The Markers of Constipation in Palliative Care Cancer Patients: A Multicenter Cohort Study

Background There allows only for a short time of observation before diagnosis. Apart from the patient’s subjective perception, it should include the objective (measurable) symptoms, as a significant portion of patients is unable to express their subjective assessment. The aim of this study was to verify what is the correlation between the objective and subjective symptoms of constipation and what values are diagnostic to constipation in adult palliative care cancer patients. Methods A multicenter cohort study was performed. Results 547 adult cancer patients were routinely assessed by physicians in 12 in-patient, home, and ambulatory palliative care centers. 369 patients met the inclusion criteria. The time since the last spontaneous bowel movements and their frequency were correlated with the subjective measures: the difficulty of defecation, the Bowel Function Index, and the necessity to use laxatives. The difficulty of defecation was moderate to the extreme when the time since the last spontaneous bowel movements was ≥2 days or a frequency of spontaneous bowel movements was <4 per week. subjective <4

3 constipation comes down to two aspects: 1) objective (measurable) symptoms, such as the frequency of defecation, and 2) the patient's subjective perception, which reflects the level of their discomfort and changes in bowel movements (BM) pattern. In one multi-center study, constipation varied even 6fold, from 7%, if diagnosed medically only, to 43%, when patient's reporting was also considered [2].
In other research studies, constipation was diagnosed as a judgment of a clinician, without specific diagnostic criteria, or diagnosed without its clear definition. Definitions used in research are diverse and incompatible with each other [4]. Apart from that, 50% of patients understand constipation in a different way from their physicians, and the physician ought to ensure that this misunderstanding is avoided [5,6].
In one study, 42.4% of patients at the time of referral to palliative care had disturbed bowel scores over zero value in a numeric rating scale (NRS) [0-10] [7]. The values 1-3 usually refer to constipation of mild intensity [8]. However, not all deviations from zero may automatically mean constipation, particularly if the scale is based on unidimensional judgment. It is necessary to find a discriminating cut-off value. Otherwise, constipation would be overdiagnosed. For instance, the Bowel Function Index [0-100] (BFI) discriminates constipated from non-constipated patients at ≥28.8 value with 95% confidence [9]. With this cut-off value, constipation was diagnosed in 66.3% of patients at admission [3].
Any deviation, even mild, from the patient's normal pattern of bowel movements, may lead to but does not necessarily mean constipation. Constipation is difficult to treat in palliative care patients, and once it develops, it deteriorates health-related quality of life and the effectiveness of symptomatic therapy and is associated with incremental costs, and that is why if the intensity of the patient-reported perception of the symptom is moderate or higher, a diagnosis is sure, and a clinician should undertake appropriate measures [10,11].
There is no widely accepted definition of constipation in palliative care patients despite its high prevalence. The review of the definitions of constipation used in the research revealed that there is no single set of diagnostic criteria, and different combinations of patient-reported and objective measures were identified instead [4]. What's more, only one out of 20 identified definitions of 4 constipation in that review included a patient's self-assessment as the main reason to diagnose constipation, which stands in contrast with the subjective nature of the symptom [4]. Bearing in mind that quality of life is the main aim of palliative care, the patient-reported assessment should be superior to the frequency of bowel movements, or at least equally important, as it reflects a patient's health-related quality of life.
Opioid-induced constipation (OIC) is a frequent problem in palliative care. The Rome Criteria IV definition of OIC was not validated among the palliative care patients and might be used only in patients with a long expectancy of life, as it requires the observation of several acts of defecation [12]. Most of the definitions of constipation used in palliative care refer to a reasonably shorter period of observation (7 or 14 days).
Taking all the above into consideration, there is a need for some tangible metrics that would be helpful in the decision-making process on laxative intervention or augmentation of preventive measures. The tool should be easy to use, fast, based on short history (i.e., recent 7 days), and include a patient's assessment if possible, as to allow for a quick clinical reaction. Not only the diagnosis of constipation but also the severity of its symptoms should be comprised. This study aims to verify the following clinical questions:

1.
In adult palliative care cancer patients, what is the correlation between the objective criteria of constipation (frequency of SBM, days since the last SBM) and the patientreported assessment of constipation (difficulty of defecation, the necessity of laxatives)?

2.
What values of the objective criteria are diagnostic to constipation defined as moderately to severely disturbed ease of defecation in adult palliative care cancer patients?

Data
The data come from two multi-center observational cohort studies that were performed in adult palliative care patients in 2010-11 (Study 1) [13] and 2018-19 (Study 2) [14]. The same structured questionnaire and the same methodology of data collection were used in both studies to allow for combined analysis and attain a balanced representation of in-patient and out-patient patients.
The questionnaires in both studies included the same items: 1. Demographic data.

5.
The medications used in the last 7 days.
For any symptom/metrics, an intensity value of ≥2 (moderate or higher) was regarded as pathognomonic (diagnostic).

Eligibility criteria
For the analysis there were qualified palliative care patients aged ≥18 years with malignancy, excluding colostomy, diarrhea, bowel obstruction, and the use of prokinetics or peripherally acting mu-opioid receptor antagonists used before or during the observation period.

Statistical analysis
Frequency analysis was performed using the Chi-square exact test. For non-parametric data, the Mann-Whitney U test was applied. The correlation between non-parametric (ordinal numeric) measures was tested with Spearman's rank coefficient. P values less than 0.05 were considered statistically significant. Whenever possible, the exact P-value has been presented.
The analysis was performed in Statistica 13.3 (TIBCO Software Inc.). 7

Results
Structured data sets were collected from 547 patients (286 from Study 1 and 261 from Study 2) in 12 centers across Poland. 369 patients were eligible for further analysis.

Demographics
The demographic data are presented in Table 1 There was a positive correlation between ECOG performance status and age. The older the patient, the worse status was.
61% of all patients received strong opioids, and the mean oral morphine equivalent of opioids (OME) was 99 mg/day. The differences between the study groups were statistically significant. 56% of patients in Study 1 received strong opioids, and the mean OME was 87 mg/day (median 60), while 71% of patients in Study 2 were treated with opioids, and the mean OME was 113 mg/day (median 95), p = 0.004.
Diet modification to ease bowel movements was implemented in approximately 45% of patients. The same proportion of patients had used oral laxatives in the last seven days. 29% used suppositories (bisacodyl, glycerol, or both). Referring to interventional procedures,12% of patients received an enema, and in 5% of patients, manual stool evacuation was performed.

The cut-offs for objective criteria for moderate to the severe difficulty of defecation
There is a linear relationship between the difficulty of defecation and mean frequency of SBM, days since last SBM, and the necessity of laxatives ( Figure 2). On average, patients assessed the difficulty of defecation as moderately disturbed when the time since the last SBM was 2 days. A frequency of SBM 3 per week was associated with the mild to moderate difficulty of defecation, and if it was <3 per week, the difficulty of defecation became severe (mean > 2.71 (95% CI 2.62-2.81).
Any necessity of laxatives was associated with the worsening of ease of defecation. When laxatives were used often (2 in [0-4] scale), the difficulty of defecation ranged from moderate to significant.

Opioid-induced constipation
There were no statistically significant differences for any results between subgroups of patients treated with opioid analgesics and not taking the opioids.

Discussion
Main findings/results of the study 9 The study was performed in 12 centers in all forms of palliative care: out-patient palliative clinics, home care, and in-patient hospices. Thus, a balanced representation of end-stage cancer patients regarding sex, age, primary tumor diagnosis, and performance status was attained. After scrutinous data quality checks, 178 (33%) cases were withdrawn.
In both study groups, patients were treated with laxatives in a similar way. What is interesting, in Study 2, which was conducted roughly eight years later than Study 1, more patients (71% vs. 56%) were treated with strong opioids, and the mean dose was higher. This likely reflects the tendency of improving access to opioid analgesics in Poland [16].
The main finding of this study is that patient-reported and objective criteria of constipation are highly correlated with each other and equally indicate constipation. In our opinion, subjective judgment (i.e., With the assumption that the intensity of a symptom of constipation scored 2 (moderate) or higher is diagnostic, a clinician should diagnose constipation and implement appropriate modifications of the laxative management in any of the following cases: distinguish. The other problem was with the translation of "ease of defecation" as more natural to the Polish language is "difficulty of defecation" [13]. In the light of that fact and the results of this study, a simple question on the difficulty of defecation alone seems sufficient for the assessment of subjective aspects of constipation and equally effective to BFI with high certainty. Another observation during a pilot phase of Study 1 was that the numeric analog scale [0-100] for BFI was too difficult to understand for many patients. Simplifying it to a numeric rating scale [0-10] improved their ability to respond, which was reported in other review papers as well [17]. In conclusion, simpler Likert-style scales, like [0-4] with definitions assigned to the numbers (i.e., 0 -no symptom, 1 -mild, 2 -moderate, 3 -severe/often, 4 -extreme/always) should be used in everyday practice. And such an approach was applied in further research and in this study. Apart from that, I believe that the metrics used in research should be easy to use, repetitive, and useful in daily practice. Both PAC-SYM and BFI appeared too complex or too time-consuming for practitioners involved in the study, and none of the assessing physicians continued using these on a regular basis after the study.

Strengths and weaknesses/limitations of the study
The strength of this study is a large number of patients and a balanced representation of in-patient, home, and ambulatory palliative care patients, which allowed for statistically significant conclusions.
The assessing physicians did not participate in research, and all questionnaires were filled-in as a part of a clinician's job, so the potential bias is negligible. The failure in the validation of BFI should also be regarded as a limitation of the study, although it revealed the real importance of its particular 11 elements. The ECOG scale for the assessment of general status was used instead of a more precise one, i.e., Palliative Performance Status, or Karnofsky Score, but they are not validated for the Polish language yet.

Conclusions
A definition of constipation in palliative care should consist of both objective and patient-reported measures, based on a reasonably short period of observation, i.e., 7 days; however, if at least one of them reaches or overpasses the cut-off value, constipation should be diagnosed, and the laxative treatment modified. An algorithm for the diagnosis of constipation in palliative care patients for further validation is presented in Figure 3.

Funding
The study was performed without external funding.

Conflict of interest/Competing interests
The Author declares that there is no conflict of interests.

Ethics approval
The Ethical Committee of the Maria Sklodowska-Curie Institute -Oncology Center in Warsaw

Consent to participate
Not applicable

Consent for publication
Not applicable

Availability of data and material
Combined data in .csf or .xlsx files can be obtained upon direct request to the corresponding author for verification process or academic purposes.

Code availability
Statistica 13.3 (TIBCO Software Inc.)   Figure 1 Mean values of symptoms of constipation (± SD) Figure 2 The difficulty of defecation versus A. last SBM, B. frequency of SBM, C. necessity of laxatives (SBM -spontaneous bowel movements).

Authors contribution
18 Figure 3 The proposed algorithm for the diagnosing of constipation.