Introduction
The incidence of cancer increases with age, with 50% of
newly diagnosed cancer patients being over 65 years of
age.[] According to 2016 data from the United States,
it is the leading cause of death between the ages of 60
and 80 and the second most common cause of death above the age of 80.[] Geriatric (>65 years old) patients
are frequently encountered in oncology clinics.
In cancer patients, early side effects due to CRT
usually occur during and immediately after treatment.
CRT aims to destroy cancer cells using both ionizing
radiation and systemic chemotherapy. Essentially,
it aims to potentiate the effectiveness of two different treatments. Radiotherapy provides local control,
while chemotherapy increases the effectiveness of radiotherapy
and prevents the escape of tumor cells into
the system. With the cumulative effect of both therapies
on the tumor, CRT predisposes normal tissues to
an increase in toxicity. The balance between efficacy
and toxicity of the treatment is crucial in determining
therapeutic success. At this stage, patient selection becomes
important. In a treatment that has a profile of
increased side effects, selecting a patient group that is
generally considered vulnerable is highly undesirable.
Elderly patients constitute this vulnerable group due
to physiologically aged and generally inadequate organ
functions, as well as comorbidities.
In cancer patients, factors such as the patient"s age,
the presence of other chronic diseases, and the stage of
the disease affect the choice of treatment. It has been
observed that, in cancer treatment for elderly patients,
third and fourth-grade hematological toxicities increase,
and some patients require treatment modification
due to treatment toxicities.[,] Two cohort prospective
studies have shown that a geriatric assessment
can predict chemotherapy-related toxicity.[,] The
International Association of Geriatric Oncology[]
recommends conducting a geriatric assessment prior
to the treatment of elderly cancer patients. However,
the intensity and scope of comprehensive geriatric assessments
in oncology practice are still limited due to
time constraints. Elderly cancer patients are usually
underrepresented in clinical studies, and little data is
available on curative radiotherapy in these patients regarding
CRT toxicity and compliance.[,]
This study aimed to evaluate acute toxicity and adverse
events, such as treatment interruption, abandonment,
and weight loss, in cancer patients treated with
CRT, according to age.
Methods
This study was performed in accordance with the principles
of the Declaration of Helsinki and was approved by
the ethical committee of Sivas Cumhuriyet University.
Data on 813 cancer patients, who were treated and
followed up at the oncology center of Sivas Cumhuriyet
University Medical Faculty Hospital between January
2010 and December 2018, were obtained from RTOG's
acute toxicities criteria evaluation tables, routinely performed
at the center, and analyzed retrospectively. The
study included older, nonmetastatic, curative patients
who were eligible for CRT. Patients who had received palliative radiotherapy or chemotherapy were excluded
from the study. The patients were divided into two
groups: over and under the age of 65. The results were
analyzed separately for five regions-brain, head and
neck, thorax, abdomen, and pelvis.
The performance status of the patients was recorded
according to the performance scale of the Eastern
Cooperative Oncology Group. Weight loss was defined
as the loss of more than 5% of the patient's weight.
Concurrent Chemoradiotherapy Protocols
? Brain site: Temozolomide (75 mg/m² daily during
radiotherapy) with a total radiation dose of 60 Gy
from 2 Gy per day.
• Head and neck site: Cisplatin (40 mg/m² weekly)
or cisplatin + 5-FU (cisplatin 75 mg/m² D1 and
5-FU 1000 mg/m² D1-5) with a daily radiation dose
of 1.8?2.12 Gy and a total radiation dose of 66?72
Gy was applied every 28 days.
• Thoracic site: Cisplatin (40 mg/m² weekly) or carboplatin
+ paclitaxel (carboplatin 2 AUC/m²/week
and paclitaxel 50 mg/m²/week) with a total radiation
dose of 66.6 Gy from 1.8-2 Gy daily for nonsmall
cell cancers/weekly, or cisplatin + etoposide
(cisplatin 50 mg/m² D1, 8 and etoposide 50 mg/m²
D1?5 every 28 days).
• Abdominal site: Concurrent FUFA (5-FU 400 mg/
m² D1-5 and folinic acid 200 mg/m² D1-5 every
28 days) with a total radiation dose of 50.4 Gy from
1.8 Gy daily for stomach, pancreas, and gallbladder
cancers.
• Pelvis site: Weekly cisplatin (40 mg/m²) was used
in cervical cancers with a daily radiation dose of
1.8-2 Gy, totaling 50.4 Gy.
Evaluation of Treatment Side Effects
Acute toxicities were observed within 90 days from the
start of CRT. Treatment toxicities were evaluated weekly
during treatment and after one and three months following
the end of treatment, according to the RTOG
acute radiation morbidity criteria. Both hematological
and non-hematological toxicities were graded between
0 and 5.[] Hematological aspects include assessments
of white blood cells, neutrophils, platelets, hemoglobin,
and hematocrit. Non-hematological areas
include the skin, mucous membrane, eye, ear, salivary
gland, pharynx/esophagus, larynx, lung, upper gastrointestinal
system, lower gastrointestinal system, genitourinary
system, and central nervous system. Patients
were actively questioned for each of the ten symptoms
during each interview. To minimize observer bias, assessment
forms detailed the specifics of each grade of toxicity, allowing the assessor to directly compare and
select the most appropriate grade for the patient. The
adverse events examined included weight loss during
CRT, deterioration of performance status, cessation of
CRT, death during CRT, and interruption of CRT.
Statistical Evaluation
In this study, descriptive tests using the Statistical
Package for Social Sciences for Windows (v23.0) were
employed, along with the chi-square test, Student"s ttest
(for data with a near-normal distribution), and the
Mann-Whitney U test (also for those with a near-normal
distribution) to compare group means. The mean,
standard deviation, mean deviation, and median of the
data were calculated using descriptive statistical methods.
The results were assessed at a 5% level of significance
(p≤0.05).
Results
Of the 813 patients, 542 (67%) were aged <65 years and
271 (33%) were ≥65 years. Weight loss during CRT was
observed in 145 (27%) patients aged <65 years and in
63 (23%) patients aged ≥65 years (p=0.153). Deterioration
of performance status was noted in 134 (25%) patients
aged <65 years and in 63 (23%) patients aged ?65
years (p=0.145). Non-completion of planned CRT was
observed in 27 (5%) patients aged <65 years and in 33
(12%) patients aged ≥65 years (p<0.001). CRT was interrupted
in 83 (15%) patients aged <65 years and in 35
(13%) patients aged ≥65 years (p=0.204). The median
CRT interruption time was 7 days for patients aged <65
years (range, 1-25) and 7 days for patients aged ?65
years (range, 1-28) (p=0.543).
A total of 19 (2%) patients died during CRT. Seven
(1%) of these patients were aged <65 years, and 12 (4%)
were aged ≥65 years (p=0.007). Causes of death included
pulmonary embolism (n=4), heart attack (n=3), gastrointestinal
bleeding (n=2), cerebral hemorrhage (n=2),
and treatment toxicity (n=8). For all patients, three (1%)
of the eight who died due to treatment toxicity were
younger patients, and five (2%) were elderly (p=0.088).
Data from 82 (10%) brain cancer patients were examined;
62 (76%) were aged <65 years, and 20 (34%)
were aged ≥65 years. A comparison is presented in Table
1. The table includes terms for the performance status
of the patients (p=0.010), CRT interruption (p=0.001),
cessation (p=0.043), and death during treatment
(p=0.026). During CRT, one (2%) younger patient had
treatment toxicity (febrile neutropenia), while among
the elderly patients, one (5%) had a pulmonary embolism, one (5%) had gastrointestinal bleeding, and one
(5%) had treatment toxicity (severe thrombocytopenia).
Table 1 Tumors in the brain site by age, clinical features, treatments, adverse events and
hematological and non-hematological side effects
Data from 113 (14%) head and neck cancer patients
were analyzed. Of these, 81 (72%) were aged <65 years,
and 32 (28%) were aged ≥65. The clinical features of patients
with head and neck tumors, the characteristics of
treatments, treatment side effects, and the comparison of
adverse events by age are given in Table 2. According to
Table 2, comorbidity (p<0.001), CRT prior to chemotherapy
(p=0.005), death during CRT (p=0.021), grade 1-2
ear toxicity (p=0.006), and grade 1-2 pharynx/esophagus
toxicity (p=0.046) showed statistically significant differences
between the groups. There were no deaths in the
younger cohort, but in the elderly group, one (3%) died
of a heart attack, and two (6%) from treatment toxicity
(febrile neutropenia, mucositis, malnutrition).
Table 2 Tumors in the head and neck site by age, clinical features, treatments, adverse
events and hematological and non-hematological side effects
Data from 226 (28%) thoracic cancer patients were
analyzed, 144 (64%) aged <65 years, and 82 (36%)
aged ≥65. The clinical characteristics of patients with
tumors in the thoracic region, the characteristics of
their treatment, and a comparison of the side effects
and adverse reactions by age are presented in Table
3. Comorbidity (p=0.015), surgery (p=0.031), CRT
interruption time (p=0.014), grade 1-2 skin toxicity
(p=0.025), grade 1-2 pharynx/esophagus (p=0.002),
grade 1-2 upper gastrointestinal toxicity (p=0.036),
and grade 1-2 hematocrit toxicity (p=0.032) showed
statistically significant differences between the
groups. One younger patient (0.4%) died due to gastrointestinal
bleeding, and two younger patients (1%)
died from treatment toxicity (hematological toxicity
with grade 3-4 esophagitis). One elderly patient (1%)
died from treatment toxicity (neutropenic fever).
Data from 187 (23%) patients treated for abdominal
cancer was examined. Of these, 132 (71%) were
aged <65 years, and 55 (29%) were aged ≥65. Table 4
shows the clinical characteristics of patients with tumors
in the abdomen, the characteristics of treatment,
and a comparison of side effects and adverse reactions
by age. According to Table 4, comorbidities (p<0.001)
and grade 1-2 platelet toxicity (p=0.029) showed statistically
significant differences between the groups.
One younger patient (0.7%) died of a heart attack,
while in the elderly group, one (2%) died from cranial
hemorrhage, one (2%) from a pulmonary embolism,
and one (2%) from treatment toxicity (neutropenic
fever with gastrointestinal bleeding).
Table 3 Tumors in the thorax region by age, clinical features, treatments, adverse events
and hematological and non-hematological side effects
Table 4 Tumors in the abdomen region by age, clinical features, treatments, adverse events
and hematological and non-hematological side effects
Data from 205 (25%) patients treated for pelvic cancer
was analyzed. Of these, 122 (60%) were aged <65 years,
and 83 (40%) were aged ≥65. Table 5 presents a comparison
of clinical features, treatment characteristics, side effects, and adverse events by age in patients with pelvic
tumors. Table 5 shows that comorbidity (p<0.001),
performance status (p=0.045), surgery (p=0.011), and CRT interruption (p=0.032) were statistically significant
differences between the groups. Among the younger
patients, one (0.4%) died from a heart attack, and one (0.4%) died from a pulmonary embolism. In the elderly
group, one (1%) died from a pulmonary embolism, and
one (1%) from cranial hemorrhage.
Table 5 Tumors in the pelvis region by age, clinical features, treatments, adverse events and
hematological and non-hematological side effects
Discussion
This study examined the toxicity of CRT by age and
treatment location. The results show that elderly patients
had more comorbidities in the brain, head, and
neck regions, while poorer performance status was observed
in patients undergoing pelvic irradiation. This
study also found higher rates of CRT cessation and
death during CRT in elderly patients, particularly in
the head and neck, brain, and pelvic regions.
For thoracic cancer patients, the rate of CRT interruption
was higher among younger patients than older
ones, though statistically, this was not significant. No
significant differences were detected between the groups
in terms of grade 3-4 toxicities. However, grade 1-2
toxicities (e.g., ear, pharynx/esophagus, upper gastrointestinal,
platelet, hematocrit) varied between the two
groups. Although no significant difference in treatment
toxicities was observed between younger and older patients,
toxic deaths due to CRT were more common in
elderly patients. In elderly patients, 5% of toxic deaths
occurred in the brain, 6% in the head and neck, 1% in
the thorax, and 2% in the abdomen, while for younger
patients, toxic deaths occurred in 2% of brain cases
and 1% of thoracic cases. This higher incidence of toxic
deaths in elderly patients suggests that CRT-related adverse
events may be of greater concern in this age group.
In a trial by Stupp, temozolomide chemotherapy
during and after radiotherapy significantly prolonged
survival in glioblastoma patients aged 70 or younger
at diagnosis.[] Especially for fit patients over 70, temozolomide
with conventional or hypofractionated
radiotherapy remains a treatment option.[,] Few
studies compare CRT-associated toxicity by age in patients
with brain tumors. A study conducted by Saito
et al.[] investigated the toxicity of concomitant and
adjuvant temozolomide in patients with brain tumors
(≥65 years, N=27 vs <65 years, N=49). This study found
that thrombocytopenia and grade 4 toxicity rates were
higher in the elderly group, but no difference was observed
in non-hematological toxicity. Sijben et al.[]
evaluated CRT toxicity in glioblastoma patients over
65 and found no treatment-related deaths, though CRT
cessation and death during CRT were more common
in elderly patients. However, CRT interruption was
more frequent in younger patients. No difference was
observed between the groups in terms of hematological and non-hematological toxicity. The higher incidence
of adverse events in elderly patients may be attributed
to greater comorbidity and poorer performance status.
Though temozolomide appears well-tolerated in elderly
patients, caution is warranted, given the 5% mortality
rate associated with treatment toxicity in this group.
Concurrent CRT has been demonstrated to improve
survival compared to radiotherapy alone in locoregionally
advanced squamous cell head and neck
cancer.[] However, this approach is associated with
significant acute toxicity, such as mucositis, dysphagia,
and skin reactions, which can impede patient
compliance and disrupt treatment delivery.[] Merlano
et al.[] investigated the effect of age on acute
toxicity caused by CRT in 317 head and neck cancer
patients, categorizing them into <65 years (N=224)
and ≥65 years (N=93). They evaluated CRT-related
acute toxicities and treatment compliance (e.g., delays,
non-completion, and death during treatment). Except
for a higher frequency of infection and pneumonia in
the elderly group, no differences were found between
the groups in terms of treatment compliance and hematological
or non-hematological side effects. In another
retrospective study by Grün et al.,[] the acute
toxicity results of 158 head and neck cancer patients
undergoing CRT were examined by age. Grade 3 and
higher leukopenia occurred more frequently in elderly
patients, though the percentage of patients completing
the prescribed chemotherapy was similar between
the groups. Non-hematological toxicities such as dermatitis,
dysphagia, mucositis, and pain did not differ
significantly. Michal et al.[] compared CRT toxicities
between 44 patients ≥70 years and 137 patients <70
years with head and neck cancer, finding comparable
rates of acute toxicities, including nausea and vomiting,
mucositis, dysphagia, and skin reactions. Toxic
death rates were also similar between the groups. Like
prior studies, this study found no difference in grade
3-4 hematological and non-hematological complications
between the two groups. However, more deaths
occurred in elderly patients during CRT, with 6% of
deaths in elderly patients attributed to treatment toxicity,
indicating that more caution should be exercised
during CRT in this population.
Semrau et al.[] investigated the impact of comorbidity
and age on treatment outcomes and acute toxicity
in 66 lung cancer patients who underwent CRT. The
patients were grouped into those aged under and over
70. Grade 3-4 thrombocytopenia and leukopenia were
more common in elderly patients. A prospective study
by Servagi-Vernet et al.[] demonstrated the feasibility of CRT in selected esophageal cancer patients over 75.
A review by Zimmerman et al.[] found either no or a
low incidence of both acute and late high-grade toxicity
in elderly patients. Stinchcombe et al.[] compared
treatment-related side effects in elderly and younger
patients with non-small cell lung cancer, analyzing
2,768 patients under and over the age of 70. Toxicity
rates for all grade 3 and higher, and for both hematological
and non-hematological grade 3 and higher, were
more frequent in elderly patients. The study also found
that elderly patients completed treatment less often
(47% vs 57%; p<0.010), ended treatment due to adverse
events more frequently (20% vs 13%; p<0.010), refused
treatment at higher rates (5.8% vs 3.9%; p=0.020), and
died during treatment more frequently (7.8% vs 2.9%;
p<0.010). Unlike the current study, no difference was
observed in grade 3?4 hematological or non-hematological
side effects between younger and elderly patients.
However, grade 1-2 hematocrit side effects and
treatment interruptions were more common in elderly
patients. Younger patients more frequently experienced
grade 1-2 skin, upper gastrointestinal, and esophagus
toxicities. Deaths due to treatment toxicity occurred at
a rate of 1% for both groups. In this study, both young
and elderly patients tolerated CRT similarly.
In the abdominal region, CRT may be involved in
both adjuvant and definitive therapy for cancers of the
stomach, pancreas, and gallbladder. Diarrhea, nausea,
vomiting, and hematological side effects, which arise
from the rapidly dividing gastrointestinal mucosa, are
the most common acute side effects of abdominal CRT.
However, external beam radiotherapy in this region
is limited by the small intestine's sensitivity to radiation,
so doses are relatively lower than in other regions.
Few studies have examined CRT toxicity by age in this
region. Wilkowski et al.[] evaluated the toxicity of
CRT in 32 patients with inoperable pancreatic cancer,
stratifying them by age (≥75 years). They found
no difference between groups in terms of grade 3?4
gastrointestinal side effects or grade 3-4 leukopenia
and thrombocytopenia. Miyamoto et al.[] evaluated
CRT toxicity in pancreatic cancer patients aged ?75
years and reported that 7% ended CRT, and 17% were
hospitalized, with nausea, pain, and failure to thrive
being the most common side effects. Slagter et al.[]
used data from the Critics study to evaluate perioperative
treatment results and toxicity in 788 gastric cancer
patients by age (<70 vs ≥70). In their study, 79%
of younger patients and 63% of elderly patients were
able to begin postoperative CRT, with elderly patients
initiating CRT at statistically significantly lower rates.
However, no difference was observed in grade 3-4 gastrointestinal
or hematological toxicities. In this study,
as in others, no differences were found between age
groups in terms of adverse events or grade 3-4 toxicity.
Only grade 1-2 thrombocytopenia rates were higher in
younger patients. The findings suggest that young and
elderly patients tolerate abdominal CRT similarly, although
no treatment-related deaths were observed in
younger patients, while elderly patients had a 2% death
rate. Thus, more caution is needed when administering
abdominal CRT to elderly patients.
CRT is an important treatment modality for cervical,
bladder, rectal, and anal canal tumors in the pelvic
region. Acute toxicities in this area primarily involve the
lower gastrointestinal and genitourinary tracts, as well
as hematological side effects. Wang et al.[] evaluated
treatment outcomes and toxicities by age in patients
receiving definitive radiotherapy or CRT for cervical
cancer. The study compared older (≥70 years, N=70)
and younger (<60 years, N=991) patients, finding no
difference in acute hematologic toxicity (58% vs 46%,
respectively). These results suggest that elderly patients
can tolerate definitive CRT well. However, grade 3?4
chronic gastrointestinal side effects were more common
in elderly patients. A retrospective analysis compared
CRT treatment results in patients with muscle-invasive
bladder cancer, aged <75 years (N=106) and ≥75 years
(N=61).[] Comorbidities and impaired performance
status were significantly higher in elderly patients. Of
the younger patients, 75% completed the planned radiotherapy
dose compared to 93% of elderly patients.
However, younger patients were more likely to complete
four cycles of chemotherapy (19% vs 36%, respectively,
p=0.017). Genitourinary and gastrointestinal toxicities
were the primary reasons for not completing chemotherapy.
Overall, elderly patients tolerated CRT as well
as younger patients. Hofheinz et al.[] investigated the
effect of age on oxaliplatin in preoperative CRT and adjuvant
chemotherapy for rectal cancer (N=1,232). Dividing
the patients into <60 years, 60-70 years, and ≥70
years, they found no difference between the groups in
terms of CRT toxicity, morbidity, or treatment completion.
Sung et al.[] investigated the oncological results
and morbidity of 1,232 patients with rectal cancer who
underwent preoperative CRT and subsequent total mesorectal
excision. When patients were grouped by 70
years (<70 years vs. ≥70 years), grade 3-4 acute hematologic
toxicity was observed more frequently in the
elderly than that in the younger group (9.0% vs 16.1%,
p=0.008). However, these differences were not detected
in acute non-hematological side effects.
Limitations
The most important limitation of this study is that it
was retrospective.
Conclusion
In this study, although it was observed that elderly
patients had more comorbid diseases and their performance
status was worse, no difference was found
between the groups in terms of adverse events and
toxicity. It was observed that interruption to CRT was
more common in elderly patients. In addition, treatment-
related death was not observed in any of the
young and old patients in this region of CRT. Elderly
patients were able to tolerate CRT applied to the pelvic
area similar to younger patients.
Ethics Committee Approval: The study was approved by the
Sivas Cumhuriyet University Non-interventional Clinical Research
Ethics Committee (no: 2021-04/29, date: 14/04/2021).
Authorship contributions: Concept - E.E., M.U.; Design
- E.E., M.Y.; Supervision - E.E., M.Y., M.U., B.Y.; Materials -
E.E.; Data collection and/or processing - E.E.; Data analysis
and/or interpretation - B.Y.; Literature search - M.Y., M.U.,
B.Y.; Writing - E.E.; Critical review - E.E.
Conflict of Interest: All authors declared no conflict of interest.
Use of AI for Writing Assistance: No AI technologies utilized.
Financial Support: None declared.
Peer-review: Externally peer-reviewed.
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