Summary

METHODS
A total of 813 patients, 67% aged <65 years and 33% aged ?65 years, were analyzed retrospectively. Toxicities were graded according to the acute radiation morbidity measurement criteria of the Radiation Therapy Oncology Group.

RESULTS
For all patients, 5% of the younger and 12% of the elderly patients (p<0.001) ended CRT, 1% of the younger and 4% of the elderly patients died during treatment (p=0.007). There were differences between the groups treated for brain cancer in terms of performance status (p=0.010), cessation (p=0.001), interruption (p=0.026), and death during treatment (p=0.043). For head and neck cancer, the results showed differences in comorbidity (p<0.001), performance status (p=0.017), and death during CRT (p=0.021). In the thoracic area, differences were found in comorbidity (p=0.015), CRT interruption (p=0.014), grade 1?2 skin toxicity (p=0.025), pharynx/esophagus (p=0.002), upper gastrointestinal tract (p=0.036), and hematocrit (p=0.032). For the abdominal area, differences were observed in comorbidity (p<0.001) and grade 1?2 platelet toxicity (p=0.029). For the pelvis, differences were seen in comorbidity (p<0.001), performance status (p=0.045), and CRT interruption (p=0.032).

CONCLUSION
Cessation, interruption, and death during CRT were observed more frequently in elderly patients.

Introduction

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.[3,4] Two cohort prospective studies have shown that a geriatric assessment can predict chemotherapy-related toxicity.[5,6] The International Association of Geriatric Oncology[7] 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.[8,9]

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

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.[10] 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

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

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.[11] Especially for fit patients over 70, temozolomide with conventional or hypofractionated radiotherapy remains a treatment option.[12,13] Few studies compare CRT-associated toxicity by age in patients with brain tumors. A study conducted by Saito et al.[14] 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.[15] 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.[16] 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.[17] Merlano et al.[18] 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.,[19] 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.[20] 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.[21] 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.[22] demonstrated the feasibility of CRT in selected esophageal cancer patients over 75. A review by Zimmerman et al.[23] found either no or a low incidence of both acute and late high-grade toxicity in elderly patients. Stinchcombe et al.[24] 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.[25] 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.[26] 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.[27] 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.[28] 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).[29] 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.[30] 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.[31] 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

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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