Laparoscopic Prostatectomy Robot Open (LAPPRO) is an ongoing open, controlled and non-randomized prospective longitudinal trial comparing open retropubic and robot-assisted laparoscopic radical prostatectomy for localized prostate cancer at 14 centers in Sweden. The trial has been previously described in detail [27]. Patient scheduled for prostatectomy at the participating centers fulfilling the inclusion criteria (informed consent, age < 75 yr., ability to read and write Swedish, tumour stage cT1, cT2, or cT3 (TNM Classification of Malignant Tumors, [28]) with no signs of distant metastases, and a prostate-specific antigen level of < 20 ng/ml) were included.
Information was collected at 6–12 weeks, 12 and 24 months postoperatively both from case report forms by study personnel (either the operating urologist or clinical nurses) and from questionnaires filled out by the patients with regard to the following five outcomes: 1. swelling of groin or lower extremities, 2. complications and re-admissions, 3. re-operations, 4. added pharmacological therapy after surgery or due to local or distant recurrence and 5. local recurrence and metastases, see Fig. 1.
The questionnaires were based on concepts introduced in previous research projects [11, 29] and were content validated by experts in the field of urology and then face validated face with patients with prostate cancer. The case report forms were face validated with professional caregivers. The case report forms and questionnaires were further tested in a pilot study, after which final revisions were made [27]. The different questions in the case report forms and the questionnaires are presented in Supplement 1.
Definition of outcomes and predictors
In the derivation of the outcome variables a broad approach was used with binary outcomes where the presence (positive) or absence (negative) of at least one occurrence of interest, for example a readmission, was required to be reported in both sources (case report form and questionnaire) to reach agreement. A higher level of similarity, for example the exact number of readmissions, was not required. The reason is that the recall of the patient and the case report form may not refer to exactly the same time period. The derived outcomes can hence be grouped according to concordant (positive/positive or negative/negative) and discordant (positive/negative or negative/positive) pairs.
When the recall of the patient and the case report form refer to the same time period a higher agreement is more likely compared to when there is no defined time period. However, in the study the personnel did to some extent complete the clinical record form retrospectively by investigating medical records. Therefore the time period cannot be accurately assed and is not used in the analysis. Lastly, the events studied here were anticipated to have relatively low incidence.
Swelling of groin or lower extremities
At 6–12 weeks follow-up the case report form addressed signs of swelling (lymph oedema) in groin (left or right side) and lower extremities (left or right) with response categories “Yes”/“No”. At 3 months the questionnaire addressed feeling of swelling and heaviness in (left or right) groin or leg and heaviness in legs. A positive outcome was defined as “Yes” on at least one of the questions. A negative outcome was defined as responding No on all the questions. Otherwise the outcome was set to missing.
Complications, readmissions and reoperations
The case report form collected information on complications related to surgery, complications occurring after 6–12 weeks, and if the patient had been re-admitted to hospital for other reasons than cancer treatment later than the 12 month follow-up. At 3, 12 and 24 months the questionnaire included a question on whether the patient had contacted healthcare for a specified list of reasons. If any reason included pain from the surgical wound, lower or upper part of abdomen, bleeding from surgical wound, urinary tract or catheter it was defined as an event. There was also a question on whether that patient had been readmitted to hospital. For the questionnaire, a positive outcome was defined as responding “Yes” on any of the questions. For the case report form positive and negative outcome was defined as responding “Yes” and “No”, respectively. Responding “No information” and a non-response outcome were defined as missing.
At 12 and 24 months the case report form addressed whether the patients had been re-operated after 6–12 weeks and 12 months follow-up, respectively. The questionnaire addressed if the patient had been operation during the last 12 months. For both the case report form and the questionnaire a positive and negative outcome was defined by responding “Yes” and “No”, respectively. A non-response outcome was defined as missing.
For a yet unpublished report, [30] data on all readmissions within 3 months of surgery were collected from the Patient registry, Swedish Board of Health and Welfare. These data will be compared with the questionnaire and the CRF at 3 months.
Adjuvant therapy and local recurrence and metastases
Signs of local recurrence and detection of distant metastases were assessed in the case report form at 12 and 24 months and at the same follow-up times the patients were also asked about these matters. For both the case report form and the questionnaire a positive and negative outcome was defined by responding “Yes” and “No”, respectively. For a non-response the outcome was defined as missing.
Predictor variables
Patient characteristics and demography were collected through the questionnaires preoperatively and throughout the study. Preoperatively, information on age, education, occupation and marital status was collected and evaluated with regard to association with agreement [7, 13, 16]. In addition, use of medication, alcohol consumption, quality of life, depressed mood and presence of negative intrusive thoughts were also evaluated. Use of medication was defined as use of sleeping pills or tranquilizers. Self-assessed quality of life, negative intrusive thoughts and alcohol consumption were characterized in the same way as in an earlier analysis [31]. Depressive mood was defined as either responding ‘Yes’ to the question ‘Would you call yourself depressed?’ [32] or use of anti-depressive medication.
Sensitivity and specificity
Sensitivity and specificity will be evaluated for two scenarios with regard to choice of gold standard. First, the questionnaire will be considered as gold standard and the sensitivity and specificity of the clinical reports will be evaluated. Secondly, the Patient registry will be considered as standard regarding readmissions and the questionnaire and clinical report will be evaluated.
Statistical analysis
Group sizes in LAPPRO were set to evaluate urinary incontinence [27] and were judged to be sufficient to assess the current aim. Agreement was evaluated by percent of concordant pairs, positive and negative agreement and Gwet’s AC1. For comparison the kappa coefficient was computed as well. Association was evaluated by the odds that the two observers agree rather than disagree using the marginal quasi-independence model. Due to the hierarchical design where the surgeons are operating on several patients, who are longitudinally followed, there are dependency structures in the data that should ideally be accounted for in the statistical model. However, due to computational difficulties a standard fixed effect model was estimated separately at each time point.
In the evaluation of factors associated with agreement (positive or negative) between the two data sources, the following were evaluated: age, education, occupation, marital status, medication (sleeping pills or tranquilizers), alcohol consumption, quality of life, depressed mood and negative intrusive thoughts. For swelling of groin or lower extremities a standard simple logistic regression was used. For the outcomes with repeated measures a random intercept logistic regression model was used and time was included as a fixed effect ([26]). Results were presented with 95% confidence intervals. In each of the analyses, for information to be evaluable, data from both sources had to be ‘non-missing’ according to the definitions described above. The same analyses were made for the additional comparisons with data from the Patient registry. Analyses were conducted in SAS v9.4 (SAS Institute Inc., Cary NC), the rel package [33] and the software described by [34].