Developing content-valid tumor-specific PRO-CTCAE item sets: analysis of a cross-sectional survey in three German outpatient cancer centers

Developing content-valid tumor-specific PRO-CTCAE item sets: analysis of a cross-sectional survey in three German outpatient cancer centers | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Developing content-valid tumor-specific PRO-CTCAE item sets: analysis of a cross-sectional survey in three German outpatient cancer centers Maximilian Günther, Leopold Hentschel, Markus Schuler, Theresa Müller, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2824306/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Jul, 2023 Read the published version in BMC Cancer → Version 1 posted 9 You are reading this latest preprint version Abstract Background To include the patient perspective in the assessment of adverse events (AE) in oncology, a patient-reported outcomes (PRO) version of the Common Terminology Criteria for Adverse Events (CTCAE) was developed by the NCI, the so called PRO-CTCAE. The objective of this study was the development of disease-specific PRO-CTCAE item sets with high content validity for patients with breast cancer (BC), multiple myeloma (MM) and prostate cancer (PC). Methods A cross-sectional survey was conducted at three German outpatient cancer centers. Prevalence and importance of the 78 PRO-CTCAE symptoms were assessed using a patient questionnaire. To select the most relevant PRO-CTCAE items for each tumor entity, symptoms were ranked based on patient answers. Results 101 patients with BC, 107 with MM, and 66 with PC participated. The final item sets contained 21 symptoms (BC) or 19 symptoms (MM and PC), respectively. Eight symptoms were represented in all three item sets. Fatigue was the symptom with the highest ranking across item sets followed by sleep disorders. Symptoms with the highest rankings represented in only one item set were symptoms affecting the urogenital system in the PC item set, blurred vision in the BC item set and appetite loss in the MM item set. Conclusions Individual PRO-CTCAE item sets with high content validity were developed for three tumor diseases on the basis of patient-reported symptom patterns and perceptions. The quality and psychometric criteria of the newly compiled item sets should be further validated. Figures Figure 1 Figure 2 1 Background In oncology, adverse events are assessed by physicians using the Common Terminology Criteria for Adverse Events (CTCAE) [ 1 ]. This physician-reported assessment often differs from the patients’ experience. The severity of symptoms was underestimated by physicians most frequently for fatigue (51%), muscle cramps (49%), and musculoskeletal pain (42%), whereas the physicians overestimated the health status in 67% of cases [ 2 , 3 ]. Physicians underreported symptoms of any severity in 41–74% and severe symptoms in 13–50% of cases [ 4 ]. These findings were confirmed by a systematic review concluding that the association between CTCAE and patient-reported outcomes (PRO) was poor to moderate with a large variation across studies [ 3 ]. To address this gap between clinician- versus patient-reporting of symptoms Basch et al. conducted a randomized controlled trial. Patients in the intervention group underwent a weekly electronic monitoring of PRO symptoms with automated alerts to clinicians. Patients in the control group were treated with standard oncology care. Health-related quality of life after six months improved more and worsened less often in the intervention group. Patients who underwent the electronic PRO symptom monitoring were less frequently admitted to the emergency department or hospital and remained longer under therapy. Even the overall survival of the patients was prolonged [ 5 ]. Yet methodological limitations were critically discussed, these findings were affirmed by a further trial [ 6 ]. To complement the physician-based assessment of adverse events the United States National Cancer Institute has developed a PRO version of the CTCAE [ 7 ]. Out of the 790 adverse events listed in the CTCAE, 78 were considered to be appropriate to be rated directly by the patients. Plain language terms and up to three items characterizing severity, frequency, and interference with daily activities were designed for every symptomatic adverse event and refined in a cognitive interviewing study creating a library consisting of 124 items. The items were evaluated regarding their construct validity, reliability, responsiveness, and between-mode equivalence [ 8 , 9 ]. The PRO-CTCAE item library was translated into more than 30 languages including German [ 7 ]. A German PRO-CTCAE core item set containing 31 items for patients with chemotherapy was validated by our group [ 10 ]. The complementary nature of PRO-CTCAE to CTCAE is illustrated by the fact that patients´ and physicians´ answers to PRO-CTCAE questions differ a lot. The agreement was poor and patients tended to grade symptoms more severe than physicians [ 11 ]. The disease symptoms and treatment options differ considerably among tumor entities. Therefore, individual symptoms have not the same relevance for all cancer patients. In order to maximize the informative value of the PRO-CTCAE questionnaire and simultaneously minimize patient burden, it seems prudent to include only a selection of items with the highest impact on the patient in a PRO-CTCAE questionnaire. The aim of this project was to identify the most relevant PRO-CTCAE items and to develop item sets with high content validity for patients with different tumor diseases. In order to cover solid tumors as well as hematological malignancies three tumor entities with different characteristics were selected for this project: breast cancer, multiple myeloma, and prostate cancer. 2 Methods 2.1 Study design and participants This project was a multicentric, cross-sectional, and non-interventional patient survey. It was conducted at the Center for Integrated Oncology (CIO) of the University Hospital in Bonn, the Johanniter Hospital in Bonn, and the National Center for Tumor Diseases (NCT/UCC) at the University Hospital in Dresden. Beside the patients´ assessments of the prevalence and importance of therapy-associated symptoms contained in the PRO-CTCAE item library, the underlying tumor medication and disease-specific data were recorded. The study was approved by the Ethics Committee of the Medical Faculty of the University of Bonn (Lfd. Nr. 405/17) and by the relevant institutions of each participating center. It was carried out in accordance with the applicable German and European legal provisions and it was performed in accordance with the principles of the Declaration of Helsinki. Cancer patients with breast cancer, prostate cancer, and multiple myeloma of at least 18 years with an active treatment of their disease were included in the study. Patients with insufficient knowledge of the German language were excluded because all relevant documents and information were in German. A prespecified sample of 100 patients for every tumor entity should be included consecutively in the study. For recruitment, patients matching the inclusion criteria were identified by the treating physicians at the study centers and invited to participate. Patients were informed orally and in writing about the nature, significance, and scope of the patient survey and signed a written informed consent. Patients were recruited between February 2018 and April 2019 at the Center for Integrated Oncology (CIO) of the University Hospital in Bonn, the Johanniter Hospital Bonn, and the National Center for Tumor Diseases (NCT/UCC) in Dresden. For further data processing and statistical analysis of the anonymized data, Microsoft® Access® 2019 (Microsoft Corporation, Redmond, USA), Microsoft® Excel® 2019 (Microsoft Corporation, Redmond, USA), and IBM® SPSS® Statistics Version 27.0 for Windows (IBM Corporation, Armonk, USA) were used. Descriptive statistics were performed for patient characteristics and medication data. As applicable, mean values with standard deviations (SD) or the median with interquartile range (IQR) were calculated. Frequencies were described as absolute number and percentage. For inductive statistics in the item-redundancy analysis, a p-value of < 0.05 was considered as statistically significant. 2.2 Patient questionnaire The complete PRO-CTCAE question pool with its 124 items for 78 symptoms is too extensive to be used in complete form for prevalence recording and importance assessment of the individual symptoms in a patient survey. In order to minimize the time burden for patients, a specific questionnaire was used in this project consisting of two parts. In the first part, patients were asked to answer if the 78 symptoms have ever occurred during their tumor therapy and if they think that the symptoms should be asked for in a questionnaire for patients suffering from their tumor disease. In this study the symptoms “Nail ridging” and “Nail discoloration” were condensed to one item, resulting in 77 questions in the patient questionnaire. The questions about the prevalence of the symptoms could be answered with “Yes” or “No”. The questions about the importance of the symptoms could be answered with “Yes”, “No” or “I don’t know”. This procedure was adapted from the Guidelines for Developing Questionnaire Modules of the EORTC Quality of Life Group [ 12 ]. An example for how the questions in the administered questionnaire looked like is given in Fig. 1 . The second part of the questionnaire contained questions on sociodemographic data, the characteristics of tumor disease, and tumor therapy, which are essential for the characterization of the study populations. Additional information was collected using case report forms that were filled in by health care professionals at the study centers. 2.3 Item selection To build the entity specific PRO-CTCAE item sets, the most prevalent and most important symptoms of the patient questionnaires needed to be identified. An approach based on the clinical impact method (CIM) was used for the item selection. The CIM focuses on the severity and importance of items rated by the patients and is applicable for small sample sizes [ 13 ]. 2.4 Symptom rating and ranking According to the CIM, patients rate the severity and the importance of the questionnaire items. The ratings are combined to the clinical impact (CI) by adding the mean importance rating per item (I) and the mean severity rating per item (S) using Eq. 1 [ 13 ]. \(\text{C}\text{I}=\text{I}+\text{S}\) Equation 1 I: Symptom importance S: Symptom severity In this study, the CIM was modified. Instead of the symptom severity, the symptom prevalence was used. The scales were scored with “Yes” = 1 and “No” = 0 for the symptom prevalence and with “Yes” = 1, “No” = 0, and “I don’t know” = 0.5 for the symptom importance. In the first step, two separate scores for the symptom prevalence and the symptom importance were calculated. Therefore, the values for every symptom were added and divided by the number of completed questionnaires to avoid distortions due to missing values. By doing so, the values of the scores displayed values between 0 and 1. The values were ranked from 1 (symptom with highest score) to 77 (symptom with lowest score). In the second step, the rankings for the symptom prevalence (1 to 77) and the symptom importance (1 to 77) were added to the combined prevalence-importance (P-I) score. According to their combined P-I score, the symptoms were then ranked from lowest to highest. The lower the combined score the higher were prevalence and importance. For item selection, the symptoms with the lowest combined P-I scores were translated into PRO-CTCAE items until a maximum of 40 PRO-CTCAE items was reached. For every PRO-CTCAE symptom, up to three items are available. The items of one symptom were not split in the selection process. The cut-off value of 40 items for the PRO-CTCAE item sets was chosen because it is considered as a not too burdensome number of questions for patients, that can be asked every seven days [ 8 ]. 2.5 Item redundancy analysis The symptoms for the maximum of 40 PRO-CTCAE items for each item set were investigated for inter-item correlations to reveal redundancies among the selected symptoms. To investigate the association between the symptom items, the ϕ coefficient for dichotomous variables by Pearson was used. The ϕ coefficient can take values between − 1 and + 1. Values around 0 indicate weak correlation. Values of ± 1 indicate perfect positive or negative correlation. Values of ± 0.8 or higher indicate strong correlation between two variables [ 14 ]. The response options for the questions on symptom prevalence (“Yes” and “No”) are dichotomous already. The response scale for the questions on symptom importance (“Yes”, “No”, and “I don’t know”) were translated to the dichotomous answers “Yes” and “not Yes” (including “No” and “I don’t know”) in the course of the item-redundancy analysis. Pairs of symptom items with a ϕ value of ≥ ± 0.8 reveal possible redundancies. To analyze the significance of these correlations and to uncover random correlations, Fisher´s exact test was conducted [ 15 , 16 ]. 3 Results 3.1 Study population The sociodemographic and disease-related characteristics of the study populations are shown in Table 1 . Table 1 Sociodemographic and disease-related characteristics of the study populations [n (%)] Breast cancer Multiple myeloma Prostate cancer Number of patients 101 107 66 Study center CIO Bonn Johanniter Hospital Bonn University Hospital Dresden 80 (79.2) 21 (20.8) 0 (0) 35 (32.7) 12 (11.2) 60 (56.1) 6 (9.1) 0 (0) 60 (90.9) Gender Male Female 0 (0) 101 (100) 67 (62.6) 40 (37.4) 66 (100) 0 (0) Age Median [years] 58 (IQR: 16, range: 28–84, mean 58.0, SD 11.4) 62 (IQR: 13, range: 33–83, mean: 62.0, SD: 9.1) 76 (IQR: 8, range: 59–94, mean: 74.5, SD: 6.9) Time since the first diagnosis of cancer Median [months] 14 (IQR: 67, range: 1–506, mean: 59, SD: 86.9) 59 (IQR: 69, range: 2–255, mean: 63.7, SD: 52.8) 27 (IQR: 60, range: 1–190, mean: 41.7, SD: 43.3) Current therapy situation Outpatient therapy Inpatient therapy 101 (100) 0 (0) 87 (81.3) 20 (18.7) 56 (84.9) 10 (15.1) Current therapy intention Curative Palliative Other/unknown Therapy sequence Adjuvant Neoadjuvant Other/unknown 32 (31.7) 53 (52.5) 16 (15.8) 52 (51.5) 23 (22.8) 26 (25.7) 35 (32.7) 68 (63.6) 4 (3.7) n.a. n.a. n.a. 24 (36.4) 30 (45.5) 12 (18.2) 3 (4.5) 0 (0) 63 (95.5) Metastases Patients with metastases Number of metastases per patient 54 (53.5) 0.9 (SD: 0.9, median: 1, IQR: 1, range: 0–4) n.a. n.a. 20 (30.3) 0.3 (SD: 0.5, median: 0, IQR: 1, range: 0–2) Relapses Patients with relapse 22 (21.8) 27 (25.2) 18 (27.3) n.a. = not applicable, IQR = interquartile range, SD = standard deviation 53.5% (n = 54) of the breast cancer patients had metastases. The most often occurring metastases were located in bones (n = 34), liver (n = 20), and lung (n = 15). 22 patients (21.8%) had a relapse of their disease. 15 of them had only one relapse. An estrogen receptor-positive disease occurred in 65 patients (64.4%). Progesterone receptor-positive were 46 patients (45.6%) and HER2-positive 44 patients (43.6%). 25.2% (n = 27) of the multiple myeloma patients had a relapse of their disease. 22 of them had only one relapse. 14 patients (13.1%) were currently undergoing autologous stem cell transplantation (SCT). 77 patients (72.0%) received at least one autologous SCT during former therapy lines. 30.3% (n = 20) of the prostate cancer patients had metastases. With one exception the metastases were located in bones (n = 20). 18 patients (27.3%) had a relapse of their disease. Most patients belonged to the high-risk Gleason grade group 5 (n = 26, 39.4%). The used drug classes for the three tumor entities are shown in Fig. 2 . Overall, the mean number of anticancer drugs per patient was 7.7 (SD: 4.1, median: 7, IQR: 5, range 0–24) in the multiple myeloma patients, followed by the breast cancer patients with a mean of 5.8 (SD: 3.4, median: 5, IQR: 4, range: 0–17). The prostate cancer patients received only a mean of 1.9 (SD: 1.6, median: 2, IQR: 1, range 0–7) drugs per patient. The most used anticancer drugs in breast cancer patients were trastuzumab (n = 91, 15.7%), cyclophosphamide (n = 69, 11.9%), epirubicin (n = 68, 11.7%), pertuzumab (n = 55, 9.5%), and docetaxel (n = 44, 7.6%). The most used drugs in multiple myeloma patients were dexamethasone (n = 199, 24.1%), bortezomib (n = 124, 15.0%), cyclophosphamide (n = 113, 13.7%), melphalan (n = 111, 13.4%), and lenalidomide (n = 110, 13.3%). The most used drugs in prostate cancer patients were not further specified LH-RH analogs (n = 32, 25.4%), bicalutamide (n = 24, 19.1%), leuprorelin (n = 23, 18.3%), degarelix (n = 12, 9.5%), and abiraterone acetate (n = 10, 7.9%). Breast cancer patients were treated for a mean of 1.7 indications for supportive care (SD: 1.7, median: 1, IQR: 1, range: 0–6). They received most frequently care for nausea and emesis (n = 41, 24.3%), bone complications (n = 40, 23.7%), and gastric ulcer prophylaxis (n = 18, 10.7%). Multiple myeloma patients were treated also for a mean of 1.7 supportive care indications (SD: 1.5, median: 1, IQR: 2, range: 0–6), most frequently for bone complications (n = 48, 26.5%), gastric ulcer prophylaxis (n = 43, 23.8%), and pain (n = 34, 18.8%). Prostate cancer patients were only treated for a mean of 0.4 supportive care indications (SD: 0.9, median: 0, IQR: 0, range: 0–4), the most frequently for bone complications (n = 7, 25.9%), gastric ulcer prophylaxis (n = 6, 22.2%), and pain (n = 5, 18.5%). 3.2 Completion of questionnaires Missing values occurred if patients did not answer a question at all or not clear enough by marking an answer on the paper-based questionnaires. Within the 101 questionnaires filled in by the breast cancer patients, the questions regarding the prevalence of the symptoms were not answered in 2.2% of cases (mean number of cases 2.2, SD 3.17, range 0–16). The questions about the importance of the symptoms were not answered in 4.2% of cases (mean number of cases 4.2, SD 1.52, range 1–10). For the 107 questionnaires of the multiple myeloma patients, the missing values amount to 0.8% of cases (mean number of cases 0.9, SD 1.38, range 0–6) for the prevalence questions and 1.6% of cases (mean number of cases 1.7, SD 1.29, range 0–6) for the importance questions. For the 66 questionnaires of the prostate cancer patients, the missing values amount to 0.2% of cases (mean number of cases 0.1, SD 0.31, range 0–1) for the prevalence questions and 5.6% of cases (mean number of cases 3.7, SD 1.77, range 1–7) for the importance questions. 3.3 Symptom rating 3.3.1 Breast cancer The 101 participating breast cancer patients experienced a median of 27 symptoms each (IRQ 31, range 4–53). The symptom that occurred most often was “Hair loss” (Number 24) in 86 patients. A median of 46 symptoms per patient (IQR 36, range 0–75) was rated important. 3.3.2 Multiple myeloma The 107 participating multiple myeloma patients experienced a median of 28 symptoms each (IRQ 14, range 7–61). The symptom that occurred most often was “Fatigue” (Number 52) in 92 patients. A median of 48 symptoms per patient (IQR 32, range 0–75) was rated important. 3.3.3 Prostate cancer The 66 participating prostate cancer patients experienced a median of 20 symptoms each (IRQ 13, range 4–51). The symptom that occurred most often was “Achieve and maintain erection” (Number 64) in 59 patients. A median of 46 symptoms per patient (IQR 26, range 0–72) was rated important. 3.4 Symptom ranking and item set compilation For each of the three tumor diseases, the symptoms were ranked according to their combined prevalence-importance (P-I) score. Then, the symptoms with the lowest scores indicating high prevalence and importance for the respective tumor disease were compiled to an item set until a maximum of 40 PRO-CTCAE items was reached. The final PRO-CTCAE item set for breast cancer included 39 items related to 21 symptoms, for multiple myeloma 39 items related to 19 symptoms, and for prostate cancer 40 items related to 19 symptoms, respectively. A comparison of the three tumor disease-specific PRO-CTCAE item sets ranked by their combined P-I scores is shown in Table 2 . The three individual PRO-CTCAE item sets are shown in the Supplementary Information. Table 2 Comparison of the tumor entity-specific PRO-CTCAE item sets according to the combined prevalence-importance (P-I) scores of the symptoms Breast cancer Combined P-I score Multiple myeloma Combined P-I score Prostate cancer Combined P-I score Fatigue #§ 3 Fatigue #§ 4 Insomnia #§ 9 Numbness and tingling § 9 Numbness and tingling § 6 Urinary frequency 9 Nausea § 16 General pain #§ 11 Achieve and maintain erection 9 Muscle pain # 19 Insomnia #§ 12 Urinary incontinence 10 Insomnia #§ 23 Nausea § 15 Ejaculation 10 Hair loss 24 Shortness of breath #§ 19 Fatigue #§ 11 Joint pain # 24 Hair loss 20 Urinary urgency 12 Blurred vision 27 Joint pain # 21 Unable to have orgasm 16 Concentration § 28 Diarrhea § 24 Joint pain # 21 General pain #§ 30 Muscle pain # 25 Anxious § 19 Diarrhea § 33 Anxious § 25 Decreased libido 21 Constipation § 34 Decreased appetite § 30 General pain #§ 27 Taste changes 35 Swelling 37 Hot flashes 28 Dizziness # 36 Dizziness # 37 Swelling # 32 Shortness of breath #§ 37 Heart palpitations 38 Shortness of breath #§ 37 Heart palpitations 44 Concentration § 39 Sad § 37 Memory 44 Constipation § 43 Muscle pain # 40 Swelling # 45 Taste changes 47 Painful urination 41 Rash 46 Mouth/throat sores § 49 Dizziness # 45 Nail ridging + 47 Nail discoloration + 47 # : Part of all three PRO-CTCAE item sets; BOLD : Part of only one PRO-CTCAE item set; §: Part of the PRO-CTCAE core item set; +: Symptoms were combined in the patient questionnaire Eight symptoms are included in all three item sets. The symptoms with the highest rankings across the item sets were “Fatigue” and “Insomnia”. Symptoms with the highest rankings included in only one item set were symptoms affecting the urogenital system in the prostate cancer item set, “Blurred vision” in the breast cancer item set and “Decreased appetite” in the multiple myeloma item set. 3.5 Item redundancy analysis For the prevalence of symptoms, high correlations with a ϕ coefficient of 0.8 or higher did not appear throughout the three tumor entities. Table 3 shows the ϕ coefficients for the correlations of the symptom prevalence. Table 3 Symptom prevalence in breast cancer (n = 101), multiple myeloma (n = 107) and prostate cancer patients (n = 66), correlations with a φ coefficient ≥ 0.5 Symptoms ϕ coefficient Fisher´s exact test Breast cancer General pain (46) and Joint pain (49) 0.50 0.000* Muscle pain (48) and Joint pain (49) General pain (46) and Muscle pain (48) 0.52 0.50 0.000* 0.000* Multiple myeloma Muscle pain (48) and Joint pain (49) 0.51 0.000* Prostate cancer Decreased libido (60) and Delayed orgasm (61) 0.52 0.000* Decreased libido (60) and Achieve and maintain erection (64) 0.51 0.001* Achieve and maintain erection (64) and Ejaculation (65) 0.69 0.000* * p < 0.05: statistically significant For the importance of symptoms, high correlations with a ϕ coefficient of 0.8 or higher were observed (see Table 4 ). Compared to the other tumor entities, prostate cancer symptom importance shows the greatest number of high ϕ values. Three symptom clusters with possibly redundant symptom pairs were detected for which redundancy is pathophysiologically highly plausible: sexual, hormonally-related and urogenital symptoms. Table 4 Symptom importance in breast cancer (n = 101), multiple myeloma (n = 107) and prostate cancer patients (n = 66), correlations with a φ coefficient ≥ 0.8 Symptoms ϕ coefficient Fisher´s exact test Breast cancer Memory (39) and Concentration (40) 0.82 0.000* Muscle pain (48) and Joint pain (49) 0.84 0.000* Multiple myeloma Swelling (35) and Heart palpitations (36) 0.82 0.000* Prostate cancer General pain (46) and Joint pain (49) 0.92 0.000* Muscle pain (48) and Joint pain (49) 0.85 0.000* Anxious (50) and Fatigue (52) 0.82 0.000* Painful urination (55) and Urinary urgency (56) 0.83 0.000* Painful urination (55) and Urinary frequency (57) 0.83 0.000* Painful urination (55) and Urinary incontinence (59) 0.83 0.000* Urinary urgency (56) and Urinary incontinence (59) 1.00 0.000* Decreased libido (60) and Delayed orgasm (61) 1.00 0.000* Decreased libido (60) and Achieve and maintain erection (64) 0.88 0.000* Decreased libido (60) and Ejaculation (65) 0.88 0.000* Delayed orgasm (61) and Achieve and maintain erection (64) 0.88 0.000* Delayed orgasm (61) and Ejaculation (65) 0.88 0.000* Achieve and maintain erection (64) and Ejaculation (65) 1.00 0.000* * p < 0.05: statistically significant 4 Discussion The aim of this project was to develop PRO-CTCAE item sets with high content validity for three different cancer types. The EORTC guidelines for developing questionnaire modules include four phases of the development process: 1. Generation of relevant PRO issues, 2. Converting the PRO issues into an item set, 3. Pre-testing of the item set and 4. Large-scale international field testing [ 12 ]. While developing the PRO-CTCAE item library by the US National Cancer Institute, the above-mentioned steps have already been taken for the item library in general. From the CTCAE catalogue containing 790 adverse events, 78 symptomatic adverse events that are relevant for cancer patients in general, were derived (Phase 1). Plain language terms and up to three items were designed for every symptomatic adverse event and refined in a cognitive interviewing study (Phase 2). The items were evaluated regarding their construct validity, reliability, responsiveness, and between-mode equivalence (Phase 3 and 4) [ 8 , 9 , 17 ]. Despite being a valid PRO instrument in general, the complete PRO-CTCAE question pool with 124 items is too extensive to be administered in total. This circumstance raises the question which symptoms are relevant to patients with different cancer types. The question refers to phase 1 of the development process in which the foundation for high content validity of the PRO tool is laid. For compiling the relevant PRO issues three sources should be used: literature, patients, and healthcare professionals. Since PRO-CTCAE is a well-characterized instrument for detecting symptomatic adverse events, and it is known that the physician-reported assessment often differs from the patients’ experience [ 2 , 3 ], the patient perspective was chosen over the perspective of healthcare professionals. This is also encouraged by the EORTC guidelines [ 12 ]. Therefore, a questionnaire-based patient survey on the prevalence and importance of the symptoms was conducted. Nevertheless, a physician-based approach could be an adequate comprehensive method for future research. The goal of item selection was to reduce the number of items for the entity-specific PRO-CTCAE item sets to a maximum of 40. The EORTC QLQ-C30 (30 items) plus entity-specific modules like QLQ-MY20 (multiple myeloma, 20 items), QLQ-BR23 (breast cancer, 23 items) or QLQ-PR25 (prostate cancer, 25 items) contain about 50 items in total [ 18 ]. The Functional Assessment of Cancer Therapy (FACT) questionnaires of the FACIT group consist of 27 items for the FACT-G (general) questionnaire, 37 items for the FACT-B (breast cancer), 41 items for the FACT-MM (multiple myeloma) and 39 items for FACT-P (prostate cancer) [ 19 ]. Whereas these instruments cover a broad range of domains of health-related quality of life, PRO-CTCAE focuses on symptomatic toxicities only. In general, it is recommended that the answering of a PRO questionnaire should be limited to 10 to 15 minutes or less if the questionnaire is administered repeatedly to minimize the response burden for patients [ 20 ]. Answering a 28-item PRO-CTCAE questionnaire takes four to six minutes [ 8 ]. Therefore, a number of 40 items was chosen as a cut-off because it is considered as a not too burdensome number of questions. Comparing the three tumor entity-specific PRO-CTCAE item sets, some symptoms appear in all three item sets. This is not surprising since fatigue as a multifactorial syndrome is the most frequently observed symptom across most malignant diseases, which is also the case for mood-related symptoms like insomnia and pain-related symptoms [ 21 ]. In particular, the breast cancer and multiple myeloma PRO-CTCAE item set have 16 symptoms in common. Nevertheless, both item sets differ from the German PRO-CTCAE core item set that was designed and validated for patients under chemotherapy [ 10 ]. Of the 16 symptoms included in the PRO-CTCAE core item set, nine are included in the breast cancer item set, and 12 are included in the multiple myeloma item set. The PRO-CTCAE prostate cancer set shares six symptoms with the core item set. The item redundancy analysis for the prevalence and importance of the symptoms revealed some possible redundancies. High inter-item correlations that could indicate a redundancy of symptoms appear more often in relation to the importance of the symptoms compared to their prevalence. This difference may be explained by the fact that the question on importance also applies to symptoms that do not likely occur during the patients’ therapy but are nevertheless important according to their perception. Especially pathophysiologically plausible symptom pairs that showed possible redundancies for prevalence and importance, like the pain-related symptoms of the breast cancer patients and the cluster of sexual and hormonally-related symptoms of the prostate cancer patients, might be candidates for exclusion from the PRO-CTCAE item sets. The final decision might be taken in a validation study of the item sets determining their psychometric quality criteria reliability and construct validity, as it was conducted for the PRO-CTCAE core item set [ 10 ]. In terms of measuring the reliability of a questionnaire, internal consistency can be determined using Cronbach´s alpha. To evaluate which items negatively influence the reliability of a scale, Alpha-if-item-deleted values can be calculated. The tumor disease-specific PRO-CTCAE item sets for breast cancer, multiple myeloma, and prostate cancer are designed to be valid for all patients of the respective tumor entity. Patients are treated in very different ways according to their stages of disease and clinical situation, leading to the importance of developing PRO-CTCAE item sets for different therapy situations within one tumor entity. In the future new therapy options can change the symptom patterns of the cancer diseases. Therefore, the patient survey should be repeated if significant changes in treatment are introduced to maintain content validity of the item sets. 5 Conclusions Based on patient-reported differences in symptom pattern and perception, specific PRO-CTCAE item sets with high content validity were developed for breast cancer, multiple myeloma, and prostate cancer. In order to validate the quality and psychometric criteria of the new item sets further studies are required. Declarations Ethics approval and consent to participate – The study was approved by the Ethics Committee of the Medical Faculty of the University of Bonn (Lfd. Nr. 405/17) and the relevant institutions of each participating center. It was carried out in accordance with the applicable German and European legal provisions and performed in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study. Consent for publication – Consent for publication is not applicable. Only anonymized data are published. Availability of data and materials – The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests – Maximilian Günther, Leopold Hentschel, Markus Schuler, Theresa Müller, Katharina Schütte, Yon-Dschun Ko, Ingo Schmidt-Wolf, and Ulrich Jaehde declare that they have no competing interests. Funding – No funding was received to conduct the study and assist with the preparation of the manuscript. Authors’ contributions – All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Maximilian Günther, Leopold Hentschel, Theresa Müller, and Katharina Schütte. The first draft of the manuscript was written by Maximilian Günther and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements – The CIO Bonn is kindly supported by the Deutsche Krebshilfe, Bonn, Germany. Especially, we express our gratitude to all patients who participated in our project despite their challenging situation. References National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0 from 27/11/2017. Available from: https://ctep.cancer.gov . Last access: December 3rd, 2022. Efficace F, Rosti G, Aaronson N, et al. Patient- versus physician-reporting of symptoms and health status in chronic myeloid leukemia. Haematologica. 2014;99:788–93. Atkinson TM, Ryan SJ, Bennett AV, et al. The association between clinician-based common terminology criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review. Support Care Cancer. 2016;24:3669–76. Di Maio M, Gallo C, Leighl NB, et al. Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials. J Clin Oncol. 2015;33:910–5. Basch E, Deal AM, Kris MG, et al. Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial. J Clin Oncol. 2016;34:557–65. Denis F, Basch E, Septans AL, et al. Two-Year Survival Comparing Web-Based Symptom Monitoring vs Routine Surveillance Following Treatment for Lung Cancer. JAMA. 2019;321:306–7. National Cancer Institute. Patient-Reported Outcomes version Of The Common Terminology Criteria For Adverse Events (PRO-CTCAE). Version 3/11/2020. Available from: https://healthcaredelivery.cancer.gov/pro-ctcae . Last access: updated December 3rd, 2022. Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst. 2014;106:1–11. Dueck AC, Mendoza TR, Mitchell SA, et al. Validity and Reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol. 2015;1:1051–9. Hagelstein V, Ortland I, Wilmer A, et al. Validation of the German patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). Ann Oncol. 2016;27:2294–9. Liu L, Suo T, Shen Y, et al. Clinicians versus patients subjective adverse events assessment: based on patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). Qual Life Res. 2020;29:3009–15. Johnson C, Aaronson N, Blazeby J. Guidelines for Developing Questionnaire Modules. 4th ed. Brussels: EORTC Quality of Life Group; 2011. Marx RG, Bombardier C, Hogg-Johnson S. How should importance and severity ratings be combined for item reduction in the development of health status instr. J Clin Epidemiol. 1999;52:193–7. Rea LMPR. Designing and conducting survey research: A comprehensive guide. 4th ed. San Francisco: Jossey-Bass; 2014. McHugh ML. The chi-square test of independence. Biochem Med (Zagreb). 2013;23:143–9. Kim HY. Statistical notes for clinical researchers: Chi-squared test and Fisher's exact test. Restor Dent Endod. 2017;42:152–5. Bennett AV, Dueck AC, Mitchell SA, et al. Mode equivalence and acceptability of tablet computer-, interactive voice response system-, and paper-based administration of the U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Health Qual Life Outcomes. 2016;14:1–12. European Organisation for Research and Treatment of Cancer. EORTC Quality of Life Questionnaires. Available from: https://qol.eortc.org/questionnaires . Last access: December 3rd, 2022. FACIT, Measures. and Languages. Available from: https://www.facit.org/measures-language-availability . Last access: December 3rd, 2022. Basch E, Abernethy AP, Mullins CD, et al. Recommendations for incorporating patient-reported outcomes into clinical comparative effectiveness research in adult oncology. J Clin Oncol. 2012;30:4249–55. Reilly CM, Bruner DW, Mitchell SA, et al. A literature synthesis of symptom prevalence and severity in persons receiving active cancer treatment. Support Care Cancer. 2013;21:1525–50. Additional Declarations No competing interests reported. Supplementary Files GuentheretalSupplementaryInformation2.docx Cite Share Download PDF Status: Published Journal Publication published 05 Jul, 2023 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Major revision 01 Jun, 2023 Reviews received at journal 23 May, 2023 Reviewers agreed at journal 22 May, 2023 Reviewers agreed at journal 08 May, 2023 Reviewers invited by journal 08 May, 2023 Editor assigned by journal 08 May, 2023 Editor invited by journal 04 May, 2023 Submission checks completed at journal 04 May, 2023 First submitted to journal 16 Apr, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2824306","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":197457302,"identity":"4efb5799-7683-469f-ae61-61beb23208bb","order_by":0,"name":"Maximilian Günther","email":"","orcid":"","institution":"University of Bonn","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maximilian","middleName":"","lastName":"Günther","suffix":""},{"id":197457303,"identity":"ef96daba-d1d3-44f6-8847-2852a074c154","order_by":1,"name":"Leopold Hentschel","email":"","orcid":"","institution":"University Hospital Carl Gustav Carus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Leopold","middleName":"","lastName":"Hentschel","suffix":""},{"id":197457306,"identity":"0bc0feff-1fbb-465b-9e27-0c2d5bfa97d1","order_by":2,"name":"Markus Schuler","email":"","orcid":"","institution":"Technical University Dresden","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Markus","middleName":"","lastName":"Schuler","suffix":""},{"id":197457307,"identity":"67af1ea6-7893-442d-a540-756a43084602","order_by":3,"name":"Theresa Müller","email":"","orcid":"","institution":"University Hospital Carl Gustav Carus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Theresa","middleName":"","lastName":"Müller","suffix":""},{"id":197457309,"identity":"f528524b-aa8f-4db1-b545-e563a7ec07c6","order_by":4,"name":"Katharina Schütte","email":"","orcid":"","institution":"University Hospital Carl Gustav 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Jaehde","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYHCCBAbGBmYGfiDrAGMDWMSAOC2SDSRoYQBrMTgAZhChBajy4YePO6zljG/kHjzAuMMmz5yBeeMDAlqSJWeeSTc2u5GXcIDxTFqxZQNbMV5rgFoSpHnbDiduu5FjcPgvkLHhAI+ZBCFbfgNV1m+ekWNwgBGixfwHAS1p0kCVCQYSCC1m+HQwSB5mSLPsbUs3nHHmjQHIL4kbDrMV43UY3/Ge5Bs/26zl+dtzjD8AQyxxw/HmjR/wWsPMk4Auglc9CLAfIKhkFIyCUTAKRjgAAJA7UN+wn/ZfAAAAAElFTkSuQmCC","orcid":"","institution":"University of Bonn","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ulrich","middleName":"","lastName":"Jaehde","suffix":""}],"badges":[],"createdAt":"2023-04-16 19:14:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2824306/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2824306/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-023-11115-7","type":"published","date":"2023-07-05T21:33:17+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":36706906,"identity":"4627e0f5-2b2d-4e01-a650-521df7a522b8","added_by":"auto","created_at":"2023-05-08 14:27:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":76491,"visible":true,"origin":"","legend":"\u003cp\u003eExample questions from the patient questionnaire (English translation)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2824306/v1/4982864892ac9bdf36900798.png"},{"id":36706907,"identity":"7620dc8f-0136-4ace-a028-9430dc904d9d","added_by":"auto","created_at":"2023-05-08 14:27:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26631,"visible":true,"origin":"","legend":"\u003cp\u003eDrug classes used in the therapy of the participating breast cancer (n = 101), multiple myeloma (n = 107) and prostate cancer (n = 66) patients\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2824306/v1/173d4e21fba950e0c259afc1.png"},{"id":44734444,"identity":"6a16bae0-6a86-4792-b2f4-cb63c349d8dd","added_by":"auto","created_at":"2023-10-16 22:18:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":691121,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2824306/v1/c5f150b8-0b00-41c6-a97d-a192df3f6539.pdf"},{"id":36707489,"identity":"eed652ca-53aa-476f-bcb4-b8dbdb2d4852","added_by":"auto","created_at":"2023-05-08 14:35:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23739,"visible":true,"origin":"","legend":"","description":"","filename":"GuentheretalSupplementaryInformation2.docx","url":"https://assets-eu.researchsquare.com/files/rs-2824306/v1/7f221964cffe645f8002db92.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Developing content-valid tumor-specific PRO-CTCAE item sets: analysis of a cross-sectional survey in three German outpatient cancer centers","fulltext":[{"header":"1 Background","content":"\u003cp\u003eIn oncology, adverse events are assessed by physicians using the Common Terminology Criteria for Adverse Events (CTCAE) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This physician-reported assessment often differs from the patients\u0026rsquo; experience. The severity of symptoms was underestimated by physicians most frequently for fatigue (51%), muscle cramps (49%), and musculoskeletal pain (42%), whereas the physicians overestimated the health status in 67% of cases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Physicians underreported symptoms of any severity in 41\u0026ndash;74% and severe symptoms in 13\u0026ndash;50% of cases [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These findings were confirmed by a systematic review concluding that the association between CTCAE and patient-reported outcomes (PRO) was poor to moderate with a large variation across studies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo address this gap between clinician- versus patient-reporting of symptoms Basch et al. conducted a randomized controlled trial. Patients in the intervention group underwent a weekly electronic monitoring of PRO symptoms with automated alerts to clinicians. Patients in the control group were treated with standard oncology care. Health-related quality of life after six months improved more and worsened less often in the intervention group. Patients who underwent the electronic PRO symptom monitoring were less frequently admitted to the emergency department or hospital and remained longer under therapy. Even the overall survival of the patients was prolonged [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Yet methodological limitations were critically discussed, these findings were affirmed by a further trial [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo complement the physician-based assessment of adverse events the United States National Cancer Institute has developed a PRO version of the CTCAE [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Out of the 790 adverse events listed in the CTCAE, 78 were considered to be appropriate to be rated directly by the patients. Plain language terms and up to three items characterizing severity, frequency, and interference with daily activities were designed for every symptomatic adverse event and refined in a cognitive interviewing study creating a library consisting of 124 items. The items were evaluated regarding their construct validity, reliability, responsiveness, and between-mode equivalence [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The PRO-CTCAE item library was translated into more than 30 languages including German [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. A German PRO-CTCAE core item set containing 31 items for patients with chemotherapy was validated by our group [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The complementary nature of PRO-CTCAE to CTCAE is illustrated by the fact that patients\u0026acute; and physicians\u0026acute; answers to PRO-CTCAE questions differ a lot. The agreement was poor and patients tended to grade symptoms more severe than physicians [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe disease symptoms and treatment options differ considerably among tumor entities. Therefore, individual symptoms have not the same relevance for all cancer patients. In order to maximize the informative value of the PRO-CTCAE questionnaire and simultaneously minimize patient burden, it seems prudent to include only a selection of items with the highest impact on the patient in a PRO-CTCAE questionnaire. The aim of this project was to identify the most relevant PRO-CTCAE items and to develop item sets with high content validity for patients with different tumor diseases. In order to cover solid tumors as well as hematological malignancies three tumor entities with different characteristics were selected for this project: breast cancer, multiple myeloma, and prostate cancer.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and participants\u003c/h2\u003e \u003cp\u003eThis project was a multicentric, cross-sectional, and non-interventional patient survey. It was conducted at the Center for Integrated Oncology (CIO) of the University Hospital in Bonn, the Johanniter Hospital in Bonn, and the National Center for Tumor Diseases (NCT/UCC) at the University Hospital in Dresden. Beside the patients\u0026acute; assessments of the prevalence and importance of therapy-associated symptoms contained in the PRO-CTCAE item library, the underlying tumor medication and disease-specific data were recorded.\u003c/p\u003e \u003cp\u003e The study was approved by the Ethics Committee of the Medical Faculty of the University of Bonn (Lfd. Nr. 405/17) and by the relevant institutions of each participating center. It was carried out in accordance with the applicable German and European legal provisions and it was performed in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eCancer patients with breast cancer, prostate cancer, and multiple myeloma of at least 18 years with an active treatment of their disease were included in the study. Patients with insufficient knowledge of the German language were excluded because all relevant documents and information were in German. A prespecified sample of 100 patients for every tumor entity should be included consecutively in the study.\u003c/p\u003e \u003cp\u003eFor recruitment, patients matching the inclusion criteria were identified by the treating physicians at the study centers and invited to participate. Patients were informed orally and in writing about the nature, significance, and scope of the patient survey and signed a written informed consent. Patients were recruited between February 2018 and April 2019 at the Center for Integrated Oncology (CIO) of the University Hospital in Bonn, the Johanniter Hospital Bonn, and the National Center for Tumor Diseases (NCT/UCC) in Dresden.\u003c/p\u003e \u003cp\u003eFor further data processing and statistical analysis of the anonymized data, Microsoft\u0026reg; Access\u0026reg; 2019 (Microsoft Corporation, Redmond, USA), Microsoft\u0026reg; Excel\u0026reg; 2019 (Microsoft Corporation, Redmond, USA), and IBM\u0026reg; SPSS\u0026reg; Statistics Version 27.0 for Windows (IBM Corporation, Armonk, USA) were used.\u003c/p\u003e \u003cp\u003eDescriptive statistics were performed for patient characteristics and medication data. As applicable, mean values with standard deviations (SD) or the median with interquartile range (IQR) were calculated. Frequencies were described as absolute number and percentage. For inductive statistics in the item-redundancy analysis, a p-value of \u0026lt;\u0026thinsp;0.05 was considered as statistically significant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Patient questionnaire\u003c/h2\u003e \u003cp\u003eThe complete PRO-CTCAE question pool with its 124 items for 78 symptoms is too extensive to be used in complete form for prevalence recording and importance assessment of the individual symptoms in a patient survey. In order to minimize the time burden for patients, a specific questionnaire was used in this project consisting of two parts.\u003c/p\u003e \u003cp\u003eIn the first part, patients were asked to answer if the 78 symptoms have ever occurred during their tumor therapy and if they think that the symptoms should be asked for in a questionnaire for patients suffering from their tumor disease. In this study the symptoms \u0026ldquo;Nail ridging\u0026rdquo; and \u0026ldquo;Nail discoloration\u0026rdquo; were condensed to one item, resulting in 77 questions in the patient questionnaire. The questions about the prevalence of the symptoms could be answered with \u0026ldquo;Yes\u0026rdquo; or \u0026ldquo;No\u0026rdquo;. The questions about the importance of the symptoms could be answered with \u0026ldquo;Yes\u0026rdquo;, \u0026ldquo;No\u0026rdquo; or \u0026ldquo;I don\u0026rsquo;t know\u0026rdquo;. This procedure was adapted from the Guidelines for Developing Questionnaire Modules of the EORTC Quality of Life Group [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. An example for how the questions in the administered questionnaire looked like is given in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe second part of the questionnaire contained questions on sociodemographic data, the characteristics of tumor disease, and tumor therapy, which are essential for the characterization of the study populations. Additional information was collected using case report forms that were filled in by health care professionals at the study centers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Item selection\u003c/h2\u003e \u003cp\u003eTo build the entity specific PRO-CTCAE item sets, the most prevalent and most important symptoms of the patient questionnaires needed to be identified. An approach based on the clinical impact method (CIM) was used for the item selection. The CIM focuses on the severity and importance of items rated by the patients and is applicable for small sample sizes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Symptom rating and ranking\u003c/h2\u003e \u003cp\u003eAccording to the CIM, patients rate the severity and the importance of the questionnaire items. The ratings are combined to the clinical impact (CI) by adding the mean importance rating per item (I) and the mean severity rating per item (S) using Eq.\u0026nbsp;1 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{C}\\text{I}=\\text{I}+\\text{S}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eEquation 1\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI: Symptom importance\u003c/p\u003e \u003cp\u003eS: Symptom severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn this study, the CIM was modified. Instead of the symptom severity, the symptom prevalence was used. The scales were scored with \u0026ldquo;Yes\u0026rdquo; = 1 and \u0026ldquo;No\u0026rdquo; = 0 for the symptom prevalence and with \u0026ldquo;Yes\u0026rdquo; = 1, \u0026ldquo;No\u0026rdquo; = 0, and \u0026ldquo;I don\u0026rsquo;t know\u0026rdquo; = 0.5 for the symptom importance. In the first step, two separate scores for the symptom prevalence and the symptom importance were calculated. Therefore, the values for every symptom were added and divided by the number of completed questionnaires to avoid distortions due to missing values. By doing so, the values of the scores displayed values between 0 and 1. The values were ranked from 1 (symptom with highest score) to 77 (symptom with lowest score). In the second step, the rankings for the symptom prevalence (1 to 77) and the symptom importance (1 to 77) were added to the combined prevalence-importance (P-I) score. According to their combined P-I score, the symptoms were then ranked from lowest to highest. The lower the combined score the higher were prevalence and importance.\u003c/p\u003e \u003cp\u003eFor item selection, the symptoms with the lowest combined P-I scores were translated into PRO-CTCAE items until a maximum of 40 PRO-CTCAE items was reached. For every PRO-CTCAE symptom, up to three items are available. The items of one symptom were not split in the selection process. The cut-off value of 40 items for the PRO-CTCAE item sets was chosen because it is considered as a not too burdensome number of questions for patients, that can be asked every seven days [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Item redundancy analysis\u003c/h2\u003e \u003cp\u003eThe symptoms for the maximum of 40 PRO-CTCAE items for each item set were investigated for inter-item correlations to reveal redundancies among the selected symptoms.\u003c/p\u003e \u003cp\u003eTo investigate the association between the symptom items, the ϕ coefficient for dichotomous variables by Pearson was used. The ϕ coefficient can take values between \u0026minus;\u0026thinsp;1 and +\u0026thinsp;1. Values around 0 indicate weak correlation. Values of \u0026plusmn;\u0026thinsp;1 indicate perfect positive or negative correlation. Values of \u0026plusmn;\u0026thinsp;0.8 or higher indicate strong correlation between two variables [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe response options for the questions on symptom prevalence (\u0026ldquo;Yes\u0026rdquo; and \u0026ldquo;No\u0026rdquo;) are dichotomous already. The response scale for the questions on symptom importance (\u0026ldquo;Yes\u0026rdquo;, \u0026ldquo;No\u0026rdquo;, and \u0026ldquo;I don\u0026rsquo;t know\u0026rdquo;) were translated to the dichotomous answers \u0026ldquo;Yes\u0026rdquo; and \u0026ldquo;not Yes\u0026rdquo; (including \u0026ldquo;No\u0026rdquo; and \u0026ldquo;I don\u0026rsquo;t know\u0026rdquo;) in the course of the item-redundancy analysis.\u003c/p\u003e \u003cp\u003ePairs of symptom items with a ϕ value of \u0026ge;\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 reveal possible redundancies. To analyze the significance of these correlations and to uncover random correlations, Fisher\u0026acute;s exact test was conducted [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study population\u003c/h2\u003e \u003cp\u003eThe sociodemographic and disease-related characteristics of the study populations are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSociodemographic and disease-related characteristics of the study populations [n (%)]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBreast cancer\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMultiple myeloma\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProstate cancer\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of patients\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e101\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e107\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e66\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStudy center\u003c/b\u003e\u003c/p\u003e \u003cp\u003eCIO Bonn\u003c/p\u003e \u003cp\u003eJohanniter Hospital Bonn\u003c/p\u003e \u003cp\u003eUniversity Hospital Dresden\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (79.2)\u003c/p\u003e \u003cp\u003e21 (20.8)\u003c/p\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (32.7)\u003c/p\u003e \u003cp\u003e12 (11.2)\u003c/p\u003e \u003cp\u003e60 (56.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (9.1)\u003c/p\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003cp\u003e60 (90.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003cp\u003e101 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (62.6)\u003c/p\u003e \u003cp\u003e40 (37.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66 (100)\u003c/p\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMedian [years]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (IQR: 16, range: 28\u0026ndash;84, mean 58.0, SD 11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (IQR: 13, range: 33\u0026ndash;83, mean: 62.0, SD: 9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76 (IQR: 8, range: 59\u0026ndash;94, mean: 74.5, SD: 6.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime since the first diagnosis of cancer\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMedian [months]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (IQR: 67, range: 1\u0026ndash;506, mean: 59, SD: 86.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (IQR: 69, range: 2\u0026ndash;255, mean: 63.7, SD: 52.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (IQR: 60, range: 1\u0026ndash;190, mean: 41.7, SD: 43.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCurrent therapy situation\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOutpatient therapy\u003c/p\u003e \u003cp\u003eInpatient therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101 (100)\u003c/p\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87 (81.3)\u003c/p\u003e \u003cp\u003e20 (18.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56 (84.9)\u003c/p\u003e \u003cp\u003e10 (15.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCurrent therapy intention\u003c/b\u003e\u003c/p\u003e \u003cp\u003eCurative\u003c/p\u003e \u003cp\u003ePalliative\u003c/p\u003e \u003cp\u003eOther/unknown\u003c/p\u003e \u003cp\u003e\u003cb\u003eTherapy sequence\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAdjuvant\u003c/p\u003e \u003cp\u003eNeoadjuvant\u003c/p\u003e \u003cp\u003eOther/unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (31.7)\u003c/p\u003e \u003cp\u003e53 (52.5)\u003c/p\u003e \u003cp\u003e16 (15.8)\u003c/p\u003e \u003cp\u003e52 (51.5)\u003c/p\u003e \u003cp\u003e23 (22.8)\u003c/p\u003e \u003cp\u003e26 (25.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (32.7)\u003c/p\u003e \u003cp\u003e68 (63.6)\u003c/p\u003e \u003cp\u003e4 (3.7)\u003c/p\u003e \u003cp\u003en.a.\u003c/p\u003e \u003cp\u003en.a.\u003c/p\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (36.4)\u003c/p\u003e \u003cp\u003e30 (45.5)\u003c/p\u003e \u003cp\u003e12 (18.2)\u003c/p\u003e \u003cp\u003e3 (4.5)\u003c/p\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003cp\u003e63 (95.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetastases\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePatients with metastases\u003c/p\u003e \u003cp\u003eNumber of metastases per patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (53.5)\u003c/p\u003e \u003cp\u003e0.9 (SD: 0.9, median: 1, IQR: 1, range: 0\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (30.3)\u003c/p\u003e \u003cp\u003e0.3 (SD: 0.5, median: 0, IQR: 1, range: 0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRelapses\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePatients with relapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (21.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (25.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (27.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003en.a. = not applicable, IQR\u0026thinsp;=\u0026thinsp;interquartile range, SD\u0026thinsp;=\u0026thinsp;standard deviation\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e53.5% (n\u0026thinsp;=\u0026thinsp;54) of the breast cancer patients had metastases. The most often occurring metastases were located in bones (n\u0026thinsp;=\u0026thinsp;34), liver (n\u0026thinsp;=\u0026thinsp;20), and lung (n\u0026thinsp;=\u0026thinsp;15). 22 patients (21.8%) had a relapse of their disease. 15 of them had only one relapse. An estrogen receptor-positive disease occurred in 65 patients (64.4%). Progesterone receptor-positive were 46 patients (45.6%) and HER2-positive 44 patients (43.6%).\u003c/p\u003e\u003cp\u003e25.2% (n\u0026thinsp;=\u0026thinsp;27) of the multiple myeloma patients had a relapse of their disease. 22 of them had only one relapse. 14 patients (13.1%) were currently undergoing autologous stem cell transplantation (SCT). 77 patients (72.0%) received at least one autologous SCT during former therapy lines.\u003c/p\u003e \u003cp\u003e30.3% (n\u0026thinsp;=\u0026thinsp;20) of the prostate cancer patients had metastases. With one exception the metastases were located in bones (n\u0026thinsp;=\u0026thinsp;20). 18 patients (27.3%) had a relapse of their disease. Most patients belonged to the high-risk Gleason grade group 5 (n\u0026thinsp;=\u0026thinsp;26, 39.4%).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThe used drug classes for the three tumor entities are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Overall, the mean number of anticancer drugs per patient was 7.7 (SD: 4.1, median: 7, IQR: 5, range 0\u0026ndash;24) in the multiple myeloma patients, followed by the breast cancer patients with a mean of 5.8 (SD: 3.4, median: 5, IQR: 4, range: 0\u0026ndash;17). The prostate cancer patients received only a mean of 1.9 (SD: 1.6, median: 2, IQR: 1, range 0\u0026ndash;7) drugs per patient.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe most used anticancer drugs in breast cancer patients were trastuzumab (n\u0026thinsp;=\u0026thinsp;91, 15.7%), cyclophosphamide (n\u0026thinsp;=\u0026thinsp;69, 11.9%), epirubicin (n\u0026thinsp;=\u0026thinsp;68, 11.7%), pertuzumab (n\u0026thinsp;=\u0026thinsp;55, 9.5%), and docetaxel (n\u0026thinsp;=\u0026thinsp;44, 7.6%). The most used drugs in multiple myeloma patients were dexamethasone (n\u0026thinsp;=\u0026thinsp;199, 24.1%), bortezomib (n\u0026thinsp;=\u0026thinsp;124, 15.0%), cyclophosphamide (n\u0026thinsp;=\u0026thinsp;113, 13.7%), melphalan (n\u0026thinsp;=\u0026thinsp;111, 13.4%), and lenalidomide (n\u0026thinsp;=\u0026thinsp;110, 13.3%). The most used drugs in prostate cancer patients were not further specified LH-RH analogs (n\u0026thinsp;=\u0026thinsp;32, 25.4%), bicalutamide (n\u0026thinsp;=\u0026thinsp;24, 19.1%), leuprorelin (n\u0026thinsp;=\u0026thinsp;23, 18.3%), degarelix (n\u0026thinsp;=\u0026thinsp;12, 9.5%), and abiraterone acetate (n\u0026thinsp;=\u0026thinsp;10, 7.9%).\u003c/p\u003e \u003cp\u003eBreast cancer patients were treated for a mean of 1.7 indications for supportive care (SD: 1.7, median: 1, IQR: 1, range: 0\u0026ndash;6). They received most frequently care for nausea and emesis (n\u0026thinsp;=\u0026thinsp;41, 24.3%), bone complications (n\u0026thinsp;=\u0026thinsp;40, 23.7%), and gastric ulcer prophylaxis (n\u0026thinsp;=\u0026thinsp;18, 10.7%). Multiple myeloma patients were treated also for a mean of 1.7 supportive care indications (SD: 1.5, median: 1, IQR: 2, range: 0\u0026ndash;6), most frequently for bone complications (n\u0026thinsp;=\u0026thinsp;48, 26.5%), gastric ulcer prophylaxis (n\u0026thinsp;=\u0026thinsp;43, 23.8%), and pain (n\u0026thinsp;=\u0026thinsp;34, 18.8%). Prostate cancer patients were only treated for a mean of 0.4 supportive care indications (SD: 0.9, median: 0, IQR: 0, range: 0\u0026ndash;4), the most frequently for bone complications (n\u0026thinsp;=\u0026thinsp;7, 25.9%), gastric ulcer prophylaxis (n\u0026thinsp;=\u0026thinsp;6, 22.2%), and pain (n\u0026thinsp;=\u0026thinsp;5, 18.5%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Completion of questionnaires\u003c/h2\u003e \u003cp\u003eMissing values occurred if patients did not answer a question at all or not clear enough by marking an answer on the paper-based questionnaires. Within the 101 questionnaires filled in by the breast cancer patients, the questions regarding the prevalence of the symptoms were not answered in 2.2% of cases (mean number of cases 2.2, SD 3.17, range 0\u0026ndash;16). The questions about the importance of the symptoms were not answered in 4.2% of cases (mean number of cases 4.2, SD 1.52, range 1\u0026ndash;10). For the 107 questionnaires of the multiple myeloma patients, the missing values amount to 0.8% of cases (mean number of cases 0.9, SD 1.38, range 0\u0026ndash;6) for the prevalence questions and 1.6% of cases (mean number of cases 1.7, SD 1.29, range 0\u0026ndash;6) for the importance questions. For the 66 questionnaires of the prostate cancer patients, the missing values amount to 0.2% of cases (mean number of cases 0.1, SD 0.31, range 0\u0026ndash;1) for the prevalence questions and 5.6% of cases (mean number of cases 3.7, SD 1.77, range 1\u0026ndash;7) for the importance questions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Symptom rating\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e3.3.1 Breast cancer\u003c/h2\u003e \u003cp\u003eThe 101 participating breast cancer patients experienced a median of 27 symptoms each (IRQ 31, range 4\u0026ndash;53). The symptom that occurred most often was \u0026ldquo;Hair loss\u0026rdquo; (Number 24) in 86 patients. A median of 46 symptoms per patient (IQR 36, range 0\u0026ndash;75) was rated important.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e3.3.2 Multiple myeloma\u003c/h2\u003e \u003cp\u003eThe 107 participating multiple myeloma patients experienced a median of 28 symptoms each (IRQ 14, range 7\u0026ndash;61). The symptom that occurred most often was \u0026ldquo;Fatigue\u0026rdquo; (Number 52) in 92 patients. A median of 48 symptoms per patient (IQR 32, range 0\u0026ndash;75) was rated important.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.3.3 Prostate cancer\u003c/h2\u003e \u003cp\u003eThe 66 participating prostate cancer patients experienced a median of 20 symptoms each (IRQ 13, range 4\u0026ndash;51). The symptom that occurred most often was \u0026ldquo;Achieve and maintain erection\u0026rdquo; (Number 64) in 59 patients. A median of 46 symptoms per patient (IQR 26, range 0\u0026ndash;72) was rated important.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Symptom ranking and item set compilation\u003c/h2\u003e \u003cp\u003eFor each of the three tumor diseases, the symptoms were ranked according to their combined prevalence-importance (P-I) score. Then, the symptoms with the lowest scores indicating high prevalence and importance for the respective tumor disease were compiled to an item set until a maximum of 40 PRO-CTCAE items was reached. The final PRO-CTCAE item set for breast cancer included 39 items related to 21 symptoms, for multiple myeloma 39 items related to 19 symptoms, and for prostate cancer 40 items related to 19 symptoms, respectively. A comparison of the three tumor disease-specific PRO-CTCAE item sets ranked by their combined P-I scores is shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The three individual PRO-CTCAE item sets are shown in the Supplementary Information.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of the tumor entity-specific PRO-CTCAE item sets according to the combined prevalence-importance (P-I) scores of the symptoms\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast cancer\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombined P-I score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMultiple myeloma\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCombined P-I score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eProstate cancer\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCombined P-I score\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFatigue\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInsomnia\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumbness and tingling\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNumbness and tingling\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eUrinary frequency\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGeneral pain\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eAchieve and maintain erection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle pain\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInsomnia\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eUrinary incontinence\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsomnia\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNausea\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eEjaculation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHair loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eShortness of breath\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFatigue\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJoint pain\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHair loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eUrinary urgency\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlurred vision\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJoint pain\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eUnable to have orgasm\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcentration\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDiarrhea\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eJoint pain\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral pain\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMuscle pain\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAnxious\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnxious\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eDecreased libido\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConstipation\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eDecreased appetite\u003c/b\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGeneral pain\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTaste changes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSwelling\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eHot flashes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDizziness\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDizziness\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSwelling\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShortness of breath\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHeart palpitations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eShortness of breath\u003csup\u003e#\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart palpitations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eConcentration\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eSad\u003c/b\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMemory\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eConstipation\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMuscle pain\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSwelling\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTaste changes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003ePainful urination\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRash\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eMouth/throat sores\u003c/b\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDizziness\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNail ridging\u003c/b\u003e\u003csup\u003e\u003cb\u003e+\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNail discoloration\u003c/b\u003e\u003csup\u003e\u003cb\u003e+\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cem\u003e#\u003c/em\u003e\u003c/sup\u003e: \u003cem\u003ePart of all three PRO-CTCAE item sets;\u003c/em\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eBOLD\u003c/span\u003e: \u003cem\u003ePart of only one PRO-CTCAE item set; \u0026sect;: Part of the PRO-CTCAE core item set; +: Symptoms were combined in the patient questionnaire\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eEight symptoms are included in all three item sets. The symptoms with the highest rankings across the item sets were \u0026ldquo;Fatigue\u0026rdquo; and \u0026ldquo;Insomnia\u0026rdquo;. Symptoms with the highest rankings included in only one item set were symptoms affecting the urogenital system in the prostate cancer item set, \u0026ldquo;Blurred vision\u0026rdquo; in the breast cancer item set and \u0026ldquo;Decreased appetite\u0026rdquo; in the multiple myeloma item set.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Item redundancy analysis\u003c/h2\u003e \u003cp\u003eFor the prevalence of symptoms, high correlations with a ϕ coefficient of 0.8 or higher did not appear throughout the three tumor entities. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the ϕ coefficients for the correlations of the symptom prevalence.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSymptom prevalence in breast cancer (n\u0026thinsp;=\u0026thinsp;101), multiple myeloma (n\u0026thinsp;=\u0026thinsp;107) and prostate cancer patients (n\u0026thinsp;=\u0026thinsp;66), correlations with a φ coefficient\u0026thinsp;\u0026ge;\u0026thinsp;0.5\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptoms\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eϕ coefficient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFisher\u0026acute;s exact test\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBreast cancer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral pain (46) and Joint pain (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle pain (48) and Joint pain (49)\u003c/p\u003e \u003cp\u003eGeneral pain (46) and Muscle pain (48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultiple myeloma\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle pain (48) and Joint pain (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eProstate cancer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased libido (60) and Delayed orgasm (61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased libido (60) and Achieve and maintain erection (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAchieve and maintain erection (64) and Ejaculation (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003e* p\u0026thinsp;\u0026lt;\u0026thinsp;0.05: statistically significant\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFor the importance of symptoms, high correlations with a ϕ coefficient of 0.8 or higher were observed (see Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Compared to the other tumor entities, prostate cancer symptom importance shows the greatest number of high ϕ values. Three symptom clusters with possibly redundant symptom pairs were detected for which redundancy is pathophysiologically highly plausible: sexual, hormonally-related and urogenital symptoms.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSymptom importance in breast cancer (n\u0026thinsp;=\u0026thinsp;101), multiple myeloma (n\u0026thinsp;=\u0026thinsp;107) and prostate cancer patients (n\u0026thinsp;=\u0026thinsp;66), correlations with a φ coefficient\u0026thinsp;\u0026ge;\u0026thinsp;0.8\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptoms\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eϕ coefficient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFisher\u0026acute;s exact test\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBreast cancer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMemory (39) and Concentration (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle pain (48) and Joint pain (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultiple myeloma\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSwelling (35) and Heart palpitations (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eProstate cancer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral pain (46) and Joint pain (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle pain (48) and Joint pain (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnxious (50) and Fatigue (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePainful urination (55) and Urinary urgency (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePainful urination (55) and Urinary frequency (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePainful urination (55) and Urinary incontinence (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary urgency (56) and Urinary incontinence (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased libido (60) and Delayed orgasm (61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased libido (60) and Achieve and maintain erection (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased libido (60) and Ejaculation (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelayed orgasm (61) and Achieve and maintain erection (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelayed orgasm (61) and Ejaculation (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAchieve and maintain erection (64) and Ejaculation (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003e* p\u0026thinsp;\u0026lt;\u0026thinsp;0.05: statistically significant\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThe aim of this project was to develop PRO-CTCAE item sets with high content validity for three different cancer types. The EORTC guidelines for developing questionnaire modules include four phases of the development process: 1. Generation of relevant PRO issues, 2. Converting the PRO issues into an item set, 3. Pre-testing of the item set and 4. Large-scale international field testing [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile developing the PRO-CTCAE item library by the US National Cancer Institute, the above-mentioned steps have already been taken for the item library in general. From the CTCAE catalogue containing 790 adverse events, 78 symptomatic adverse events that are relevant for cancer patients in general, were derived (Phase 1). Plain language terms and up to three items were designed for every symptomatic adverse event and refined in a cognitive interviewing study (Phase 2). The items were evaluated regarding their construct validity, reliability, responsiveness, and between-mode equivalence (Phase 3 and 4) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite being a valid PRO instrument in general, the complete PRO-CTCAE question pool with 124 items is too extensive to be administered in total. This circumstance raises the question which symptoms are relevant to patients with different cancer types. The question refers to phase 1 of the development process in which the foundation for high content validity of the PRO tool is laid. For compiling the relevant PRO issues three sources should be used: literature, patients, and healthcare professionals. Since PRO-CTCAE is a well-characterized instrument for detecting symptomatic adverse events, and it is known that the physician-reported assessment often differs from the patients\u0026rsquo; experience [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], the patient perspective was chosen over the perspective of healthcare professionals. This is also encouraged by the EORTC guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Therefore, a questionnaire-based patient survey on the prevalence and importance of the symptoms was conducted. Nevertheless, a physician-based approach could be an adequate comprehensive method for future research.\u003c/p\u003e \u003cp\u003eThe goal of item selection was to reduce the number of items for the entity-specific PRO-CTCAE item sets to a maximum of 40. The EORTC QLQ-C30 (30 items) plus entity-specific modules like QLQ-MY20 (multiple myeloma, 20 items), QLQ-BR23 (breast cancer, 23 items) or QLQ-PR25 (prostate cancer, 25 items) contain about 50 items in total [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The Functional Assessment of Cancer Therapy (FACT) questionnaires of the FACIT group consist of 27 items for the FACT-G (general) questionnaire, 37 items for the FACT-B (breast cancer), 41 items for the FACT-MM (multiple myeloma) and 39 items for FACT-P (prostate cancer) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Whereas these instruments cover a broad range of domains of health-related quality of life, PRO-CTCAE focuses on symptomatic toxicities only. In general, it is recommended that the answering of a PRO questionnaire should be limited to 10 to 15 minutes or less if the questionnaire is administered repeatedly to minimize the response burden for patients [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Answering a 28-item PRO-CTCAE questionnaire takes four to six minutes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Therefore, a number of 40 items was chosen as a cut-off because it is considered as a not too burdensome number of questions.\u003c/p\u003e \u003cp\u003eComparing the three tumor entity-specific PRO-CTCAE item sets, some symptoms appear in all three item sets. This is not surprising since fatigue as a multifactorial syndrome is the most frequently observed symptom across most malignant diseases, which is also the case for mood-related symptoms like insomnia and pain-related symptoms [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In particular, the breast cancer and multiple myeloma PRO-CTCAE item set have 16 symptoms in common. Nevertheless, both item sets differ from the German PRO-CTCAE core item set that was designed and validated for patients under chemotherapy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Of the 16 symptoms included in the PRO-CTCAE core item set, nine are included in the breast cancer item set, and 12 are included in the multiple myeloma item set. The PRO-CTCAE prostate cancer set shares six symptoms with the core item set.\u003c/p\u003e \u003cp\u003eThe item redundancy analysis for the prevalence and importance of the symptoms revealed some possible redundancies. High inter-item correlations that could indicate a redundancy of symptoms appear more often in relation to the importance of the symptoms compared to their prevalence. This difference may be explained by the fact that the question on importance also applies to symptoms that do not likely occur during the patients\u0026rsquo; therapy but are nevertheless important according to their perception.\u003c/p\u003e \u003cp\u003eEspecially pathophysiologically plausible symptom pairs that showed possible redundancies for prevalence and importance, like the pain-related symptoms of the breast cancer patients and the cluster of sexual and hormonally-related symptoms of the prostate cancer patients, might be candidates for exclusion from the PRO-CTCAE item sets. The final decision might be taken in a validation study of the item sets determining their psychometric quality criteria reliability and construct validity, as it was conducted for the PRO-CTCAE core item set [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In terms of measuring the reliability of a questionnaire, internal consistency can be determined using Cronbach\u0026acute;s alpha. To evaluate which items negatively influence the reliability of a scale, Alpha-if-item-deleted values can be calculated.\u003c/p\u003e \u003cp\u003eThe tumor disease-specific PRO-CTCAE item sets for breast cancer, multiple myeloma, and prostate cancer are designed to be valid for all patients of the respective tumor entity. Patients are treated in very different ways according to their stages of disease and clinical situation, leading to the importance of developing PRO-CTCAE item sets for different therapy situations within one tumor entity. In the future new therapy options can change the symptom patterns of the cancer diseases. Therefore, the patient survey should be repeated if significant changes in treatment are introduced to maintain content validity of the item sets.\u003c/p\u003e"},{"header":"5 Conclusions","content":"\u003cp\u003eBased on patient-reported differences in symptom pattern and perception, specific PRO-CTCAE item sets with high content validity were developed for breast cancer, multiple myeloma, and prostate cancer. In order to validate the quality and psychometric criteria of the new item sets further studies are required.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate \u0026ndash; The study was approved by the Ethics Committee of the Medical Faculty of the University of Bonn (Lfd. Nr. 405/17) and the relevant institutions of each participating center. It was carried out in accordance with the applicable German and European legal provisions and performed in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003eConsent for publication \u0026ndash; Consent for publication is not applicable. Only anonymized data are published.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials \u0026ndash; The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests \u0026ndash; Maximilian G\u0026uuml;nther, Leopold Hentschel, Markus Schuler, Theresa M\u0026uuml;ller, Katharina Sch\u0026uuml;tte, Yon-Dschun Ko, Ingo Schmidt-Wolf, and Ulrich Jaehde declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding \u0026ndash; No funding was received to conduct the study and assist with the preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions \u0026ndash; All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Maximilian G\u0026uuml;nther, Leopold Hentschel, Theresa M\u0026uuml;ller, and Katharina Sch\u0026uuml;tte. The first draft of the manuscript was written by Maximilian G\u0026uuml;nther and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003cstrong\u003e\u0026nbsp;\u0026ndash;\u0026nbsp;\u003c/strong\u003eThe CIO Bonn is kindly supported by the Deutsche Krebshilfe, Bonn, Germany. Especially, we express our gratitude to all patients who participated in our project despite their challenging situation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNational Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0 from 27/11/2017. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ctep.cancer.gov\u003c/span\u003e\u003cspan address=\"https://ctep.cancer.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Last access: December 3rd, 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEfficace F, Rosti G, Aaronson N, et al. Patient- versus physician-reporting of symptoms and health status in chronic myeloid leukemia. Haematologica. 2014;99:788\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtkinson TM, Ryan SJ, Bennett AV, et al. The association between clinician-based common terminology criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review. Support Care Cancer. 2016;24:3669\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDi Maio M, Gallo C, Leighl NB, et al. Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials. J Clin Oncol. 2015;33:910\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasch E, Deal AM, Kris MG, et al. Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial. J Clin Oncol. 2016;34:557\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDenis F, Basch E, Septans AL, et al. Two-Year Survival Comparing Web-Based Symptom Monitoring vs Routine Surveillance Following Treatment for Lung Cancer. JAMA. 2019;321:306\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Cancer Institute. Patient-Reported Outcomes version Of The Common Terminology Criteria For Adverse Events (PRO-CTCAE). Version 3/11/2020. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://healthcaredelivery.cancer.gov/pro-ctcae\u003c/span\u003e\u003cspan address=\"https://healthcaredelivery.cancer.gov/pro-ctcae\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Last access: updated December 3rd, 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst. 2014;106:1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDueck AC, Mendoza TR, Mitchell SA, et al. Validity and Reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol. 2015;1:1051\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHagelstein V, Ortland I, Wilmer A, et al. Validation of the German patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). Ann Oncol. 2016;27:2294\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu L, Suo T, Shen Y, et al. Clinicians versus patients subjective adverse events assessment: based on patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). Qual Life Res. 2020;29:3009\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson C, Aaronson N, Blazeby J. Guidelines for Developing Questionnaire Modules. 4th ed. Brussels: EORTC Quality of Life Group; 2011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarx RG, Bombardier C, Hogg-Johnson S. How should importance and severity ratings be combined for item reduction in the development of health status instr. J Clin Epidemiol. 1999;52:193\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRea LMPR. Designing and conducting survey research: A comprehensive guide. 4th ed. San Francisco: Jossey-Bass; 2014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcHugh ML. The chi-square test of independence. Biochem Med (Zagreb). 2013;23:143\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim HY. Statistical notes for clinical researchers: Chi-squared test and Fisher's exact test. Restor Dent Endod. 2017;42:152\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBennett AV, Dueck AC, Mitchell SA, et al. Mode equivalence and acceptability of tablet computer-, interactive voice response system-, and paper-based administration of the U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Health Qual Life Outcomes. 2016;14:1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Organisation for Research and Treatment of Cancer. EORTC Quality of Life Questionnaires. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://qol.eortc.org/questionnaires\u003c/span\u003e\u003cspan address=\"https://qol.eortc.org/questionnaires\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Last access: December 3rd, 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFACIT, Measures. and Languages. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.facit.org/measures-language-availability\u003c/span\u003e\u003cspan address=\"https://www.facit.org/measures-language-availability\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Last access: December 3rd, 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasch E, Abernethy AP, Mullins CD, et al. Recommendations for incorporating patient-reported outcomes into clinical comparative effectiveness research in adult oncology. J Clin Oncol. 2012;30:4249\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReilly CM, Bruner DW, Mitchell SA, et al. A literature synthesis of symptom prevalence and severity in persons receiving active cancer treatment. Support Care Cancer. 2013;21:1525\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2824306/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2824306/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo include the patient perspective in the assessment of adverse events (AE) in oncology, a patient-reported outcomes (PRO) version of the Common Terminology Criteria for Adverse Events (CTCAE) was developed by the NCI, the so called PRO-CTCAE. The objective of this study was the development of disease-specific PRO-CTCAE item sets with high content validity for patients with breast cancer (BC), multiple myeloma (MM) and prostate cancer (PC).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA cross-sectional survey was conducted at three German outpatient cancer centers. Prevalence and importance of the 78 PRO-CTCAE symptoms were assessed using a patient questionnaire. To select the most relevant PRO-CTCAE items for each tumor entity, symptoms were ranked based on patient answers.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e 101 patients with BC, 107 with MM, and 66 with PC participated. The final item sets contained 21 symptoms (BC) or 19 symptoms (MM and PC), respectively. Eight symptoms were represented in all three item sets. Fatigue was the symptom with the highest ranking across item sets followed by sleep disorders. Symptoms with the highest rankings represented in only one item set were symptoms affecting the urogenital system in the PC item set, blurred vision in the BC item set and appetite loss in the MM item set.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIndividual PRO-CTCAE item sets with high content validity were developed for three tumor diseases on the basis of patient-reported symptom patterns and perceptions. The quality and psychometric criteria of the newly compiled item sets should be further validated.\u003c/p\u003e","manuscriptTitle":"Developing content-valid tumor-specific PRO-CTCAE item sets: analysis of a cross-sectional survey in three German outpatient cancer centers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-05-08 14:27:46","doi":"10.21203/rs.3.rs-2824306/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-06-01T05:21:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-05-23T10:04:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"592769a2-a848-4590-9576-ef98af3170e5","date":"2023-05-22T12:41:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"12a7865a-2d9c-4839-ab38-1cb7d1bbac25","date":"2023-05-08T08:44:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-05-08T08:22:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-05-08T08:19:48+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-05-04T10:06:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-05-04T10:03:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2023-04-16T19:11:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a2d6480d-7fb4-4d8e-94db-06a9fe9d2f7f","owner":[],"postedDate":"May 8th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T21:59:48+00:00","versionOfRecord":{"articleIdentity":"rs-2824306","link":"https://doi.org/10.1186/s12885-023-11115-7","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2023-07-05 21:33:17","publishedOnDateReadable":"July 5th, 2023"},"versionCreatedAt":"2023-05-08 14:27:46","video":"","vorDoi":"10.1186/s12885-023-11115-7","vorDoiUrl":"https://doi.org/10.1186/s12885-023-11115-7","workflowStages":[]},"version":"v1","identity":"rs-2824306","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2824306","identity":"rs-2824306","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}