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The Impact of Postoperative Complications on Short- and Long-Term Health-Related Quality of Life After Total Mesorectal Excision for Rectal Cancer

Open AccessPublished:September 16, 2022DOI:https://doi.org/10.1016/j.clcc.2022.07.004

      Abstract

      Background

      Survival for rectal cancer patients has improved over the past decades. In parallel, long-term health-related quality of life (HRQoL) is gaining interest. This study focuses on the effect of complications following rectal cancer surgery on HRQoL and survival.

      Methods

      The TME-trial (1996-1999) randomized patients with operable rectal cancer between surgery with preoperative short-course radiotherapy and surgery. Questionnaires including the Rotterdam Symptom Checklist were sent at 6 time points within the first 24 months and after 14 years the EORTC QLQ-C30 and EORTC QLQ-CR29 questionnaires. Differences in HRQoL and survival between patients with and without complications were analyzed.

      Results

      A total of 1207 patients were included, of which 482 (39.9%) patients experienced complications, surgical complications occurred in 177 (14.6%) patients, non-surgical complications in 197 (16.3%) and 108 patients (8.9%) had a combination of both types of complications. Three months after surgery, patients with a combination of surgical- and non-surgical complications, especially patients with anastomotic leakage, had the worst HRQoL. Twelve months postoperative HRQoL returned to a similar level as before surgery, regardless of complications. In patients who survived 14 years, no significant differences in HRQoL were seen between patients with and without complications. However, patients with complications did have lower overall survival.

      Conclusion

      This study shows that survival and short-term HRQoL are negatively affected by complications. Twelve months after surgery HRQoL had returned to the preoperative level regardless, of complications. Also, in patients that survived 14 years, there was no effect of complications on HRQoL detected.

      Keywords

      Abbreviations:

      EORTC (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core), HRQoL (Health-Related Quality of Life), RSCL (Rotterdam Symptom Checklist), TME (Total Mesorectal Excision), ERAS (Enhanced Recovery After Surgery), APR (Abdominoperineal Resection)

      Introduction

      Colorectal cancer is one of the most common types of cancer in western countries with increasing incidence, of which approximately a third is located in the rectum. Fortunately, survival has improved substantially.
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      Postoperative complications are associated with increased morbidity and mortality, as well as increased hospital length of stay and health care costs. Another major issue in rectal cancer treatment is local recurrence. The Dutch TME-trial demonstrated that reduction from 10.9% to 5.6% of local recurrence rates was achieved by adding short-course preoperative radiotherapy to the standard treatment.
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      Therefore, HRQoL after rectal cancer should be investigated as well as factors influencing this, both to inform patients and to gain insight into possible improvements of perioperative care.
      This study aims to objectify the difference in short- and long-term HRQoL between uncomplicated and complicated postoperative recovery after total mesorectal excision (TME) surgery for rectal cancer. The hypothesis is that postoperative complications lead to a decreased HRQoL. Furthermore, the differences in overall survival between patients with- and without postoperative complications are studied.

      Methods

      Study Population and Treatment

      Between January 1996 and December 1999 patients with resectable rectal cancer were enrolled in the Dutch multicenter TME-Trial.
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      Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.
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      Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.
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      • et al.
      Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients–a Dutch colorectal cancer group study.
      • van Gijn W
      • Marijnen CA
      • Nagtegaal ID
      • et al.
      Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial.
      The trial was approved by the medical ethics committees of all the participating hospitals. During this trial, patients were randomly allocated to TME surgery or preoperative radiotherapy followed by TME surgery. Eligibility criteria were a clinically resectable adenocarcinoma with an inferior tumor margin below the level of S1/S2 and within 15 cm from the anal verge, without evidence of distant metastases. Patients were excluded from analysis when not having filled out the baseline HRQoL questionnaire or when deceased within 30 days after surgery. Patients assigned to preoperative radiotherapy received a total dose of 25 Gy in 5 fractions delivered by a 3- or 4-field technique over 5 to 7 days. The clinical target volume included the primary tumor and the mesentery containing the sacral, perirectal, and internal iliac nodes up to the S1/S2 junction. The perineum was also included in this volume if an abdominoperineal resection (APR) was planned. Otherwise, the lower field border was 3 cm above the anal verge. All patients underwent surgery following the TME principle.
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      • Marijnen CA
      • Nagtegaal ID
      • et al.
      Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.
      ,
      • Heald RJ.
      Rectal cancer: the surgical options.
      Following our previous report, survival was calculated from the day of surgery.
      • Kapiteijn E
      • Marijnen CA
      • Nagtegaal ID
      • et al.
      Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.
      The status, alive, of patients, was censored at the time of the last follow-up.

      Health-Related Quality of Life (HRQoL) Assessment

      HRQoL was measured using different questionnaires on 7 different time points. Preoperatively and 3, 6, 12, 18 and 24 months after surgery the Rotterdam Symptom Checklist (RSCL) was used supplemented with questions concerning sexual functioning as reported previously (Table A.1).
      • Marijnen CA
      • van de Velde CJ
      • Putter H
      • et al.
      Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.
      ,
      • Peeters KC
      • van de Velde CJ
      • Leer JW
      • et al.
      Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients–a Dutch colorectal cancer group study.
      ,
      • Wiltink LM
      • Chen TY
      • Nout RA
      • et al.
      Health-related quality of life 14 years after preoperative short-term radiotherapy and total mesorectal excision for rectal cancer: report of a multicenter randomised trial.
      ,
      • de Haes JC
      • van Knippenberg FC
      • Neijt JP.
      Measuring psychological and physical distress in cancer patients: structure and application of the Rotterdam Symptom Checklist.
      In July - August 2012, after a median follow-up of 14.4 years after surgery the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC) questionnaires: cancer-specific QLQ-C30 and colorectal- cancer-specific QLQ-CR29 was sent by mail to the surviving patients.
      • Aaronson NK
      • Ahmedzai S
      • Bergman B
      • et al.
      The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
      ,
      • Whistance RN
      • Conroy T
      • Chie W
      • et al.
      Clinical and psychometric validation of the EORTC QLQ-CR29 questionnaire module to assess health-related quality of life in patients with colorectal cancer.
      In all questionnaires, a 4-point Likert scale was used and subsequently all responses were linearly converted to 0 to 100 scales.

      Complications

      All complications that occurred during admission were registered and reviewed, of which the following definitions were used. Surgical complications are considered complications directly related to the surgical intervention (eg, anastomotic leakage. Non-surgical complications are complications not directly related to the surgical intervention (eg, urinary tract infection). Anastomotic leakage included all leakages clinically diagnosed or confirmed by contrast enema, furthermore, an abscess around the anastomosis was also recorded as anastomotic leakage. Rare complications were classified as other.

      Statistics

      Linear mixed models with random patient intercepts and time (categoric) and treatment group as fixed factors were used to obtain estimates for the subscales of the RSCL of each of the scheduled time points, to account for drop-out. At each time point, the difference in quality of life between groups was tested by Wald's tests, using linear mixed-effects model the “lme” package. A univariable Poisson regression analysis was carried out using the “lme” package to analyze the effect of individual variables on HRQoL. Cox regression analysis were carried out using the "survival" and "survminer" packages. Analysis were performed in R Version 3.6.3.

      Results

      Patient Characteristics

      A total of 1530 patients were selected of which 323 were excluded because of the following reasons: ineligible at randomization (n = 50), no resection (n = 37), no informed consent for HRQL questionnaires (n = 89), 30-day mortality (n = 41) and no baseline HRQL forms returned (n = 106), leaving 1207 patients for analysis (Figure 1). Patient, tumor and treatment characteristics are listed in Table 1. In total 482 (39.9%) patients suffered from complications, of which urinary tract infection (n = 106) was the most common followed by pulmonary complication (n = 85), anastomotic leakage (n = 79) and abdominal wound infection (n = 75) (Table A.2). Patients were divided into 4 separate groups based on the type of complications: no complications, surgical complications, non-surgical complications or a combination of surgical and non-surgical complications. There was a significant difference between the different groups in age, the distance of the tumor to the anal verge and stoma formation during primary surgery. There were no significant differences observed in comorbidities (Table 1). Response to the HRQoL questionnaires did not significantly differ between the groups at any time point (Table 2).
      Figure 1
      Figure 1Flowchart of patient selection for study
      Table 1Patient, Tumor- and Treatment Characteristics
      Characteristics(n = 1248)No Complications(n = 725 (60.1%))Surgical Complications(n = 177 (14.6%))Non-Surgical Complications(n = 197 (16.3%))Surgical and Non-Surgical Complications(n= 108 (8.9%))P-value
      Median age [range]64 [23-88]65 [41-86]66 [26-92]67 [43-88]< .01
      Male447 (61.7%)123 (69.5%)121 (61.4%)76 (70.4%).09
      Mean BMI at baseline25.4 [16.2-53.1]26.1 [18.4-45.9]25.4 [17.1-45.4]25.4 [17.7-35.3].13
      Comorbidities
        Any comorbidity195 (26.9%)39 (22.0%)55 (27.9%)20 (18.5%).36
        Hypertension104 (14.3%)24 (13.6%)27 (13.7%)6 (5.5%).38
        Cardiac comorbidity35 (4.8%)8 (4.5%)7 (3.3%)7 (6.5%).21
        Pulmonary comorbidity23 (3.2%)4 (2.3%)6 (3.0%)4 (3.7%).65
        Diabetes46 (6.3%)14 (7.9%)6 (3.0%)4 (3.7%).15
        Previous abdominal surgery50 (6.9%)10 (5.6%)11 (5.6%)7 (6.5%).66
      Chronic drug use164 (22.6%)36 (20.3%)44 (22.3%)17 (15.7%).50
      TNM stage.80
        014 (1.9%)5 (2.8%)4 (2.0%)0 (0.0%)
        I221 (30.5%)52 (29.4%)67 (34.0%)33 (30.6%)
        II193 (26.6%)48 (27.1%)43 (21.8%)32 (29.6%)
        III262 (36.1%)60 (33.9%)74 (37.6%)36 (33.3%)
        IV35 (4.8%)12 (6.8%)9 (4.6%)7 (6.5%)
      Distance to anal verge.01
        <5203 (28.0%)69 (39.0%)54 (27.4%)41 (38.0%)
        5-10303 (41.8%)72 (40.7%)76 (38.5%)40 (37.0%)
        >10219 (30.2%)35 (19.8%)67 (34.0%)27(25.0%)
        Unknown0 (0,0%)1 (0.6%)0 (0.0%)0 (0.0%)
      Neo-adjuvant RT.32
        Yes345 (47.6%)89 (50.3%)104 (52.8%)60 (55.6%)
        No380 (52.4%)88 (47.7%)93 (47.2%)48 (44.4%)
      Operation type<.01
        LAR490 (67.6%)92 (52.0%)135 (68.5%)64 (59.3%)
        APR203 (28.0%)82 (46.3%)41 (20.8%)41 (38.0%)
        Hartmann32 (4.4%)3 (1.7%)21 (10.7%)3 (2.8%)
      Stoma<.01
        None210 (29.0%)45 (25.4%)48 (24.4%)35 (32.4%)
        Diverting312 (43.0%)50 (28.2%)107 (54.3%)32 (29.6%)
        Permanent203 (28.0%)82 (46.3%)41 (20.8%)41 (38.0%)
        Missing0 (0.0%)0 (0.0%)1 (0.5%)0 (0.0%)
      Table 2Questionnaire Response Per Time Point. Percentages are Calculated Using the Patients That Were Alive at the Time of the Questionnaire
      No ComplicationsSurgical ComplicationsNon-Surgical ComplicationsSurgical and Non-surgical ComplicationsOverallP-value
      Completed questionnaires
      Baseline725 (100.0%)177 (100.0%)197 (100.0%)108 (100.0%)1207 (100.0%)
        3 months672 (93.1%)161 (92.0%)182 (92.9%)101 (90.2%)1205 (92.6%).22
        6 months662 (92.3%)157 (91.3%)174 (90.6%)93 (86.1%)1086 (91.3%).20
        12 months623 (90.2%)145 (88.4%)167 (88.8%)87 (85.3%)1022 (89.3%).31
        18 months590 (87.7%)137 (89.0%)155 (86.6%)77 (81.1%)959 (87.1%).34
        24 months543 (83.8%)129 (86.0%)146 (83.0%)74 (84.1%)892 (84.0%).81
        14 years251 (76.3%)57 (82.9%)66 (82.5%)25 (71.4%)400 (77.8%).44

      Survival After TME Surgery

      The 5-year overall survival was 67.5%, the 10-year overall survival was 51.6% in the study cohort (Figure 2A). When leaving out the condition for 30-day survival the 5-year survival was lower in the patients with both surgical- and non-surgical complications, 5-year survival was 45.5% and 56.5% respectively (Figure 2B). Decreased survival after surgery was associated with postoperative complications, the 5-year and 10-year overall survival were poorest in patients with both surgical- and non-surgical complications 56.5% and 40.7% respectively (adjusted HR: 1.37, 95%CI 1.04-1.78) (Table 3).
      Figure 2
      Figure 2Overall survival probability analysis using Cox regression, subgroups are patient without complications, with surgical complications, non-surgical complications, and patients with a combination of surgical- and non-surgical complications. (A) represents survival cure of patients included in HRQoL analyses, (B) represents the survival curve without conditional-survival. HRQoL = Health-related Quality of Life.
      Table 3Survival Analysis of Using Cox Regression. *Adjusted for Age, Sex, TNM-Stage
      Univariate CoxMultivariate Cox
      HR (95%CI)P-valueHR (95%CI)P-value
      Age1.03 (1.02-1.04)<0.01
      Male sex0.76 (0.64-0.91)<0.01
      BMI0.99 (0.97-1)0.67
      Level of education0.79 (0.49-1.27)0.34
      Type of complications
        No complicationsrefref
        Surgical complications1.33 (1.06-1.67)0.011.23* (0.92-1.550.07
        Non-surgical complications1.24 (0.99-1.55)0.061.18* (0.95-1.48)0.14
        Both surgical and non-surgical complications1.56 (1.19-2.03)<0.011.37* (1.043-1.78)0.02
        Anastomotic leakage1.10 (0.80-1.52)0.541.12* (0.81-1.54)0.49
      Type of surgery
        LARrefref
        APR1.23 (1.03-1.46)0.021.20* (1.00-1.43)<0.05
        Hartmann1.86 (1.33-2.60)<0.011.45* (1.04-2.04)0.03
        TNM-stage1.91 (1.74-2.10)<0.01
      Stoma
        No stomarefref
        Diverting1.23 (1.00-1.51)<0.051.12* (0.92-1.38)0.27
        Permanent1.33 (1.07-1.65)0.011.25* (1.0-1.56)<0.05
      Neoadjuvant RT0.99 (0.85-1.17)0.98
      Any comorbidity1.00 (1.00-1.00)0.99
      Previous malignancy3.67 (0.38-35.2)0.26
      Chronic medication0.55 (0.09-3.3)0.51

      Health-Related Quality of life (0-24 Months)

      The HRQoL measured by the global health status, activity level and physical level was lower after 3 months compared to the preoperative measurements but after approximately 12 months the levels were back to the preoperative level for all groups (Table A.3, Figure 3). In the patients with a combination of both surgical and non-surgical complications the impact of surgery was significantly larger (P < .05) in the first 12 months after surgery. Likewise, patients that suffered from anastomotic leakage had a significantly decreased global health status and activity level (Table A.4, Figure A.1). A decrease in male sexual functioning and psychological distress was seen after surgery, these changes were comparable in all subgroups.
      Figure 3
      Figure 3Health-related quality of life measured by the Rotterdam Symptoms Check List questionnaire on 6 time points, preoperatively, 3, 6, 12, 18 and 24 months postoperative. Overall health, a higher score is a better health, for all other scores a higher score is more problems. (A) Global health status, (B) Activity level, (C) Physical distress scale, (D) Psychological distress scale, (E) Sexual functioning (female), (F) Sexual functioning (male). The scores of Overall health and Activity Scale are 0 to 100, a higher score means a better health. For the other subscale the scores are linearly transformed (0-100) a higher score is indicating more distress. Raw results are shown in .

      Impact of Individual Variables

      Univariate regression analysis was performed to identify influential factors for postoperative overall health and the activity level at the 3-month, 12 month and 24 month time point (Table 4). A combination of surgical and non-surgical complications was significantly associated with a decreased global health (RR: 0.88, 95%CI 0.80-0.97) and activity level (RR: 0.84, 95%CI 0.70-0.98) 3 months after TME surgery. Anastomotic leakage was also significantly associated with a decreased global health status 3 months after surgery (RR: 0.91, 95%CI 0.82-1.00). Additionally, a more advanced tumor stage (RR: 0.98, 95%CI 0.95-0.99) and Hartmann resection (RR: 0.82, 95C%CI 0.70-0.95) were associated with a decreased global health status 12 months after surgery.
      Table 4Univariable Regression Analysis of the Effect of Variables on Global Health Status and Activity Level, Measured by the Rotterdam Symptom Checklist at 3 Months, 12 Months, and 24 Months After Surgery. * Ileostoma of Colostoma Present at Time of the Questionnaire
      3 Months12 Months24 Months
      Global Health Status
      Unadjusted RR (95%CI)P-valueUnadjusted RR (95%CI)P-valueUnadjusted RR (95%CI)P-value
      Age1.00 (1.00-1.00).271.00 (1.00-1.00).391.00 (1.00-1.00).20
      Sex0.99 (0.94-1.04).660.97 (0.93-1.02).270.97 (0.92-1.02).28
      BMI at baseline1.00 (0.99 -1.01).730.99 (0.99-1.00).080.99 (0.98-1.00)< .05
      Level of education1.01 (0.99-1.02).411.01 (0.99-1.02).281.01 (0.99-1.02).49
      Type of complications
        No complications1.001.001.00
        Surgical complications0.99 (0.92-1.05).721.00 (0.93-1.06).920.97 (0.90-1.00).39
        Non-surgical complications0.97 (0.91-1.04).401.00 (0.93-1.06).920.98 (0.91-1.04).52
        Both surgical and non-surgical complications0.88 (0.80-0.97)< .010.97 (0.89-1.06).510.98 (0.89-1.07).61
        Anastomotic leakage0.91 (0.82-1.00).040.95 (0.86-1.04).320.94 (0.84-1.04).21
      Type of surgery
        LAR1.001.001.00
        APR1.04 (0.99-1.09).080.99 (0.94-1.04).780.99 (0.94-1.05).84
        Hartmann0.91 (0.80-1.02).130.82 (0.70-0.95)< .010.89 (0.76-1.03).13
        TNM-stage0.98 (0.96-1.00).070.98 (0.95-0.99)< .050.98 (0.96-1.01).20
        Stoma*1.02 (0.99-1.05).131.00 (0.97-1.03).871.00 (0.97-1.03).98
        Neoadjuvant RT1.02 (0.98-1.07).341.01 (0.97-1.06).551.00 (0.95-1.05).97
      Activity level
        Age1.00 (0.99-1.00).071.00 (0.99-1.00).061.00 (0.99-1.00).13
        Sex0.96 (0.88-1.03).280.97 (0.89-1.05).390.95 (0.87-1.04).25
        BMI at baseline1.00 (0.99-1.01).831.00 (0.99-1.01).711.00 (0.98-1.01).64
        Level of education1.01 (0.99-1.03).341.01 (0.99-1.03).431.01 (0.99-1.03).29
      Type of complications
        No complications1.001.001.00
        Surgical complications0.97 (0.86-1.08).611.00 (0.89-1.11)0.970.99 (0.88-1.11).92
        Non-surgical complications0.97 (0.86-1.07).510.98 (0.87-1.09).720.97 (0.85-1.08).60
        Both surgical and non-surgical complications0.84 (0.70-0.98)< .050.94 (0.79-1.08).400.96 (0.80-1.11).58
        Anastomotic leakage0.92 (0.77-1.07).320.96 (0.81-1.12).960.99 (0.82-1.15).87
      Type of surgery
        LAR1.001.001.00
        APR1.00 (0.92-1.08).991.00 (0.92-1.09).930.99 (0.90-1.08).90
        Hartmann0.95 (0.77-1.13).570.94 (0.75-1.13.550.95 (0.74-1.17).67
        TNM-stage0.99 (0.96-1.03).730.99 (0.95-1.03).760.99 (0.95-1.04).73
        Stoma*1.00 (0.95-1.05).971.00 (0.95-1.05).971.00 (0.94-1.05).92
        Neoadjuvant RT1.02 (0.94-1.09).671.00 (0.93-1.08).951.00 (0.92-1.08).94

      Health-Related Quality of Life (14 Years)

      After a median follow-up of 14 years, 429 patients filled out the quality-of-life questionnaires, which entails 84.0% of the patients that survived. Global health status was not significantly different between the different (sub)groups with and without complications (Table A.5). We do see significant changes in constipation, urinary frequency, which are more common in the patients after both surgical and non-surgical complications.

      Discussion

      The HRQoL, as measured by our approach, of patients that survived 12 months after TME surgery for rectal cancer is comparable with the preoperative status and no significant differences were witnessed between patients with an uncomplicated and complicated recovery. However, short-term postoperative recovery was affected in patients with complicated TME surgery, especially when there was a combination of surgical and non-surgical complications and in case of anastomotic leakage. Nevertheless, in patients who survived 1 year up to 14 years after surgery no significant HRQoL differences were seen between uncomplicated and complicated surgery, suggesting the deficit of HRQoL as a result of complications is temporary. Nonetheless, this study showed that postoperative complications negatively impact overall survival, this effect was the highest in patients that suffered a combination of surgical and non-surgical complications.
      The results of the short-term postoperative HRQoL are in line with a previously conducted study about patients undergoing oncological colorectal surgery, as they did observe a decrease in physical functioning after complications requiring reoperation.
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      Complications after surgery for colorectal cancer affect quality of life and surgeon-patient relationship.
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      • Monson JR.
      Predictors of early postoperative quality of life after elective resection for colorectal cancer.
      This is not supported by our study, since we see a high preoperative psychological distress and a decrease in psychological distress after surgery which is comparable in both patients with and without postoperative complications. This might be the result of improved preoperative informing and counseling of patients over the past decades, leading to patients having lower preoperative anxiety.
      • Sharma A
      • Sharp DM
      • Walker LG
      • Monson JR.
      Predictors of early postoperative quality of life after elective resection for colorectal cancer.
      Additionally, a study on HRQoL after oncological esophagectomy showed no significant difference on short- or long-term HRQoL after postoperative complications or anastomotic leakage compared to an uncomplicated postoperative course.
      • Jezerskyte E
      • van Berge Henegouwen MI
      • van Laarhoven HWM
      • et al.
      Postoperative complications and long-term quality of life after multimodality treatment for esophageal cancer: an analysis of the prospective observational cohort study of esophageal-gastric cancer patients (POCOP).
      However, in a study measuring HRQoL after restorative proctocolectomy a difference in HRQoL in patients with and without postoperative pelvic sepsis was observed.
      • Kiely JM
      • Fazio VW
      • Remzi FH
      • Shen B
      • Kiran RP.
      Pelvic sepsis after IPAA adversely affects function of the pouch and quality of life.
      The differences in outcome between these studies might be subjected to the patient population, especially benign versus malignant, or the different questionnaires used in the studies. It might be related to the coping style which might differ between different patient populations, since patients with malignant diseases might be more resilient and cope differently with health deficits following postoperative complications, leading to a relative underestimation of the effect of complications on HRQoL.
      • Gomez D
      • Jimenez-Fonseca P
      • Fernández AM
      • et al.
      Impact of obesity on quality of life, psychological distress, and coping on patients with colon cancer.
      ,
      • Boban S
      • Downs J
      • Codde J
      • Cohen PA
      • Bulsara C.
      Women diagnosed with ovarian cancer: patient and carer experiences and perspectives.
      Time points of measuring HRQoL were not equal in all studies, however, most studies measured HRQoL within the first 2 years after surgery. Only Constantinides et al. measured HRQoL at 3 to 6 years after surgery.
      • Constantinides VA
      • Aydin HN
      • Tekkis PP
      • Fazio VW
      • Heriot AG
      • Remzi FH.
      Long-term, health-related, quality of life comparison in patients undergoing single stage vs staged resection for complicated diverticular disease.
      This may lead to different outcomes as this study shows that HRQoL is subjected to time.
      This study has shown that patients with postoperative complications have lower overall survival. These outcomes are in line with previous studies.
      • Ha GW
      • Kim JH
      • Lee MR.
      Oncologic impact of anastomotic leakage following colorectal cancer surgery: a systematic review and meta-analysis.
      • Ramphal W
      • Boeding JRE
      • Gobardhan PD
      • et al.
      Oncologic outcome and recurrence rate following anastomotic leakage after curative resection for colorectal cancer.
      • Artus A
      • Tabchouri N
      • Iskander O
      • et al.
      Long term outcome of anastomotic leakage in patients undergoing low anterior resection for rectal cancer.
      Furthermore, anastomotic leakage has been shown to be associated with increased local recurrence which impacts survival as well.
      • Ha GW
      • Kim JH
      • Lee MR.
      Oncologic impact of anastomotic leakage following colorectal cancer surgery: a systematic review and meta-analysis.
      Several mechanisms might explain this, first the overall survival might be affected by postoperative complications causing an impaired health status.
      • van der Geest LG
      • Portielje JE
      • Wouters MW
      • et al.
      Complicated postoperative recovery increases omission, delay and discontinuation of adjuvant chemotherapy in patients with Stage III colon cancer.
      Additionally, it is thought that a systemic inflammatory response after complications leads to decreased (recurrence-free) survival. This inflammatory response is responsible for the release of pro-inflammatory cytokines and growth factors that subsequently might stimulate the growth of residual cancer cells.
      • Salvans S
      • Mayol X
      • Alonso S
      • et al.
      Postoperative peritoneal infection enhances migration and invasion capacities of tumor cells in vitro: an insight into the association between anastomotic leak and recurrence after surgery for colorectal cancer.
      ,
      • McMillan DC
      • Canna K
      • McArdle CS.
      Systemic inflammatory response predicts survival following curative resection of colorectal cancer.
      This study is based on data obtained during a multicenter randomized-controlled trial on preoperative short-course radiotherapy and TME surgery versus TME surgery alone. Since there was no significant difference in the postoperative complication rate between irradiated- and non-irradiated patients, making this study data is representable for this research question as well. However, our study was not designed to answer whether radiotherapy does increase postoperative complications. Furthermore, previous studies have shown that patients with preoperative radiotherapy may have an impaired activity level in the first 2 years after surgery, no effect on HRQoL was shown 14 years postoperative
      • Marijnen CA
      • van de Velde CJ
      • Putter H
      • et al.
      Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.
      ,
      • Wiltink LM
      • Chen TY
      • Nout RA
      • et al.
      Health-related quality of life 14 years after preoperative short-term radiotherapy and total mesorectal excision for rectal cancer: report of a multicenter randomised trial.
      Additionally, the more recent RAPIDO trial, reported no influence of (neo-)adjuvant therapy on long term HRQoL in rectal cancer patients.
      • Dijkstra EA
      • Hospers GAP
      • Kranenbarg EM
      • et al.
      Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer - The RAPIDO trial.
      The current improvements in overall survival of rectal cancer patients result in a larger population that has to live with the physical-, psychological- and societal consequences of rectal cancer surgery, such as having a stoma, bowel dysfunction, physical and psychological stress.
      • Jehle EC
      • Haehnel T
      • Starlinger MJ
      • Becker HD.
      Level of the anastomosis does not influence functional outcome after anterior rectal resection for rectal cancer.
      ,
      • Påhlman L.
      The rectal cancer debate.
      . The results of this study give insights in the impact of postoperative complications after rectal cancer surgery on the development of HRQoL overtime after postoperative compilations. This information may serve in optimizing patient information and shared decision-making before engaging treatment.
      • Snijders HS
      • Kunneman M
      • Bonsing BA
      • et al.
      Preoperative risk information and patient involvement in surgical treatment for rectal and sigmoid cancer.
      Additionally, information on the postoperative HRQoL development can be used for preparatory education of patients planned for surgery on what to expect in the short- and long-term. Preoperative education of patients has been shown to reduce postoperative anxiety and postoperative pain.
      • Waller A
      • Forshaw K
      • Bryant J
      • Carey M
      • Boyes A
      • Sanson-Fisher R.
      Preparatory education for cancer patients undergoing surgery: A systematic review of volume and quality of research output over time.
      ,
      • Spalding NJ.
      Reducing anxiety by pre-operative education: make the future familiar.
      Furthermore, this study gives leads for alteration of (p)rehabilitation programs that should be focusing on enhancing activity and physical fitness and in case of postoperative complications rehabilitation programs might be directed on regaining activity level and physical fitness. The use of prehabilitation programs seems to be especially effective in high-risk patients, therefore preoperative detection of high-risk patients will be needed.
      • Barberan-Garcia A
      • Ubré M
      • Roca J
      • et al.
      Personalised prehabilitation in high-risk patients undergoing elective major abdominal surgery: a randomized blinded controlled trial.
      ,
      • van Kooten RT
      • Bahadoer RR
      • Peeters K
      • et al.
      Preoperative risk factors for major postoperative complications after complex gastrointestinal cancer surgery: A systematic review.
      A limitation of this study is that postoperative complications are significantly associated with lower survival. This may cause bias in HRQoL measurements, especially 14 years after surgery. Furthermore, between surgery and the 14-year postoperative HRQoL questionnaires other events may have occurred which may have influenced the HRQoL, leading to a possible underestimation of the effect of complications. Furthermore, rectal cancer care has evolved over the past years leading to improvements in treatment, advanced diagnostics and early detection by screening contributing to improved survival. Also, treatment and detection of postoperative complications have been improved, which may lead to a lower burden of postoperative complications. The strength of this study is the high response (77.8%) of long-term follow-up (14 years) HRQoL questionnaires. To our knowledge, this study has currently the longest follow-up of all studies on the impact of complications after rectal surgery. However, although the TME trial is a well-designed and documented RCT, this study has been conducted in 1996-1999 and since then perioperative care and surgical techniques have been improved. Currently, postoperative outcomes after colorectal surgery are improved due to progress in surgical techniques and perioperative care. A major improvement in perioperative care is the introduction of Enhanced Recovery After Surgery (ERAS) protocols. ERAS protocols have been proven to reduce postoperative complications and mortality.
      • Greer NL
      • Gunnar WP
      • Dahm P
      • et al.
      Enhanced recovery protocols for adults undergoing colorectal surgery: a systematic review and meta-analysis.
      • Ljungqvist O
      • Scott M
      • Fearon KC.
      Enhanced recovery after surgery: a review.
      • Ketelaers SHJ
      • Orsini RG
      • Burger JWA
      • Nieuwenhuijzen GAP
      • Rutten HJT.
      Significant improvement in postoperative and 1-year mortality after colorectal cancer surgery in recent years.
      Preadmission exercise interventions, incorporated in ERAS protocols, are associated with a positive impact on HRQoL.
      • Mishra SI
      • Scherer RW
      • Geigle PM
      • et al.
      Exercise interventions on health-related quality of life for cancer survivors.
      The progress in surgical techniques is marked by the introduction of minimally-invasive surgery. However, in a meta-analysis no clinically significant difference was found in postoperative HRQoL between laparoscopic surgery and open colorectal surgery.
      • Bartels SA
      • Vlug MS
      • Ubbink DT
      • Bemelman WA.
      Quality of life after laparoscopic and open colorectal surgery: a systematic review.
      Despite, the absence of a significant effect on HRQoL, minimally invasive surgery is thought to lead to a faster postoperative recovery and less use of parenteral and oral analgesics.
      • Straatman J
      • Cuesta MA
      • Tuynman JB
      • Veenhof A
      • Bemelman WA
      • van der Peet DL
      C-reactive protein in predicting major postoperative complications are there differences in open and minimally invasive colorectal surgery? Substudy from a randomized clinical trial.
      ,
      • Vlug MS
      • Wind J
      • Hollmann MW
      • et al.
      Laparoscopy in combination with fast track multimodal management is the best perioperative strategy in patients undergoing colonic surgery: a randomized clinical trial (LAFA-study).
      There are no significant differences between laparoscopic and open surgery regarding intra-operative or postoperative complications.
      • Guillou PJ
      • Quirke P
      • Thorpe H
      • et al.
      Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial.
      ,
      • Nelson H
      • Sargent DJ
      • Wieand HS
      • et al.
      A comparison of laparoscopically assisted and open colectomy for colon cancer.
      In conclusion, this study did show a decreased overall survival after postoperative complications. Furthermore, this study presents that short-term HRQoL is affected in patients with a combination of surgical and non-surgical complications and in patients with anastomotic leakage. Moreover, after 12 months HRQoL in all patients returned to the pretreatment level. No significant effects of postoperative complications were seen on long-term HRQoL (24 months and 14 years) in patients with- and without postoperative complications. These results suggest that the effects of postoperative complications on the HRQoL are temporary.

      Clinical Practice Points

      • Postoperative complications lead to a decreased overall survival.
      • Short-terms health-related quality of life was negatively affected by postoperative complications.
      • Twelve months after surgery health-related quality of life returned to the preoperative level regardless, of complications.
      • Fourteen years after rectal cancer surgery there was no effect of postoperative complications on health-related quality of life detected.

      Acknowledgements

      The TME trial was supported by a research grant of the Dutch Cancer Society ( CKVO 95-04 ) and the Dutch National Health Council ( OWG 97/026 ). These funding sources did not have any role in the conduct of the present follow-up study.

      Disclosure

      The authors have stated that they have no conflicts of interest.

      APPENDIX 1

      Figure A1
      Figure A.1Health-related quality of life in patients with anastomotic leakage and without anastomotic leakage. Measured by the Rotterdam Symptoms Check List questionnaire on 6-time points, preoperative, 3, 6, 12, 18 and 24 months postoperative. Overall health, a higher score is better health, for all other scores a higher score is more problems. (A) Global health status, (B) Activity level, (C) Physical distress scale, (D) Psychological distress scale. The scores of overall health and Activity Scale are 0 to 100, a higher score means better health. For the other subscale, the scores are linearly transformed (0-100) a higher score is indicating more distress.
      Table A.1Overview of the Items Included in the Rotterdam Symptom Checklist (RSCL) and the Sexual Functioning Scale
      • Marijnen CA
      • van de Velde CJ
      • Putter H
      • et al.
      Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.
      Items Containing HRQoL Questionnaires
      RSCL physical symptom distress (23 items)
      1 Lack of appetite
      2 Tiredness
      3 Sore muscle
      4 Lack of energy
      5 Low back pain
      6 Nausea
      7 Difficulty sleeping
      8 Headaches
      9 Vomiting
      10 Dizziness
      11 Decreased sexual interest
      12 Abdominal (stomach) aches
      13 Constipation
      14 Diarrhea
      15 Acid indigestion
      16 Shivering
      17 Tingling of hands or feet
      18 Difficulty concentrating
      19 Sore mouth/pain when swallowing
      20 Loss of hair
      21 Burning/sore eyes
      22 Shortness of breath
      23 Dry mouth
      RSCL psychologic distress scale (7 items)
      1 Irritability
      2 Worrying
      3 Depressed mood
      4 Nervousness
      5 Despairing about future
      6 Tension
      7 Anxiety
      RSCL activity level scale (8 items)
      1 Care for myself (wash, etc.)
      2 Walk about the house
      3 Light housework/household jobs
      4 Climb stairs
      5 Heavy housework/household jobs
      6 Walk out of doors
      7 Go shopping
      8 Go to work
      Sexual Functioning (4 items)
      1 Feeling sexual attractive
      2 Sexually interested
      3 Sexual pleasure
      4 Sexual satisfaction
      Table A.2Overview of Complications
      Surgical Complications(n = 177 (14.6%))Non-Surgical Complications(n = 197 (16.3%))Surgical and Non-Surgical Complications(n = 108 (8.9%))
      Surgical complications
      Abdominal wound dehiscence13-16
      Perineal wound dehiscence31-11
      Wound infection abdomen48-27
      Wound infection perineal26-11
      Intestinal necrosis2-3
      Anastomotic leakage41-38
      Hemorrhage23-12
      Intestinal fistula7-9
      Stoma complication11-7
      Intestinal perforation1-6
      Non-surgical complications
      Urinary tract infection-6541
      Abdominal abscess-2716
      Sepsis-1734
      Infected hematoma-53
      Pulmonary complication-5035
      Renal complication-15
      Neurological complication-118
      Thromboembolism-89
      Cardiac complications-2210
      Delirium-188
      Multi-organ failure-12
      Tension complication-40
      Line sepsis-123
      Cholecystitis-57
      Table A.3Raw results of health-related quality of life (HRQoL) measured by the Rotterdam Symptoms Check List (RSCL) questionnaire on 6 time points, preoperative, 3, 6, 12, 18 and 24 months postoperative, graphical presentation of results is shown in Figure 3
      No Complications(n = 725 (60.1%))Surgical Complications(n = 177 (14.6%))Non-Surgical Complications(n = 197 (16.3%))Surgical and Non-Surgical Complications(n = 108 (8.9%))P-value
      Overall health0.48 α
      Preoperative75.274.875.074.7
      3 Mo75.274.373.267.0
      6 Mo76.975.075.773.0
      12 Mo77.076.776.774.8
      18 Mo78.175.176.475.8
      24 Mo77.775.376.075.9
      Activity level< 0.01 α, γ, δ, ε
      Preoperative95.295.093.394.1
      3 Mo93.189.688.874.0
      6 Mo94.492.290.885.4
      12 Mo94.594.292.086.8
      18 Mo94.392.591.687.0
      24 Mo96.793.990.889.2
      Physical distress scale< 0.01
      Preoperative13.614.115.112.8
      3 Mo13.714.215.318.4
      6 Mo13.014.013.716.2
      12 Mo13.112.314.614.7
      18 Mo12.813.513.713.8
      24 Mo12.813.213.914.2
      Psychological distress scale0.77
      Preoperative28.027.127.825.6
      3 Mo16.218.118.118.7
      6 Mo15.116.215.216.3
      12 Mo15.813.814.916.8
      18 Mo14.613.714.213.8
      24 Mo14.212.413.712.1
      Sexual functioning (male)0.43 α
      Preoperative52.857.754.859.9
      3 Mo64.872.069.076.7
      6 Mo62.472.665.374.8
      12 Mo63.670.366.869.4
      18 Mo62.869.463.372.2
      24 Mo61.973.868.873.2
      Sexual functioning (female)0.66
      Preoperative72.082.377.280.0
      3 Mo81.085.187.092.6
      6 Mo77.286.185.095.1
      12 Mo77.678.582.091.1
      18 Mo75.378.979.591.0
      24 Mo76.272.082.579.1
      The scores of Overall health and Activity Scale (0-100), a higher score means a better health. For the other subscale the scores are linearly transformed (0-100) a higher score is indicating more distress.
      α: statistically difference between no complication and both surgical and non-surgical complications
      β: statistically difference between no complication and surgical complications
      γ: statistically difference between no complications and non-surgical complications
      δ: statistically difference between surgical complications and both surgical and non-surgical complications
      ε: statistically difference between non-surgical complications and both surgical and non-surgical complications
      Table A.4Overview of health-related quality of life (HRQoL) Subanalysis of patients with and without anastomotic leakage
      Global Health<0.01
      Preoperative75.277.0
      3 Mo75.268.0
      12 Months77.073.5
      24 Mo77.772.6
      Activity level<0.01
      Preoperative95.296.8
      3 Mo93.181.7
      12 Mo93.889.3
      24 Mo96.791.9
      Physical scale0.85
      Preoperative13.614.4
      3 Mo13.716.2
      12 Mo13.114.2
      24 Mo12.813.5
      Psychological scale<0.01
      Preoperative28.026.8
      3 Mo16.216.1
      12 Mo15.814.9
      24 Mo14.212.8
      Table A.5Health-related quality of life (HRQoL) measured by EORTC QLQ-C30 and EORTC QLQ-CR29, 14 years after surgery
      No Complications (n = 251 (49.1%))Surgical Complications (n = 57 (11.1%))Non-Surgical Complications (n = 66 (12.9%))Both Surgical and Non-Surgical complications (n = 25 (4.9%))P-value
      EORTC QLQ-C30
      Global Health status
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      78.481.574.376.9.23
      Physical functioning
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      76.777.974.077.6.35
      Role functioning
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      78.278.874.277.8.13
      Emotional functioning
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      84.089.282.988.0.15
      Cognitive functioning
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      86.384.482.682.7.74
      Social functioning
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      86.085.583.884.6.54
      Fatigue
      a Higher on This Scale Means That Patients Reported More Symptoms
      24.925.128.521.8.34
      Nausea and vomiting
      a Higher on This Scale Means That Patients Reported More Symptoms
      3.31.64.613.3.25
      Pain
      a Higher on This Scale Means That Patients Reported More Symptoms
      15.011.615.312.3.46
      Dyspnea
      a Higher on This Scale Means That Patients Reported More Symptoms
      13.311.719.118.5.35
      Insomnia
      a Higher on This Scale Means That Patients Reported More Symptoms
      24.616.924.525.3.30
      Appetite loss
      a Higher on This Scale Means That Patients Reported More Symptoms
      6.42.711.94.0.07
      Constipation
      a Higher on This Scale Means That Patients Reported More Symptoms
      14.58.218.820.8.02
      Diarrhea
      a Higher on This Scale Means That Patients Reported More Symptoms
      10.57.214.47.3.21
      Financial difficulties
      a Higher on This Scale Means That Patients Reported More Symptoms
      4.67.17.05.1.26
      EORTC QLQ-C29
      Body image
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      88.190.688.486.4.94
      Anxiety
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      83.581.977.383.3.48
      Weight
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      86.990.685.488.9.51
      Sexual interest (male)
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      57.852.149.269.4.22
      Sexual interest (female)
      a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.
      65.785.270.148.2.14
      Urinary frequency
      a Higher on This Scale Means That Patients Reported More Symptoms
      26.230.534.637.2.02
      Blood and mucus in stool
      a Higher on This Scale Means That Patients Reported More Symptoms
      1.94.73.56.0.28
      Stool frequency (stoma)12.511.811.110.8.95
      Stool frequency (no stoma)
      a Higher on This Scale Means That Patients Reported More Symptoms
      22.324.227.827.1.65
      Urinary incontinence
      a Higher on This Scale Means That Patients Reported More Symptoms
      12.810.316.418.7.27
      Dysuria
      a Higher on This Scale Means That Patients Reported More Symptoms
      1.60.01.51.3.48
      Abdominal pain
      a Higher on This Scale Means That Patients Reported More Symptoms
      4.38.511.15.1< .01
      Buttock pain
      a Higher on This Scale Means That Patients Reported More Symptoms
      7.110.911.015.4.05
      Bloating
      a Higher on This Scale Means That Patients Reported More Symptoms
      9.710.912.68.0.49
      Dry mouth
      a Higher on This Scale Means That Patients Reported More Symptoms
      15.818.424.924.0.06
      Hair loss
      a Higher on This Scale Means That Patients Reported More Symptoms
      1.84.03.53.8.45
      Taste
      a Higher on This Scale Means That Patients Reported More Symptoms
      3.73.46.510.3.17
      Flatulence (stoma)
      a Higher on This Scale Means That Patients Reported More Symptoms
      21.024.017.917.7.84
      Flatulence (no stoma)
      a Higher on This Scale Means That Patients Reported More Symptoms
      31.736.840.029.6.20
      Fecal incontinence (stoma)
      a Higher on This Scale Means That Patients Reported More Symptoms
      14.95.412.812.5.06
      Fecal incontinence (no stoma)
      a Higher on This Scale Means That Patients Reported More Symptoms
      14.021.823.13.7.08
      Sore skin (stoma)
      a Higher on This Scale Means That Patients Reported More Symptoms
      11.67.314.15.9.61
      Sore skin (no stoma)
      a Higher on This Scale Means That Patients Reported More Symptoms
      8.96.911.714.8.71
      Embarrassment (stoma)
      a Higher on This Scale Means That Patients Reported More Symptoms
      10.410.412.83.9.52
      Embarrassment (no stoma)
      a Higher on This Scale Means That Patients Reported More Symptoms
      21.226.429.218.5.54
      Impotence
      a Higher on This Scale Means That Patients Reported More Symptoms
      57.459.063.866.7.84
      Dyspareunia
      a Higher on This Scale Means That Patients Reported More Symptoms
      22.722.216.76.7.69
      a a Higher on This Scale Means That Patients Reported More Symptoms
      b a higher score on this scale means better functioning is reported by the patients. Percentages given in the top row are calculated form the total of patients that were alive (n = 511) at the time of the questionnaire.

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