Weight loss has been defined as the
loss of more than 5% of the patient's weight. HbA1c patients were measured on the 1st day they started RT.
The upper limit of HbA1c is considered to be 6.5.
Acute toxicities were observed within 90 days from
the start of RT/CRT. Treatment toxicities were evaluated
weekly during treatment and after 1 and 3 months
following the end of treatment according to the acute
radiation morbidity measurement criteria of Radiation
Therapy Oncology Group (RTOG). According to these
criteria, both hematological and non-hematological
toxicities are graded between 0 and 5,[] where grade
5 toxicity is associated with death from direct radiation.
Here, hematological aspects include the assessment of
white blood cells (WBC), neutrophils, platelets, hemoglobin,
and hematocrit, while non-hematological areas
include skin, mucous membrane, eye, ear, salivary
gland, pharynx/esophagus, larynx, lung, upper gastrointestinal
system, lower gastrointestinal system (GIS),
genitourinary system (GUS), and central nervous system.
Patients were actively questioned for each of the
10 symptoms during each interview. To minimize observer
bias, the assessment forms themselves detailed
the specifics of each grade of toxicity, so that the assessor
could directly compare and choose the most appropriate
grade of toxicity for the patient in front of them.
Statistical Evaluation
In this study, descriptive tests using the Statistical
Package for the Social Sciences for Windows (v23.0)
were used, along with the Chi-square test, the Student"s
t test (for those data with a near-normal distribution),
and the Mann-Whitney U test (for those without a
near-normal distribution) to compare the means of
the groups. In addition, the mean, standard deviation,
mean deviation, and median of the data were calculated
using descriptive statistical methods. The results
obtained from these tests were assessed according to a
5% level of significance, p≤0.05.
Results
In Table 1, demographic characteristics and treatment
schemes between Group 1 and Group 2 are compared.
Among the groups, gender (p=0.001), median
age (p<0.001), diagnosis (p=0.023), hypertension
(p<0.001), heart disease (p<0.001), chronic renal failure
(p=0.005), adjuvant (p=0.023), and concurrent
chemotherapy administration (p=0.047) were found to
be statistically significant predictors.
Table 1 Patients, cancers, and treatment characteristics
In Table 2, the groups were compared for the rate
and time of acute non-hematological toxicities of RT/CRT. According to the table, grade 3-4 skin toxicity
(p=0.001), grade 1-2 lower GIS toxicity (p<0.001), and
grade 1-2 GUS toxicity (p=0.012) were observed more
in Group 2 patients. In terms of time of appearance,
only skin toxicity appeared earlier in Group 2 patients
(3 weeks vs. 4 weeks, p=0.002).
Table 2 Incidence and time of acute non-hematological side effects
In Table 3, a comparison of the groups was made
for the rate and time of the RT/CRT acute hematological
toxicities. Grade 1-2 WBC toxicity (p=0.027)
and grade 1-2 hemoglobin toxicity (p=0.033) were observed
more in Group 1.
Table 3 Incidence and time of acute hematological side effects
In 273 patients (14% of the total sample), RT/CRT
had to be suspended due to the side effects of the treatment.
Of these patients, 231 were in Group 1 (15%
of that group), and 42 were in Group 2 (13% of that
group) (p=0.158). During the treatment, weight loss
was detected in 266 patients (14% of the total sample),
of which 220 were in Group 1 (14% of that group), and
46 were in Group 2 (14% of that group) (p=0.464). Performance
deterioration during RT/CRT was observed
in 334 patients (18% of the total sample); 271 of these patients were from Group 1 (17% of Group 1), and 63
were from Group 2 (19% of Group 2).
Hypertension accompanied diabetes in 206 of the
335 patients with DM (61%). Toxicities at a level of
grade 3-4 skin (p<0.001) and grade 1-2 lower GIS system
(p<0.001) were found to be significantly higher in
patients with DM and hypertension compared to DM
patients without hypertension (Table 4).
Table 4 Comparison of DM and hypertension association and early side effects of RT according to HbA1c values
In 256 of the 335 DM patients (76%), the HbA1c
level was ≥6.5, meaning that glucose regulation was not
under control in these patients. In the comparison of
side effects observed in patients whose blood glucose
regulation was/was not under control, only grade 1-2
lower GIS toxicity was found to differ (Table 4).
Discussion
Acute toxicities of RT are usually reversible effects that
occur in rapidly dividing cells. They are one of the most
important issues in the treatment of cancer patients
because they have the potential to prevent continuity of treatment. Adding simultaneous chemotherapy to
RT naturally increases the side effects observed during
treatment. The presence, in addition to cancer, of a disease
such as DM having systemic effects may further
increase the side effects of treatment. In this study, we
investigated how DM affected treatment toxicities in
cancer patients receiving RT/CRT. As a result of our research,
we determined that certain non-hematological
toxicities (grade 3-4 skin, grade 1-2 lower GIS, and
grade 1-2 GUS) were observed more in patients with
DM. We also observed that skin toxicity appeared earlier
in patients with DM. The situation was slightly different
in hematological toxicities. In patients without
DM (who received more adjuvant and simultaneous
chemotherapy compared to patients with DM), grade
1-2 WBC and hemoglobin toxicities were observed
more. In patients with hypertension as well as DM,
grade 3-4 skin and grade 1-2 lower GIS were observed
more, whereas in patients without DM, grade 1-2 lower
GIS toxicities were more prevalent.
Radiation dermatitis is known to be one of the most
common acute toxicities, at a historical rate above 90%.
[,] However, of these, most of the observed toxicities
are grade 1-2, and only 15-25% are grade 3-4
toxicities.[-] The radiation sensitivity of the skin
is related to rapidly growing cells. Basal keratinocytes,
hair follicle stem cells, and melanocytes are the most
sensitive.[] Tissue damage occurs through the formation
of short-lived free radicals from the beginning
of RT. Eventually, irreversible breaks and inflammation
begins in cellular DNA. This inflammatory response is mediated by pro-inflammatory cytokines (IL-1, IL-3,
IL-5, IL-6, and TNF-a) and chemokines (IL-8, eotaxin,
CCR receptor). These factors attract eosinophils and
neutrophils to the site of local inflammation. This leads
to tissue damage and the loss of the protective barrier.
[] Radiation destruction of basal keratinocytes further
impairs wound healing, so each additional exposure
to RT results in more direct tissue damage, inflammation,
and impaired epithelial regeneration.[]
In patients with DM, prolongation of the inflammatory
phase, increased susceptibility to infection, and
delayed wound healing have been shown as a result of
decreased phagocytic activity, poor macrophage activation,
and increases in cytokines and chemokines.
[-] In chronic diabetic patients, atherosclerosis
develops as a result of microvascular occlusive changes
(capillary hyalinization, arteriolar obliteration, and
decreased tissue perfusion).[] In diabetic patients,
microvascular flow is disrupted by long-term exposure
of blood cells to hyperglycemia, hardening of the spectrum
(a red blood cell membrane protein), and platelet
aggregation.[] As a result, there is a delay in wound
healing.[]
In diabetic patients receiving RT, the presence of
conditions that can potentiate each other may increase
the possible complications. Furthermore, because DM
has a pathophysiological process that can compromise
tissue oxygenation, it can potentially hinder or delay
the repair of radiation damage. Studies have shown
that, compared with the general population, diabetics
are at a higher risk for the development of complications associated with perioperative or post-operative
wound healing.[-] In the same way, the relationship
between RT complications and DM has been the
subject of research in the 1990s. Kucera et al. investigating
the relationship between radiation toxicity and DM
in patients receiving RT, they found no difference in
skin side effects between diabetics and non-diabetics.
[,] Porock investigated the predictive factors that
increased the severity of skin reactions in breast cancer
patients; they identified smoking, chemotherapy,
history of skin cancer, skin reaction to UV radiation,
lymphocele aspiration, condition of lumpectomy scar
at the beginning of treatment, weight, and breast size as
factors that predicted the severity of skin toxicity. However,
it is acknowledged that the scarcity of published
research means there is insufficient evidence to conclude
about the role of DM on radiation reactions.[]
In our study, the rate of grade 3-4 toxicity was found
to be higher in diabetics treated with external RT compared
to non-diabetic patients. It has also been found
that skin toxicity occurs earlier in patients with DM.
It is a known fact that radiation causes significant
damage to rapidly proliferating tissues such as gastrointestinal
and genitourinary system mucosa. However,
the vascular configuration that plays a key role in repairing
radiation damage deteriorates in the presence
of DM. Accordingly, an activated coagulation system
and decreased blood flow disrupt the mucosal barrier
in the gastrointestinal and genitourinary system.[-] DM disrupts vascular endothelial function and
causes dysfunctional tissue repair.[] Several studies
have identified an association between DM and latelower
GIS and GUS toxicity; however, the results are
generally mixed.[-]
Özkan et al. investigated the factors affecting gynecologic
malignancies and treatment toxicity of 129
patients who received RT/CRT for cervical carcinoma,
assessing toxicity according to the RTOG mortality
criteria.[] In the study, a relationship was found between
lower GIS toxicity and DM, but not with upper
GIS and GUS. In the study published by Alashkham
et al., higher rates of late-grade 3-4 lower GIS toxicity
(especially proctitis-like complaints) were reported
in prostate cancer patients (n=716) receiving RT compared
to non-diabetic patients.[36] This suggested that
DM increased the risk of radiation toxicity and drove
the onset of symptoms to an earlier time. Herold et al.
investigated the effects of diabetes on radiation toxicity
in 944 prostate cancer patients (13% of whom were diabetic).[] Acute lower GIS and GUS toxicities could
not be demonstrated in connection with diabetes in this study. However, grade 2-4 late-lower GIS and GUS
toxicities were shown to be significantly higher in diabetics.
In the Herold"s study, radiation dose for lower
GIS toxicity, rectal blocking, and a history of DM were
seen as predictors of having a history of DM in GUS
toxicity. Kalakota and Liauw investigated the factors affecting
RT toxicity in 626 prostate cancer patients (16%
of whom were diabetic).[] In this study was pointed
that late grade 2 and 3 GUS toxicity was negatively affected
by DM, but that this effect could not be demonstrated
for lower GIS. In the PORTEC study,[]
the factors affecting the acute toxicity of pelvic RT in
patients with post-operative endometrial cancer were
examined. It was reported that DM, hypertension, age,
and RT technique did not affect acute toxicity. As can
be seen from examining these studies, DM is often associated
with late-lower GIS and GUS toxicity rather
than acute toxicity. However, in our study, it was found
that grade 1-2 acute lower GIS and GUS toxicity were
observed more frequently in patients with DM.
DM is known to affect bone marrow maturation as
well as impairing neutrophil function and an increased
apoptosis of leukocytes.[] In addition, in cases such
as nephropathy that develops due to the microvascular
complications of DM, anemia can result from the decrease
in erythropoietin.[] Due to the effects of both
chemo/RT and DM on the bone marrow and other
complications of diabetes, hematologic. Due to the effects
of both chemo/RT and diabetes on the bone marrow
and other complications of diabetes, it seems plausible
that hematological side effects increase during
treatment. However, contrary to this proposition, in
our study, more grade1-2 WBC and hemoglobin toxicity
was observed in patients without DM compared to
those with DM. This contrast may be attributed to the
fact that patients without DM received more adjuvant
or concurrent chemotherapy in the study.
Hypertension is one of the most common comorbid
diseases in patients with malignancies.[ It causes a
number of systemic complications in hypertension
such as DM. In addition, there is no negligible association
of DM and hypertension in the society. As a matter
of fact, in our study, 62% of diabetic patients were
associated with DM and hypertension. It should not be
overlooked that the combination of DM and hypertension
may increase the side effects of cancer treatments.
Studies of some researchers related to this subject are
also included in the literature.[,-] Van Nagell
et al. examined late side effects in 271 patients who
received definitive RT for locally advanced cervical
cancer (mean follow-up 5 years). Researchers detected rectovaginal fistula in 11 cases and they observed that
DM and hypertension coexisted in 6 of these cases.[]
Maruyama et al. reported late side effects of the treatments
of 270 cervical cancer patients after 60 months
of follow-up. This study documented that 9 of the ileus
cases not associated with tumor progression were associated
with DM and hypertension. As a result, they
concluded that the risk of late toxicity was higher in
patients with DM and hypertension.[] Harwood and
Tierie. studied about 204 localized glottic cancer patients
treated with RT. They stated that DM and/or hypertension
significantly contributed to the risk of subsequent
major complications (severe edema requiring
tracheotomy, laryngeal necrosis, or laryngeal stenosis).
[] Porock and Kristjanson investigated the effect of
advanced age on radiation dermatitis, they found that
coexisting diseases such as hypertension, DM or malnutrition
affect the severity and occurrence of radiation
dermatitis in elderly patients. They associated this
situation with the coexistence of hypertension and diabetes
with impaired epidermal cycle and regeneration
ability.[] In this study, in which we examined early
side effects in cancer patients receiving RT/CRT, we
observed that grade 3-4 skin and grade 1-2 lower GIS
toxicities were statistically significantly higher in patients
with DM and hypertension compared to diabetic
patients without hypertension.
In patients with DM, it is possible to show blood
sugar regulation for the last 3 months with HbA1c.
Failure to regulate blood sugar may result in increased
complications of the disease. It has been shown in
some studies that after the diagnosis of cancer, patients
adapt less to diabetic drugs, discontinue drug use or
reduce the use of drugs.[,] Does RT/CRT toxicity
increase in patients whose blood glucose is not regulated?
Moonkyoo Kong et al. evaluated the effects of
DM and DM-related serological factors (HbA1c and
fasting glucose) on the development of radiation pneumonia
in patients with lung cancer. They considered
DM, HbA1c, and fasting glucose level as important
predictive factors for the development of grade 3 radiation
pneumonia in patients with lung cancer. They emphasized
that patients with DM, patients with HbA1c
> 6.15, and patients with fasting glucose >121 mg/dL
should be treated with care.[] In our study, it was observed
that 76% of 335 patients with DM had HbA1c
level 6.5 and glucose regulation of these patients was
not under control. Grade 1-2 lower GIS toxicity was
found to be higher in patients without blood glucose
regulation compared to patients with regulation. However,
in our study, the number of patients whose blood glucose was not regulated was not balanced with the
number of those who were regulated. If the number of
patients in the study were balanced, perhaps we could
see this difference in more side effects.
As a result; in this study was pointed that DM negatively
affected acute toxicity of RT/CRT, and having
hypertension and lack of regulation of blood glucose
contributed to this negativity.
Limitations
The main limiting factors of our study are the retrospective
nature of the data and that they come from a single
center. In addition, the following information was lacking:
the accompanying metabolic syndrome parameters
(which may affect the RT toxicities of the patients), information
on the use of metformin and other antidiabetic
agents, and data on fasting insulin levels.
Conclusion
According to this study, it was found that DM patients
generally tolerated RT very well. The incidence rates
of lower gastrointestinal and genitourinary side effects
have been found to increase. In addition, acute side effects
have started to appear at the same time as in patients
without DM.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved
by the Sivas Cumhuriyet University Non-interventional
Clinical Research Ethics Committee (no: 2021-04/28, date:
14/04/2021).
Financial Support: None declared.
Authorship contributions: Concept - E.E.; Design - E.E.,
B.Y.; Supervision - E.E.; Funding - E.E.; Materials - E.E.;
Data collection and/or processing - E.E., B.Y.; Data analysis
and/or interpretation - E.E.; Literature search - E.E., B.Y.;
Writing - E.E.; Critical review - E.E.
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