A considerable number of patients with gynecologic cancers experience psychological and emotional distress (1-4). In an analysis of survey data from a cohort study, emotional problems such as fear, nervousness, sadness, and worry were reported by 30 to 50% of patients, respectively (3). The burden of emotional distress may be particularly present in patients assigned to or undergoing radiotherapy or chemoradiation due to patient concerns regarding exposure to radiation, dependence on high-tech machines, and radiotherapy-induced adverse events (5-11). In a study of 480 patients irradiated for cervical cancer, up to 69% of the patients reported worry as a significant emotional problem (4). For these patients, psycho-oncological assistance may be important for treatment completion and outcomes. Therefore, our study aimed to investigate risk factors of pre-treatment emotional distress in order to identify those who may benefit from early psycho-oncological support.

A total of 10 potential risk factors were evaluated for associations with the six symptoms of emotional distress included in the National Comprehensive Cancer Network Distress Thermometer (worry, fear, sadness, depression, nervousness, loss of interest in usual activities) (12). This retrospective study (Ethics Committee, University of Lübeck, Germany, number 2022-412) included 122 patients who were planned to receive external-beam radiotherapy (EBRT) and/or brachytherapy (BT) for gynecologic cancer, i.e., uterine (n=62), cervical (n=46) or vaginal/vulvar (n=14) cancer. Investigated factors were COVID-19 pandemic (prior to versus after the start of the pandemic), number of physical problems (0-4 versus ≥5), age at radiotherapy (≤65 versus ≥66 years), Karnofsky performance score (KPS ≤80 versus ≥90), primary tumor site (cervix uteri versus uterus versus vagina/vulva), tumor stage according to the International Federation of Gynecology and Obstetrics (FIGO-stage I-II versus II-IV), surgery prior to radiotherapy (no versus yes), chemotherapy before and/or during radiotherapy (no versus yes), history of another malignant tumor (no versus yes), and family history of malignant tumors (no versus yes).

All but one of the 62 patients with uterine cancer received upfront surgery. Radiotherapy regimens included 4×5 Gy of BT alone (n=46), EBRT alone (n=5), or a combination of both techniques (n=11). The median EBRT dose was 50.4 Gy (5×1.8 Gy per week). One patient with uterine cancer received personalized concurrent chemotherapy with weekly carboplatin and paclitaxel. Of the 46 patients with cervical cancer, 33 patients received upfront surgery. Of this subgroup, 12 patients were treated with 50.4 Gy (5×1.8 Gy per week) of EBRT alone and 13 patients with 50.4 Gy of EBRT plus BT (2 to 5×5 Gy or 3×7 Gy). Of the 13 patients receiving definitive radiotherapy, 7 patients were treated with EBRT alone (median dose=59.4 Gy) and 6 patients with EBRT (median dose=50.4 Gy) plus BT (5×5 Gy, 4×6 Gy, or 3 to 4×7 Gy). Forty-two of the 46 patients with cervical cancer received concurrent chemotherapy with weekly cisplatin (n=34), weekly carboplatin (n=7), or two courses of mitomycin C (n=1). Upfront surgery was performed in 8 of the 14 patients with vaginal and/or vulvar cancer. Seven of these patients received postoperative EBRT alone (median dose=50.4 Gy), and one patient 50.4 Gy of EBRT plus 4×5 Gy of BT. Five of the six patients receiving definitive radiotherapy were treated with EBRT alone (median dose=50.4 Gy), and one patient with 45.0 Gy of EBRT plus 3×6 Gy of BT. Seven of the 14 patients with vaginal and/or vulvar cancer received concurrent chemotherapy with weekly cisplatin (n=3), weekly carboplatin (n=2), or two courses of mitomycin C and 5-fluorouracil (n=2).

Associations between the potential risk factors and the six symptoms of emotional distress according to the National Comprehensive Cancer Network Distress Thermometer (12) were evaluated with the Chi-square test (number of patients ≥5 in all cells) or the Fisher’s exact test (number of patients <5 in at least one cell). The Bonferroni correction was used to account for multiple comparisons, and p-values <0.005 were considered significant (alpha level <0.05). Moreover, p-values <0.06 indicated trends for associations between a potential risk factor and a symptom of emotional distress.

Frequencies of the six symptoms of emotional distress, i.e., worry, fear, sadness, depression, nervousness, and loss of interest in usual activities were 41%, 57%, 39%, 16%, 38%, and 20%, respectively. A greater number (≥5) of physical problems was significantly associated with worry (p=0.0002), fear (p=0.0041), sadness (p<0.0001), depression (p=0.0001), nervousness (p=0.0020), and loss of interest in usual activities (p<0.0001). In addition, no upfront surgery was significantly associated with worry (p=0.0007). Trends were found for associations between no upfront surgery and fear (p=0.026), nervousness (p=0.024) and loss of interest in usual activities (p=0.012), between additional chemotherapy and fear (p=0.026), between history of another malignant tumor and fear (p=0.057) or nervousness (p=0.057), between KPS ≤80 and sadness (p=0.055), and between age ≤65 years and nervousness (p=0.028). Full results with respect to associations between potential risk factors and symptoms of emotional distress are given in Table I, Table II, Table III, Table IV, Table V, and Table VI.

Gynecologic cancers are the second most common group of female malignancies (13). Many of these patients are treated with EBRT, BT or a combination of both techniques. A recommendation for radiotherapy may lead to considerable emotional distress requiring psycho-oncological assistance. There is a lack of studies focusing on the prevalence and risk factors of emotional distress prior to a course of radiotherapy for gynecologic cancer. This study investigated both aspects in a cohort of 122 patients irradiated for uterine, cervical, vaginal, or vulvar cancer. Emotional distress was characterized by the six symptoms of emotional distress included in the National Comprehensive Cancer Network Distress Thermometer, namely worry, fear, sadness, depression, nervousness, and loss of interest in usual activities (12). The frequencies of these symptoms ranged between 16% and 57%, and were not much different from those of previous studies in patients with gynecologic cancers in general (20% to 50%) or patients with cervical cancer during a course of radiotherapy (23% to 69%) (3,4). These findings demonstrate consistency of the results of the present study.

In this study, significant associations with at least one of the six symptoms of the National Comprehensive Cancer Network Distress Thermometer (12) were found for ≥5 physical problems and no upfront surgery. A positive correlation between physical problems and emotional distress has been previously observed in other studies of patients with gynecologic cancers (10,14). In the study by Cull et al. of women with early stage cervical cancer, psychological distress was significantly associated with physical complaints (p<0.001) and functional outcome (p<0.02) (10). In the study of Hazewinkle et al., better mental well-being was inversely correlated to the severity of urogenital and defecation symptoms (14). Moreover, in our previous study evaluating sleep disorders that can be a consequence of emotional distress, the prevalence of sleep problems was significantly associated with a greater number (≥4) of physical problems (p<0.0001) (15). The result that no upfront surgery was associated with increased emotional distress can be explained by the facts that the majority of these patients had advanced disease and that non-resectability is often associated with a worse prognosis. In a previous study in cervical cancer survivors, fear of disease progression was one of the three greatest fears reported by the patients (16).

In addition, trends were observed for associations between emotional distress and additional chemotherapy, history of another tumor, worse performance status, or younger age. The trend regarding additional chemotherapy can be explained by the increased toxicity of chemoradiation when compared to radiotherapy alone that was found in previous studies, reviews and meta-analyses (17-24). For example, in the randomized trial of Teng et al. in patients with cervical cancer, rates of treatment-related toxicities were 37% in the chemoradiation group and 18% in the radiotherapy alone group, respectively (p=0.02) (17). In a more recent randomized trial of patients with endometrial cancer, adverse events grade ≥2 and grade ≥3 were significantly (p<0.0001) more common in patients treated with chemoradiation than in patients receiving radiotherapy alone (18). Moreover, neuropathy persisted significantly more often after chemoradiation (19,20). Another tumor in a patient’s history may increase the level of emotional distress, as previously reported in a study of breast cancer patients receiving adjuvant radiotherapy (25). Moreover, fear of disease progression often means significant distress for many patients (16). Associations between worse performance score and high levels of distress were previously found in a large retrospective study of patients with breast and gynecologic cancers (26). An inverse correlation between age and distress was also found in previous studies of patients with gynecologic cancers and breast cancer (11,25-28).

In summary, a considerable proportion of patients with gynecologic cancers experience emotional distress prior to the start of radiotherapy. Patients with risk factors including ≥5 physical problems, unresectable tumors, additional chemotherapy, history of another tumor, worse performance status, and younger age likely benefit from immediate psycho-oncological assistance.

The Authors report no conflicts of interest in relation to this study.

All Authors participated in the study design. A. A.-S. and D.R. collected the data, which were analyzed by D.R. The article, which was drafted by D.R. and N.Y.Y., was reviewed and approved by all Authors.