Hostname: page-component-78c5997874-8bhkd Total loading time: 0 Render date: 2024-11-13T01:43:02.980Z Has data issue: false hasContentIssue false

Resilience and spiritual well-being as resources for coping with radiotherapy and surviving in patients with glioblastoma

Published online by Cambridge University Press:  05 November 2024

Loredana Dinapoli*
Affiliation:
UOS di Psicologia Clinica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Morena Caliandro
Affiliation:
Dipartimento di Radioterapia Oncologica, Ente Ecclesiastico Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti (BA), Italy
Silvia Chiesa
Affiliation:
UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Elisa Marconi
Affiliation:
UOS di Psicologia Clinica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Nikola Dino Capocchiano
Affiliation:
UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Ciro Mazzarella
Affiliation:
UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Francesco Beghella Bartoli
Affiliation:
UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Serena Bracci
Affiliation:
UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Mario Balducci
Affiliation:
UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Daniela Pia Rosaria Chieffo
Affiliation:
UOS di Psicologia Clinica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Istituto di Scienze della Vita e di Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
Alba Fiorentino
Affiliation:
Dipartimento di Radioterapia Oncologica, Ente Ecclesiastico Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti (BA), Italy Dipartimento di Medicina, Università LUM, Casamassima (BA), Italy
Vincenzo Valentini
Affiliation:
Centro di Eccellenza Oncologia Radioterapica, Medica e Diagnostica per Immagini, Ospedale Isola Tiberina-Gemelli Isola, Rome, Italy
Luca Tagliaferri
Affiliation:
UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Università Cattolica del Sacro Cuore, Istituto di Radiologia, Rome, Italy
Maria Antonietta Gambacorta
Affiliation:
UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Università Cattolica del Sacro Cuore, Istituto di Radiologia, Rome, Italy
Nicola Dinapoli
Affiliation:
UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
*
Corresponding author: Loredana Dinapoli; Email: loredana.dinapoli@policlinicogemelli.it
Rights & Permissions [Opens in a new window]

Abstract

Objectives

The primary aims of this multicenter, prospective observational study were to investigate spiritual well-being, resilience, and psychosocial distress in an Italian sample of glioblastoma patients undergoing radiochemotherapy. The secondary aim was to explore the influence of demographic, clinical, and psychological characteristics on survival.

Methods

The assessment was conducted only once, within the first week of radiochemotherapy treatment. Spiritual well-being was evaluated by the Functional Assessment of Chronic Illness Therapy-Spiritual Well-being (FACIT-Sp-12), and religious/spiritual beliefs and practices were evaluated by the System of Belief Inventory. Resilience was evaluated by the Connor−Davidson Resilience Scale (CD-RISC). Psychosocial distress was evaluated the by Distress Thermometer and Hospital Anxiety Depression Scale. We conducted an univariable analysis of overall survival (OS) using data from the most recent follow-up available, considering demographic and clinical variables that could influence survival. Follow-up was defined as either the time of death or the latest follow-up visit recorded.

Results

We recruited 104 patients, and the median follow-up time was 18.3 months. “Distressed” patients had lower scores than “not distressed” patients on the FACIT-Sp-12 and CD-RISC. While OS was not significant according to the FACIT-Sp-12 threshold, the Kaplan−Meier log-rank test was 0.05 according to the CD-RISC threshold. Among demographic variables, age showed significant associations with OS (p = 0.011). Resilience showed significant associations with OS (p = 0.025).

Significance of results

Data showed that high spiritual well-being was associated with high resilience and an absence of psychosocial distress in our sample of glioblastoma patients undergoing radiochemotherapy. Patients with greater resilience survived longer than those with lesser resilience. Profiling spiritual well-being and resilience in glioblastoma patients undergoing radiochemotherapy can be seen as a resource to identify novel characteristics to improve clinical take-in-charge of glioblastoma patients.

Type
Original Article
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2024. Published by Cambridge University Press.

Introduction

Brain tumors are rare (3% of all tumors), but they are responsible for the highest loss of life years among all tumors (NICE). The most frequent malignant brain tumor is glioblastoma, with an estimated incidence rate of 3–4 cases per 100,000 inhabitants per year in Italy (AIOM). The average age of onset of glioblastoma is approximately 65 years (NICE). Even with new therapeutic advances and longer survival rates in patients with primary brain tumors, when compared with other cancers, the prognosis for glioblastoma is poor, with a median overall survival (OS) of 14.6–20.8 months with standard of care treatment and a survival rate of less than 5% at 5 years after diagnosis (Randazzo et al. Reference Randazzo, McSherry and Herndon2021; AIOM).

Patients affected by glioblastoma are at a high risk of psychosocial distress due to the cognitive, behavioral, emotional, and functional deficits related to their disease (Trad et al. Reference Trad, Koh and Daher2015). These patients show significant levels of anxiety and depression, which can also influence the survival outcome (Trad et al. Reference Trad, Koh and Daher2015). Glioblastoma patients experience several radical challenges in their lives related to the uncertainty of their future and physical, psychological, and social changes, so most of them try to find relief through spirituality. The National Comprehensive Cancer Network defines spirituality as “a relationship between a person and a force or power beyond themselves that helps them feel connected and enriches their lives” (NCCN a). Spirituality can be nurtured through the practice of religious beliefs, prayer, and meditation and can be described as “a person’s sense of peace, purpose, connection to others, and beliefs about the meaning of life” (NCCN a). Literature data have demonstrated that spiritual well-being can help cancer patients struggling with physical and psychological symptoms by improving their coping strategies, strengthening their familial and friendship connections, and alleviating their distress (Randazzo et al. Reference Randazzo, McSherry and Herndon2021). A large meta-analysis has shown positive associations between spiritual well-being and measures of physical, emotional, and social health (Sprik et al. Reference Sprik, Tata and Kelly2021). The spirituality of cancer patients has been studied, especially among those in the terminal stage of disease or receiving palliative radiotherapy (Hematti et al. Reference Hematti, Baradaran-Ghahfarokhi and Khajooei-Fard2015; Piderman et al. Reference Piderman, Johnson and Frost2014; Samuelson et al. Reference Samuelson, Fromme and Thomas2012; Walshe et al. Reference Walshe, Roberts and Appleton2017). In the literature, only recently have studies been published on the standardization of specific tests to explore spiritual well-being in radiotherapy settings and to implement programs for spiritual well-being during radiotherapy (Elias et al. Reference Elias, Ricci and Rodriguez2015; Henderson et al. Reference Henderson, Clemow and Massion2012; Kouloulias et al. Reference Kouloulias, Kokakis and Kelekis2017; Miranda et al. Reference Miranda, Caldeira and de Oliveira2020). However, research on spirituality in glioblastoma patients is lacking.

Psychological resilience is the dynamic process by which individuals harness their psychological, personality traits, and resources, along with biological and environmental factors, to protect and sustain their mental health amidst life’s adversities (Altinok et al. Reference Altinok, Rajkumar and Nießen2021; Fradelos et al. Reference Fradelos, Latsou and Mitsi2018; Tan et al. Reference Tan, Beatty and Kemp2019). It involves positive adaptation within the context of significant challenges, reflecting an intricate interplay among various factors that mutually influence each other (Altinok et al. Reference Altinok, Rajkumar and Nießen2021; Fradelos et al. Reference Fradelos, Latsou and Mitsi2018; Tan et al. Reference Tan, Beatty and Kemp2019). High resilience has been linked to positive health outcomes in cancer patients, such as lower rates of depression (Min et al. Reference Min, Yoon and Lee2013; Sharpley et al. Reference Sharpley, Bitsika and Wootten2014). On the other hand, low resilience has been associated with poor psychopathological outcomes in cancer patients, such as increased rates of depression, anxiety, and psychological distress (Fradelos et al. Reference Fradelos, Papathanasiou and Veneti2017; Rosenberg et al. Reference Rosenberg, Syrjala and Martin2015). Resilience is considered a multifaceted process that encompasses a natural interaction of attributes, one of which is spirituality (Tan et al. Reference Tan, Beatty and Kemp2019).

In our Radiotherapy departments, we routinely perform psychological assessments for glioblastoma patients. The mission is to help patients face the disease, cope with radiotherapy and its side effects and improve their quality of life (QoL) (Caliandro et al. Reference Caliandro, Carbonara and Surgo2023; Dinapoli et al. Reference Dinapoli, Chiesa and Dinapoli2021). Patients can also benefit from personalized psychological support during radiotherapy (Dinapoli et al. Reference Dinapoli, Chiesa and Dinapoli2021). Currently, no spiritual intervention is provided in our hospital, except for religious support. However, in the literature, there are increasing data on the efficacy of spiritual interventions for cancer patients, even during radiotherapy. Group therapy (Piderman et al. Reference Piderman, Johnson and Frost2014), intercessory prayers (Miranda et al. Reference Miranda, Caldeira and de Oliveira2020), mindfulness-based stress reduction programs (Henderson et al. Reference Henderson, Clemow and Massion2012), and programs based on guided imagery/relaxation (Elias et al. Reference Elias, Ricci and Rodriguez2015) have shown good results in improving QoL, spiritual well-being, and spiritual coping. To date, no data on spiritual well-being and resilience in glioblastoma patients during radiotherapy have been documented.

The primary aims of this study were to describe spiritual well-being, resilience, and psychosocial distress in glioblastoma patients undergoing radiochemotherapy and to evaluate whether spiritual well-being and resilience are differentially related to psychological and clinical characteristics, or cross-correlated.

The secondary aim was to investigate the impact of spiritual well-being and resilience on survival, considering specific interfering clinical variables (age, performance status, etc.).

Materials and methods

This was an observational multicenter study. Two Italian centers were involved in the study: Fondazione Policlinico Universitario A. Gemelli IRCCS as a Coordinating center, and Ente Ecclesiastico Ospedale Generale Regionale Miulli, as a Participant center.

All consecutive patients with histologically proven isocitrate dehydrogenase 1 wild-type (IDH-1 wt) glioblastoma grading 4, with either complete or incomplete resection, those undergoing external beam radiotherapy with concurrent chemotherapy (radiochemotherapy) and those treated either by standard or hypofractionated regimens were enrolled in this study. Such criteria were adopted according to the recently updated publication of the World Health Organization (WHO) classification for brain tumors (Louis et al. Reference Louis, Perry and Wesseling2021) to select appropriate glioblastoma patients. Patients who were able to understand and sign the informed consent form were considered eligible for this study. The exclusion criteria were the inability or denial to express informed consent, previously diagnosed major psychiatric disorders, and severe language deficits. Patients were treated according to the current treatment standards of the EORTC-NCIC regimen (Stupp et al. Reference Stupp, Mason and den Bent Mj2005) and the International Guidelines (NCCN b). Image acquisition, treatment planning, and radiotherapy were performed according to routinely used glioblastoma protocols in the Radiotherapy departments. All patients underwent either 3D conformal radiotherapy or volumetric modulated arc therapy (VMAT) with concurrent daily chemotherapy with temozolomide (TMZ) (daily TMZ at 75 mg/mq, from the first to the last day of radiotherapy). All patients received radiochemotherapy for the first time after their initial diagnosis. The Response Assessment in Neuro-Oncology criteria were adopted for analyses (Wen et al. Reference Wen, Macdonald and Reardon2010). Duration of follow-up was defined as the difference between the date of death and the date of diagnosis or (for patients alive at the time of analysis) the difference between the date of last visit and the date of diagnosis. Median follow-up was calculated using the Kaplan−Meier (KM) method.

Psychological assessment

A thorough clinical psychological interview was conducted only once during the initial week of radiochemotherapy by psycho-oncologists from both Radiotherapy departments. During this session, the psycho-oncologists would infer whether or not the patient was able to understand the objective of the study and complete the questionnaires on their own.

Using a semi-structured clinical interview, the psychologists investigated the impact of diagnosis by exploring patients’ awareness of their illness, including their knowledge of histological data and the purpose of treatment. Then general areas of patient’s life were examined: personal history, psychopathological history, and lifestyle habits.

The spiritual sphere was investigated in the following manner: “Do you cultivate any spiritual sphere in your life? If so, how?” (For example: Catholic faith or other beliefs; believing in other higher powers). On this occasion, an assessment with specific tests was performed to evaluate psychosocial distress, spiritual well-being, and resilience. Total assessment time: 45 minutes.

The psychosocial distress (Wang et al. Reference Wang, Hsu and Feng2011) was assessed by the Distress Thermometer (DT) (Grassi et al. Reference Grassi, Johansen and Annunziata2013) to evaluate emotional distress and the Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith Reference Zigmond and Snaith1983) to evaluate mood. The DT is a visual analogue tool that is used to rate personal distress during the past week on a scale from 0 (no distress) to 10 (extreme distress). A DT cutoff score ≥4 is used to identify patients with emotional distress (“distressed patients”) (Grassi et al. Reference Grassi, Johansen and Annunziata2013). The HADS (Zigmond and Snaith Reference Zigmond and Snaith1983) is a well-validated and reliable self-report measure designed to identify the presence and severity of anxiety and depression in cancer patients (Zigmond and Snaith Reference Zigmond and Snaith1983). It represents an effective screening tool for cancer patients undergoing treatment (Moorey et al. Reference Moorey, Greer and Watson1991). The HADS is a brief 14-item scale to report symptoms experienced by patients during the previous week. The HADS is divided into anxiety (HADS-A) and depression (HADS-D) subscales. Higher scores on either of the 2 subscales (depression and/or anxiety) indicate more severe symptoms. A global score ≥16 indicates anxiety/depression (“anxious/depressed patients”) (Moorey et al. Reference Moorey, Greer and Watson1991).

Spiritual well-being was evaluated by the Functional Assessment of Chronic Illness Therapy-Spiritual Well-being (FACIT-Sp-12) (Costantini et al. Reference Costantini, Rabitti and Beccaro2016). The FACIT-Sp-12 is a 12-item scale widely used in cancer patients (Costantini et al. Reference Costantini, Rabitti and Beccaro2016). The scale was developed to measure important aspects of spirituality, such as a sense of meaning in one’s life, harmony, peacefulness, and a sense of strength and comfort from one’s faith. It is divided into 3 dimensions, faith, meaning, and peace, distributed between 2 subscales (faith: 4 items; meaning/peace: 8 items). The score ranges from 0 to 4. The total score is the sum of the subscale scores, which ranges from 0 to 48, with a higher score indicating greater spiritual well-being (Costantini et al. Reference Costantini, Rabitti and Beccaro2016).

The System of Beliefs Inventory (SBI-15R) (Ripamonti et al. Reference Ripamonti, Borreani and Maruelli2010) was used to collect useful information on the spiritual needs and resources of patients at any stage of the disease. The SBI-15R (Ripamonti et al. Reference Ripamonti, Borreani and Maruelli2010), designed by Holland et al. (Reference Holland, Kash and Passik1998), measures religious and spiritual beliefs and practices and the social support derived from a community sharing those beliefs. The SBI-15R is a tool designed to elicit main religious beliefs (beliefs on the transcendence and transcendent meaning of human life) as well as attendance to religious practices and support received by the religious community (Holland et al. Reference Holland, Kash and Passik1998; Ripamonti et al. Reference Ripamonti, Borreani and Maruelli2010). The score of each item is determined by a 4-point Likert scale (from 0 to 3). Higher scores indicate higher levels of religiosity (Holland et al. Reference Holland, Kash and Passik1998; Ripamonti et al. Reference Ripamonti, Borreani and Maruelli2010).

Resilience was evaluated by means of the Connor−Davidson Resilience Scale (CD-RISC) (Connor and Davidson Reference Connor and Davidson2003; Tan et al. Reference Tan, Beatty and Kemp2019). The CD-RISC is one of the most commonly used scales to measure resilience in cancer patients, consisting of 25 items that broadly map into the following 6 factors: (1) personal strength, (2) adaptability/flexibility, (3) self-determination, (4) giving best effort, (5) spirituality, and (6) social support (Connor and Davidson Reference Connor and Davidson2003; Tan et al. Reference Tan, Beatty and Kemp2019).

This study was performed in line with the principles of the Declaration of Helsinki. Research Protocol (ID: 3420; Protocol Number 0035698) was approved by the Ethical Committee of our institution, Fondazione Policlinico Universitario A. Gemelli IRCCS.

Sample size and statistical analysis

To explore the primary aim of the study, considering the historical case series of the 2 involved centers and the monthly access of glioblastoma patients to psychological services, a sample of at least 100 patients was predicted. With this lower bound of the predicted recruitable sample size, the collected data should be considered representative of the overall population (estimated for this calculation to be above 20,000 individuals) (AIOM) with a margin of error of 10% and a confidence level of 95%. To conservatively estimate the response distribution, a value of 50% was chosen. The sample size was calculated using the following formula:

\begin{equation*}n = {z^2}*\frac{{\frac{{p\left( {1 - p} \right)}}{{{\varepsilon ^2}}}}}{{1 + \left( {{z^2}*\frac{{p\left( {1 - p} \right)}}{{{\varepsilon ^2}N}}} \right)}}\end{equation*}

$\varepsilon = $ margin of error; N = population size; z = z score of 1.96 for a confidence level of 95%; p = response distribution.

The clinical and demographic characteristics of the sample were described through an initial exploratory analysis and successive descriptive statistics. All statistical analyses were performed using the R statistical platform, and p values ≤ 0.05 were considered significant for statistical tests.

To investigate the primary endpoints, the following analyses were performed: the differences at CD-RISC, FACIT-Sp-12 and SBI-15 between “distressed” and “not distressed” and patients who exceeded/who did not exceed clinically significant cutoffs for anxiety/depression have been compared by Mann−Whitney univariable non parametrical test. The clinical and demographic variables were analyzed with respect to the psychological questionnaires with univariable statistical tests (Mann−Whitney for numeric or chi-square for categorical variables). Considering the possible cross correlation among the results obtained by all psychological tests and specific subscales of CD-RISC and FACIT-Sp-12, these have been analyzed using Pearson’s cross correlation test.

To investigate the secondary endpoint, an univariable survival analysis was performed by the KM test for factorial variables. For numeric variables, the best threshold was computed by calculating the lowest p-value using the KM test, moving the cutoff to split the population into 2 subpopulations within the range of observed values. The clinical variables interfering with survival in glioblastoma, according to the known predictive factors in the literature (age > 70 years (Gately et al. Reference Gately, Collins and Murphy2016), gender, Eastern Cooperative Oncology Group (ECOG), O(6)-methylguanine-DNA-methyltransferase (MGMT) methylation status, or surgery type (Stupp et al. Reference Stupp, Brada and van den Bent2014)), were investigated in the analysis.

Multivariable analysis was performed by the Cox proportional hazards (CPH) model after a cross-correlation test to determine unrelated variables.

Results

Overall demographic information

We recruited 104 patients (68 male and 36 female), with a median age of 59 years (see Table 1). The median follow-up time was 18.3 months. The whole sample was histologically homogeneous according to the latest WHO classification of brain tumors (Louis et al. Reference Louis, Perry and Wesseling2021). All patients were able to sign the informed consent and easily fill the questionnaires.

Table 1. Clinical and demographic characteristics

MGMT = O(6)-Methylguanine-DNA-methyltransferase.

Primary results

From the psychological interview, the following data emerged: the majority of patients, when asked “Do you cultivate a spiritual sphere?” responded affirmatively, stating that they believe in God (85 “believers” – 81.7%). No other credo was disclosed. Furthermore, the majority of patients were fully aware of the histological grade and the purpose of the radiochemotherapy treatment (82 out of 104 total awareness) (see Table 1).

Our cohort consisted of 34 (32.7%) “not distressed” patients and 70 (67.3%) “distressed” patients. The median overall DT score was 5 (range, 0–10). With respect to the HADS score, we identified 68 patients (65.4%) who did not exceed clinically significant cutoffs for anxiety/depression and 36 (34.6%) who exceeded clinically significant cutoffs for anxiety/depression. The median overall HADS score was 13 (range, 1–40).

“Distressed” patients had lower scores than “not distressed” patients on the CD-RISC and on both subscales of the FACIT-Sp-12 (see Table 2). Patients who exceeded clinically significant cutoffs for anxiety/depression had lower scores than those who did not on the CD-RISC and on both subscales of the FACIT-Sp-12 (p = 0.003; see Table 2).

Table 2. Wilkoxon signed-rank test’s results on distribution of CD-RISC, FACIT-Sp-12 over “distressed” patients and patients with HADS ≥16

The results of the comparison among psychological tests and clinical/population features are summarized in Table 3. Of course, patients classified as “believers” showed a strong correlation with the FACIT-Sp-12 faith subscale and SBI-15R score, while married patients were found to be more resilient than unmarried patients (see Table 3).

Table 3. Univariable statistics among psychological tests and clinical/population variables

All binary variables have been used to split the scores of psychological tests into 2 populations, compared by Mann−Whitney test whose p-values are represented. The agea variable has been split into 2 groups according to the median value (59 years); the marital statusb has been analyzed comparing married versus all the other conditions, because of the low number of cases in the other options in the list; the working positionc has been analyzed comparing patients currently working coupled with on sick leave, versus all the other options in the list; being ECOGd 0 patients 51 in the entire population (49%), ECOG 1 were 45 (43.3%) and ECOG 2 and 3 only 8 (7.7%), we have compared the ECOG 0 population versus all the other conditions. These grouping among factors in variables b−d was needed because chi-square analysis was not feasible due to the small cases number in some of the options.

Temporal glioblastoma multiforme patients didnot show any difference at FACIT-Sp-12 (median total FACIT-Sp-12 score in temporal glioblastoma multiforme = 32 ± 9.3; median total FACIT-Sp-12 score in nontemporal glioblastoma multiforme = 31 ± 8.9; p = 0.77), thus excluding hyper-religiosity or religious delusions.

Pearson’s correlation test showed that the CD-RISC and FACIT-Sp-12 scores were strongly correlated (see Table 4). A correlation test was also performed between the SBI-15R score and the scores for all subdimensions of the FACIT-Sp-12 and CD-RISC (see Table 4).

Table 4. Matrix of Pearson’s cross correlation test results of SBI-15R, tests’ subscales of FACIT-Sp-12 and CD-RISC

Secondary results

OS was determined by the difference between the time of death or the time of the last available follow-up (for surviving patients) and the time of histological diagnosis. Time of death was obtained from medical records or data available in the National Health System Registry. The OS analysis updated at the last available follow-up (N = 104) showed a median OS time of 22.1 months. This analysis revealed that patients with lower spiritual well-being and lower resilience had shorter survival times than patients with higher spiritual well-being and higher resilience. The best performing cutoffs were a FACIT-Sp-12 score > 32 and a CD-RISC score > 68. While OS according to the FACIT-Sp-12 threshold was not significant, the KM log-rank (LR) test was 0.05 according to the CD-RISC threshold (Fig. 1). SBI-15R scores were not significantly related to OS. Moreover, OS was significantly correlated with age (cutoff of 70 years, p = 0.04), while OS did not show a correlation with sex, MGMT methylation or surgery type in our cohort (see Table 5). An age > 70 years was not cross-related with either low resilience or low spiritual well-being (Fisher’s test p > 0.05). Resilience and spiritual well-being were found to be cross-related, so only the most significant variable (resilience) with a lower p-value in the KMLR test was included in the multivariate analysis. CPH showed that both age and resilience were significantly related to OS (p = 0.011; p = 0.025) (see Table 6).

Figure 1. Survival curves of the patient population classified against the threshold of CD-RISC $\le 68$ or higher. The log-rank test result is 0.05.

Table 5. Descriptive statistics and univariable survival analysis of patients’ population (Kaplan−Meier)

Only the age is significant considering the threshold of 70 years age as cutoff to split the population used previously in literature (Gately et al. Reference Gately, Collins and Murphy2016).

MGMT = O(6)-Methylguanine-DNA-methyltransferase.

Table 6. Results of multivariable analysis (Cox proportional hazards test)

Both age and CD-RISC > 68 return significant p-values.

Discussion

After a cancer diagnosis, patients are prone to physical, psychological, social, and spiritual changes that may be related to anxiety, depression, and hopelessness (Cheng et al. Reference Cheng, Liu and Li2019). Previous studies have confirmed that spirituality is an important coping resource for cancer patients to adjust to their disease (Jimenez-Fonseca et al. Reference Jimenez-Fonseca, Lorenzo-Seva and Ferrando2018) Spirituality can become “an inner resource or inner aspect of a person” that is efficacious for coping with main stressors (Chaar et al. Reference Chaar, Hallit and Hajj2018). Spiritual well-being and psychological resilience (Chaar et al. Reference Chaar, Hallit and Hajj2018) are known to play an important role in individuals’ attempts to cope with adverse events; in fact, breast cancer survivors with high spiritual well-being and psychological resilience showed less fear of recurrence during follow-up (Chaar et al. Reference Chaar, Hallit and Hajj2018). Despite growing data about the role of psychological characteristics in outcomes, such topics have not been addressed extensively in patients with brain tumors. Interventions in this field have shown that writing a spiritual legacy document induced favorable changes in serenity and positive religious coping (Piderman et al. Reference Piderman, Radecki Breitkopf and Jenkins2017). Strang and Strang (Reference Strang and Strang2001) found that meaningfulness was central to brain tumors patients’ QoL and was created by close relations and faith. A recent study on a large cohort of patients with brain tumors ranging from WHO grade <III to stage IV (Randazzo et al. Reference Randazzo, McSherry and Herndon2021) showed that spiritual well-being was an independent predictor of QoL within the brain tumor population. In our study, patients with a nonsignificant level of psychosocial distress showed higher resilience and spiritual well-being, thus suggesting a relationship between being resilient or spiritual and having low psychosocial distress. In general, spiritual well-being and resilience were correlated in our sample, similar to another recent study in advanced cancer patients (Mihic-Góngora et al. Reference Mihic-Góngora, Rodriguez-Gonzalez and Velasco2022).

Numerous studies support the relationship between meaning/peace and a variety of outcomes: meaning/peace is related to coping (Merluzzi et al. Reference Merluzzi, Salamanca-Balen and Philip2023), or, in a study of cancer survivors, low scores on the meaning/peace subscale, but not the faith subscale, were associated with depressive symptoms (Mihic-Góngora et al. Reference Mihic-Góngora, Rodriguez-Gonzalez and Velasco2022). Moreover, even in the context of high levels of faith, concomitant low levels of meaning resulted in greater depressive symptoms (Bamishigbin et al. Reference Bamishigbin, Stein and Leach2020). In another study, higher baseline meaning/peace scores and an increase in these scores over time predicted a decrease in depressive symptoms, less distress, and greater vitality after 12 months in breast cancer patients compared to no increase in scores (Yanez et al. Reference Yanez, Edmondson and Stanton2009). To our knowledge, our paper is the first to report that meaning/peace is related to almost all the components of the resilience scale. Thus, our glioblastoma patients are characterized by 2 strong attributes: (1) The ability to make sense of their lives by leaning on facets of strong psychological resilience and (2) faith, which had not relented at the time the patients were interviewed, with no patient declaring any struggle with God while in a proactive phase of their path; indeed, faith was a key resource in coping with such a long radiochemotherapy treatment period.

To date, no study has evaluated the role of spiritual well-being and resilience in glioblastoma patients undergoing radiochemotherapy and their possible impact on survival. Our data showed that patients with higher resilience showed benefits in terms of survival compared with patients with lower resilience. These results, if confirmed in more structured research studies, should reflect on the implementation of psychological, personalized monitoring and interventions for glioblastoma patients, with the objective of increasing such resources. The implications of our study are as follows: screening for psychological characteristics is important to identify glioblastoma patients who might be struggling and could benefit from psychosocial support, given that resilience seems related to medical outcome. In our previous study (Dinapoli et al. Reference Dinapoli, Chiesa and Dinapoli2021), distressed glioblastoma patients had a reduced median survival time compared with “not distressed” glioblastoma patients. This observation was not confirmed in the present study, likely due to the characteristics of the actual sample size and study design. The association between spiritual well-being and psychosocial well-being found in other studies (Bai et al. Reference Bai, Lazenby and Jeon2015; Chaar et al. Reference Chaar, Hallit and Hajj2018: Randazzo et al. Reference Randazzo, McSherry and Herndon2021) was confirmed by our data.

Our study investigated a topic that is underexplored in the literature, although scientific interest in glioblastoma patients is growing. The limitations of the present study are related to our study design. A comparison with other histologies or diseases may produce more significant data. Resilience is a dynamic process (Baksi et al. Reference Baksi, Arda Sürücü and Genç2021) and may change depending on conditions. Additionally, comparisons among patients with different pathologies could provide various points of interest, especially for survival outcomes. Of course, the evaluation of spiritual well-being, resilience, and psychosocial distress in an early stage of disease would benefit from a longitudinal assessment. Certainly, one of the limitations of the study is that it has an observational design, with possible subsequent enrolment biases. Therefore, the absence of a correlation between MGMT methylation status, extent of surgery, and survival, such as in our case series, is not a general proof of their lack of correlation. This discrepancy could affect the validity and generalizability of the findings about survival, underscoring the need for cautious interpretation and further research about this topic. On the other hand, the main objective of our study was to evaluate the spiritual well-being and resilience of glioblastoma patients, and the study has shown us the association between these variables and patients’ psychosocial distress.

Psychological support in glioblastoma patients should integrate the empowerment of resilience to elicit spiritual resources and help patients better cope with such a dismal diagnosis. As psycho-oncologists on both topics, we should focus on developing an empathic presence, reflective listening, and the administration of self-care interventions (meditation, yoga, gratitude diary, life review) in the future. Cognitive behavioral therapy, mindfulness-based psychotherapy, and resilience training programs based on the positive psychology approach and on supportive–expressive group therapy can also enhance these constructs (Ludolph et al. Reference Ludolph, Kunzler and Stoffers-Winterling2019). Another approach could be taken from Eye Movement Desensitization and Reprocessing (EMDR) psychotherapy by using the Resource Development Installation technique (Korn and Leeds Reference Korn and Leeds2002) to elicit spiritual and resilience resources. Specific EMDR cancer protocol is useful to help patients resume personal control over aspects experienced as unmanageable (Faretta and Borsato Reference Faretta and Borsato2016); in fact, in initial phase of the protocol the objectives are improving self-care, and coping skills and empowering resilience (Faretta and Borsato Reference Faretta and Borsato2016). Moreover, recent data showed the beneficial effects of EMDR in alleviating affective symptoms and improving meaningfulness, comprehensibility, and manageability of glioblastoma patients’ lives (sense of coherence) (Szpringer et al. Reference Szpringer, Oledzka and Amann2018). Additionally, the implementation of spiritual support should be encouraged to provide relief for patients of all faiths in our hospital and create spaces and referral figures for each spiritual denomination. We can hypothesize that spirituality and resilience are “instrumentally linked” in cancer patients, with spirituality being a continuously evolving process similar to a “pathway” to resilience (Manning Reference Manning2013). Other factors such as social connection and internal resources, including a direct approach to challenges, curiosity, and extending oneself to others, should be explored and enhanced in order to complement spirituality in a perspective of increasing resilience (Kinsel Reference Kinsel2005).

Investigating spirituality and resilience can also help health-care professionals implement an individualized intervention plan based on patients’ values, preferences, resources, and needs. Examining spiritual well-being and resilience among glioblastoma patients undergoing radiotherapy can yield valuable insights for identifying novel prognostic indicators and improving clinical pathways tailored to the specific needs of these patients. In the near future, knowledge about spiritual well-being and resilience in these patients could lead to (1) personalized psychological interventions during radiotherapy or according to the disease trajectory and (2) personalized spiritual or resilience interventions for glioblastoma patients.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Loredana Dinapoli, Morena Caliandro, and Nicola Dinapoli. The first draft of the manuscript was written by Loredana Dinapoli, Nicola Dinapoli, Silvia Chiesa, and Elisa Marconi; all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Competing interests

The authors declare they have no conflict of interests.

References

Altinok, DCA, Rajkumar, R, Nießen, D, et al. (2021) Common neurobiological correlates of resilience and personality traits within the triple resting-state brain networks assessed by 7-Tesla ultra-high field MRI. Scientific Reports 11(1). doi:10.1038/s41598-021-91056-yCrossRefGoogle ScholarPubMed
Bai, M, Lazenby, M, Jeon, S, et al. (2015) Exploring the relationship between spiritual well-being and quality of life among patients newly diagnosed with advanced cancer. Palliative and Supportive Care 13, 927935. doi:10.1017/S1478951514000820CrossRefGoogle ScholarPubMed
Baksi, A, Arda Sürücü, H and Genç, H (2021) Psychological hardiness and spirituality in patients with primary brain tumors: A comparative study. Journal of Religion and Health 60, 27992809. doi:10.1007/s10943-021-01238-1CrossRefGoogle ScholarPubMed
Bamishigbin, ON, Stein, KD, Leach, CR, et al. (2020) Spirituality and depressive symptoms in a multiethnic sample of cancer survivors. Health Psychology 39, 589-599. doi:10.1037/hea0000878CrossRefGoogle Scholar
Caliandro, M, Carbonara, R, Surgo, A, et al. (2023) The role of telemedicine for psychological support for oncological patients who have received radiotherapy. Current Oncology 30, 51585167. doi:10.3390/curroncol30050390CrossRefGoogle ScholarPubMed
Chaar, EA, Hallit, S, Hajj, A, et al. (2018) Evaluating the impact of spirituality on the quality of life, anxiety, and depression among patients with cancer: An observational transversal study. Supportive Care in Cancer 26, 25812590. doi:10.1007/s00520-018-4089-1CrossRefGoogle ScholarPubMed
Cheng, Q, Liu, X, Li, X, et al. (2019) Improving spiritual well-being among cancer patients: Implications for clinical care. Supportive Care in Cancer 27, 34033409. doi:10.1007/s00520-019-4636-4CrossRefGoogle ScholarPubMed
Connor, KM and Davidson, JR (2003) Development of a new resilience scale: The Connor-Davidson Resilience Scale (CD-RISC). Depression and Anxiety 18, 7682. doi:10.1002/da.10113CrossRefGoogle ScholarPubMed
Costantini, M, Rabitti, E, Beccaro, M, et al. (2016) Validity, reliability and responsiveness to change of the Italian palliative care outcome scale: A multicenter study of advanced cancer patients. BMC Palliative Care 26(15), . doi:10.1186/s12904-016-0095-6Google Scholar
Dinapoli, L, Chiesa, S, Dinapoli, N, et al. (2021) Personalised support of brain tumour patients during radiotherapy based on psychological profile and quality of life. Supportive Care in Cancer 29, 45554563. doi:10.1007/s00520-021-06000-7CrossRefGoogle ScholarPubMed
Elias, AC, Ricci, MD, Rodriguez, LH, et al. (2015) The biopsychosocial spiritual model applied to the treatment of women with breast cancer, through RIME intervention (relaxation, mental images, spirituality). Complementary Therapies in Clinical Practice 21, 16. doi:10.1007/s10549-011-1738-1CrossRefGoogle Scholar
Faretta, E and Borsato, T (2016) EMDR therapy protocol for oncological patients. Journal of EMDR Practice and Research 10, 162175. doi:10.1891/1933-3196.10.3.162CrossRefGoogle Scholar
Fradelos, EC, Latsou, D, Mitsi, D, et al. (2018) Assessment of the relation between religiosity, mental health, and psychological resilience in breast cancer patients. Contemporary Oncology (Pozn) 22, 172177. doi:10.5114/wo.2018.78947Google ScholarPubMed
Fradelos, EC, Papathanasiou, IV, Veneti, A, et al. (2017) Psychological distress and resilience in women diagnosed with breast cancer in Greece. Asian Pacific Journal of Cancer Prevention 18, 25452550. doi:10.22034/APJCP.2017.18.9.2545Google ScholarPubMed
Gately, L, Collins, A, Murphy, M, et al. (2016) Age alone is not a predictor for survival in glioblastoma. Journal of Neuro-Oncology 129, 479485. doi:10.1007/s11060-016-2194-xCrossRefGoogle Scholar
Grassi, L, Johansen, C, Annunziata, MA, et al. (2013) Italian Society of Psycho-Oncology Distress Thermometer Study Group Screening for distress in cancer patients: A multicenter, nationwide study in Italy. Cancer 119, 17141721. doi:10.1002/cncr.27902CrossRefGoogle Scholar
Hematti, S, Baradaran-Ghahfarokhi, M, Khajooei-Fard, R, et al. (2015) Spiritual well-being for increasing life expectancy in palliative radiotherapy patients: A questionnaire-based study. Journal of Religion and Health 54, 15631572. doi:10.1007/s10943-014-9872-9CrossRefGoogle ScholarPubMed
Henderson, VP, Clemow, L, Massion, AO, et al. (2012) The effects of mindfulness-based stress reduction on psychosocial outcomes and quality of life in early-stage breast cancer patients: A randomized trial. Breast Cancer Research & Treatment 131, 99109. doi:10.1007/s10549-011-1738-1CrossRefGoogle ScholarPubMed
Holland, JC, Kash, KM, Passik, S, et al. (1998) A brief spiritual belief inventory for use in quality of life research in life-threatening illness. Psycho-Oncology 7, 460469. doi:10.1002/(SICI)1099-1611(199811/12)7:6<460::AID-PON328>3.0.CO;2-R3.0.CO;2-R>CrossRefGoogle ScholarPubMed
Jimenez-Fonseca, P, Lorenzo-Seva, U, Ferrando, PJ, et al. (2018) The mediating role of spirituality (meaning, peace, faith) between psychological distress and mental adjustment in cancer patients. Supportive Care in Cancer 26, 14111418. doi:10.1007/s00520-017-3969-0Google ScholarPubMed
Kinsel, B (2005) Resilience as adaptation in older women. Journal of Women & Aging 17, 2339. doi:10.1300/J074v17n03_03CrossRefGoogle ScholarPubMed
Korn, DL and Leeds, AM (2002) Preliminary evidence of efficacy for EMDR resource development and installation in the stabilization phase of treatment of complex posttraumatic stress disorder. Journal of Clinical Psychology 58, 14651487. doi:10.1002/jclp.10099CrossRefGoogle ScholarPubMed
Kouloulias, V, Kokakis, J, Kelekis, N, et al. (2017) A new questionnaire (QRFPC25) regarding the religiosity and spirituality in people with life-threatening disease: Reliability and validity in a population of cancer patients undergoing radiotherapy. Journal of Religion and Health 56, 11371154. doi:10.1007/s10943-016-0310-zCrossRefGoogle Scholar
Louis, DN, Perry, A, Wesseling, P, et al. (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro-Oncology 23, 1231–1251. doi:10.1093/neuonc/noab106CrossRefGoogle ScholarPubMed
Ludolph, P, Kunzler, AM, Stoffers-Winterling, J, et al. (2019) Interventions to promote resilience in cancer catients. Deutsches Ärzteblatt International 51-52, 865872. doi:10.3238/arztebl.2019.0865Google Scholar
Manning, LK (2013) Navigating hardships in old age: Exploring the relationship between spirituality and resilience in later life. Qualitative Health Research 23, 568575. doi:10.1177/1049732312471730CrossRefGoogle ScholarPubMed
Merluzzi, TV, Salamanca-Balen, N, Philip, EJ, et al. (2023) “Letting go” - Relinquishing control of illness outcomes to God and quality of life: Meaning/peace as a mediating mechanism in religious coping with cancer. Social Science & Medicine 317, . doi:10.1016/j.socscimed.2022.115597CrossRefGoogle ScholarPubMed
Mihic-Góngora, L, Rodriguez-Gonzalez, A, Velasco, V, et al. (2022) Impact of the COVID-19 pandemic on care and psychological impact on cancer patients. Current Opinion in Supportive and Palliative Care 16, 138143. doi:10.1097/SPC.0000000000000614CrossRefGoogle ScholarPubMed
Min, J-A, Yoon, S, Lee, C-U, et al. (2013) Psychological resilience contributes to low emotional distress in cancer patients. Supportive Care in Cancer 21, 24692476. doi:10.1007/s00520-013-1807-6CrossRefGoogle ScholarPubMed
Miranda, TPS, Caldeira, S, de Oliveira, HF, et al. (2020) Intercessory prayer on spiritual distress, spiritual coping, anxiety, depression and salivary amylase in breast cancer patients during radiotherapy: Randomized clinical trial. Journal of Religion and Health 59, 365380. doi:10.1007/s10943-019-00827-5CrossRefGoogle ScholarPubMed
Moorey, S, Greer, S, Watson, M, et al. (1991) The factor structure and factor stability of the hospital anxiety and depression scale in patients with cancer. British Journal of Psychiatry 158, 255259. doi:10.1192/bjp.158.2.255CrossRefGoogle ScholarPubMed
NICE https://www.nice.org.uk/guidance/ng99 (Last updated: 29 January 2021).Google Scholar
Piderman, KM, Johnson, ME, Frost, MH, et al. (2014) Spiritual quality of life in advanced cancer patients receiving radiation therapy. Psycho-oncology 23, 216221. doi:10.1002/pon.3390CrossRefGoogle ScholarPubMed
Piderman, KM, Radecki Breitkopf, C, Jenkins, SM, et al. (2017) The impact of a spiritual legacy intervention in patients with brain cancers and other neurologic illnesses and their support persons. Psycho-oncology 26, 346353. doi:10.1002/pon.4031CrossRefGoogle ScholarPubMed
Randazzo, DM, McSherry, F, Herndon, JE, et al. (2021) Spiritual well-being and its association with health-related quality of life in primary brain tumor patients. Neuro-oncology Practice 8, 299309. doi:10.1093/nop/npaa084CrossRefGoogle ScholarPubMed
Ripamonti, C, Borreani, C, Maruelli, A, et al. (2010) System of belief inventory (SBI-15R): A validation study in Italian cancer patients on oncological, rehabilitation, psychological and supportive care settings. Tumori 96, 10161021.Google ScholarPubMed
Rosenberg, AR, Syrjala, KL, Martin, PJ, et al. (2015) Resilience, health, and quality of life among long-term survivors of hematopoietic cell transplantation. Cancer 121, 42504257. doi:10.1002/cncr.29651CrossRefGoogle ScholarPubMed
Samuelson, BT, Fromme, EK and Thomas, CR (2012) Changes in spirituality and quality of life in patients undergoing radiation therapy. American Journal of Hospice & Palliative Medicine 29, 449454. doi:10.1002/pon.3390CrossRefGoogle ScholarPubMed
Sharpley, CF, Bitsika, V, Wootten, AC, et al. (2014) Does resilience ‘buffer’ against depression in prostate cancer patients? A multi-site replication study. European Journal of Cancer Care 23, 545552. doi:10.1111/ecc.12170CrossRefGoogle ScholarPubMed
Sprik, PJ, Tata, B, Kelly, B, et al. (2021) Religious/spiritual concerns of patients with brain cancer and their caregivers. Annals of Palliative Medicine 10, 964969. doi:10.21037/apm-20-813CrossRefGoogle ScholarPubMed
Strang, S and Strang, P (2001) Spiritual thoughts, coping and ‘sense of coherence’ in brain tumour patients and their spouses. Palliative Medicine 15, 127134. doi:10.1191/026921601670322085CrossRefGoogle ScholarPubMed
Stupp, R, Brada, M, van den Bent, MJ, et al., ESMO Guidelines Working Group (2014) High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 25, iii93101. doi:10.1093/annonc/mdu050CrossRefGoogle ScholarPubMed
Stupp, R, Mason, MP, den Bent Mj, V, et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine 352, 987996. doi:10.1056/NEJMoa043330CrossRefGoogle ScholarPubMed
Szpringer, M, Oledzka, M and Amann, BL (2018) A non-randomized controlled trial of EMDR on affective symptoms in patients with glioblastoma multiforme. Frontiers in Psychology 22, . doi:10.3389/fpsyg.2018.00785Google Scholar
Tan, WS, Beatty, L, Kemp, E, et al. (2019) What contributes to resilience in cancer patients? A principal component analysis of the Connor-Davidson Resilience Scale. Asia-Pacific Journal of Clinical Oncology 15, e115e119. doi:10.1111/ajco.13128CrossRefGoogle ScholarPubMed
Trad, W, Koh, ES, Daher, M, et al. (2015) Screening for psychological distress in adult primary brain tumor patients and caregivers: Considerations for cancer care coordination. Frontiers in Oncology 5, . doi:10.3389/fonc.2015.00203CrossRefGoogle ScholarPubMed
Walshe, C, Roberts, D, Appleton, L, et al. (2017) Coping well with advanced cancer: A serial qualitative interview study with patients and family carers. PLOS One 12, . doi:10.1371/journal.pone.0169071CrossRefGoogle Scholar
Wang, GL, Hsu, SH, Feng, AC, et al. (2011) The HADS and the DT for screening psychosocial distress of cancer patients in Taiwan. Psychooncology 20, 639646. doi:10.1002/pon.1952CrossRefGoogle Scholar
Wen, PY, Macdonald, DR, Reardon, DA, et al. (2010) Updated response assessment criteria for high grade gliomas: Response assessment in neuro-oncology working group. Journal of Clinical Oncology 28, 19631972. doi:10.1200/JCO.2009.26.3541CrossRefGoogle ScholarPubMed
Yanez, B, Edmondson, D, Stanton, AL, et al. (2009) Facets of spirituality as predictors of adjustment to cancer: Relative contributions of having faith and finding meaning. Journal of Consulting and Clinical Psychology 77, 730741. doi:10.1037/a0015820CrossRefGoogle ScholarPubMed
Zigmond, AS and Snaith, RP (1983) The hospital anxiety and depression scale. Acta Psychiatrica Scandinavica 67, 361370. doi:10.1136/bmj.292.6516.344CrossRefGoogle ScholarPubMed
Figure 0

Table 1. Clinical and demographic characteristics

Figure 1

Table 2. Wilkoxon signed-rank test’s results on distribution of CD-RISC, FACIT-Sp-12 over “distressed” patients and patients with HADS ≥16

Figure 2

Table 3. Univariable statistics among psychological tests and clinical/population variables

Figure 3

Table 4. Matrix of Pearson’s cross correlation test results of SBI-15R, tests’ subscales of FACIT-Sp-12 and CD-RISC

Figure 4

Figure 1. Survival curves of the patient population classified against the threshold of CD-RISC $\le 68$ or higher. The log-rank test result is 0.05.

Figure 5

Table 5. Descriptive statistics and univariable survival analysis of patients’ population (Kaplan−Meier)

Figure 6

Table 6. Results of multivariable analysis (Cox proportional hazards test)