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10.1093/bjsopen/zrae091
zrae091
Original Article
AcademicSubjects/MED00910
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Effect of radiotherapy on long-term quality of life in recurrence-free rectal cancer survivors (LaTE study): nationwide inverse probability of treatment-weighted registry-based cohort study and survey
https://orcid.org/0000-0002-2389-1403
Malik Yasir G Department of Digestive Surgery, Akershus University Hospital, Lørenskog, Norway
Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

Benth Jūratė Šaltytė Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Health Services Research Unit, Akershus University Hospital, Lørenskog, Norway

Hamre Hanne M Department of Internal Medicine, Oncology, Akershus University Hospital, Lørenskog, Norway

Færden Arne E Department of Digestive Surgery, Akershus University Hospital, Lørenskog, Norway

https://orcid.org/0000-0002-9427-2087
Schultz Johannes K Department of Digestive Surgery, Akershus University Hospital, Lørenskog, Norway
Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Department of Digestive Surgery, Oslo University Hospital, Oslo, Norway

Correspondence to: Yasir Gulzar Malik, Department of Digestive Surgery, Akershus University Hospital, Sykehusveien 25, 1478 Nordbyhagen, Lørenskog, Norway (e-mail: yasirgm@hotmail.com)
An ePoster of the abstract presented at the European Society of Coloproctology (ESCP) annual meeting, Thessaloniki, Greece, September 2024.

10 2024
06 9 2024
06 9 2024
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11 6 2024
06 7 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.
2024
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Abstract

Background

Radiotherapy reduces local recurrence in locally advanced rectal cancer, but may cause harm in patients who do not experience recurrence. The aim was to investigate the impact of radiotherapy on long-term quality of life after curative treatment for rectal cancer, i.e. in patients without a recurrence during the follow-up.

Methods

All patients operated on for rectal cancer in Norway under 75 years of age between 30 September 2007 and 1 October 2020 were identified using the Cancer Registry of Norway. Exclusion criteria were distant metastasis, recurrence and dementia. The primary outcome measure was the Gastrointestinal Quality of Life Index. Secondary outcome measures included the 36-item Short Form Survey. Inverse probability weights based on a multiple logistic regression model were used to balance prechosen covariates between the radiotherapy and no radiotherapy groups when assessing differences in outcomes.

Results

Of 5014 invited patients, 2142 (43%) eligible patients answered the questionnaires. Of these 762 (36%) were treated with neoadjuvant radiotherapy plus surgery and 1380 (64%) with surgery alone. The mean follow-up time was 6.4 and 7.4 years respectively. After propensity score matching, the Gastrointestinal Quality of Life Index differed significantly between irradiated and non-irradiated patients ((mean(s.d.), mean score 103.8(19.4) versus 110.8(19.6) respectively, mean difference: −6.96 (95% c.i. −8.72 to −5.19); P < 0.001). Among patients without a stoma the mean difference was −8.1 points, whereas it was −5.7 for patients with a stoma. The radiotherapy group also scored significantly lower in 7 of 8 36-item Short Form Survey domains compared with the surgery alone group.

Conclusion

Long-term quality of life was significantly lower in patients without a recurrence during the follow-up who received radiotherapy compared with patients who did not. These findings warrant a critical re-evaluation of the use of radiotherapy both in traditional neoadjuvant treatment and in modern organ-preserving treatment regimens.

The aim was to investigate the impact of radiotherapy on long-term quality of life after curative treatment for rectal cancer. Inverse probability weights based on a multiple logistic regression model were used to balance prechosen covariates between the radiotherapy and no radiotherapy group when assessing differences in outcome. Long-term quality of life was significantly lower in patients who received radiotherapy compared with patients who did not.

hospital and the surgical department
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pmcIntroduction

Neoadjuvant radiotherapy (RT) is widely used in rectal cancer treatment1. RT reduces local recurrence rates considerably, whereas the effect on overall survival (OS) has been limited after the introduction of total mesorectal excision (TME) by Bill Heald in the 1980s2–8. Long-course chemoradiotherapy (LC-CRT; 25 × 2 Gy) combined with 5-fluorouracil (5-FU) or capecitabine (Xeloda) has been the mainstay neoadjuvant treatment in Norway for many years, whereas short-course radiotherapy (SC-RT; 5 × 5 GY) has only been used more frequently in recent years9.

The proportion of irradiated patients with rectal cancer differs considerably between countries10. Norwegian guidelines recommend that patients with T4b disease, a short distance (≤2 mm) to the mesorectal fascia (MRF) or with suspected malignant lymph nodes on the pelvic sidewall, are offered preoperative chemoradiotherapy. According to the Cancer Registry of Norway (CRN) about 30–40% of Norwegian rectal cancer patients received RT annually between 2008 and 20209. In 2019, 33% of Norwegian rectal cancer patients were irradiated compared with 76% in The Netherlands11, due to very different indications (SC-RT recommended for low-risk T1–T3N1 tumours with distance to MRF >2 mm in The Netherlands but not in Norway). Despite a much lower frequency of RT, the relative 5-year survival for stage I–III patients with rectal cancer operated on is estimated to be 89.9% in Norway compared with approximately 84% in The Netherlands11,12. Likewise, the local recurrence in Norway has been around 4% since 2008 and is comparable to other countries such as Denmark, Sweden and The Netherlands, all with different irradiation rates11,13–15.

The effect of RT on quality of life (QoL) after rectal cancer treatment has primarily been studied for the first 2 years after surgery, whereas few studies have investigated long-term effects. The results of existing studies are heterogeneous, with some studies showing little and others profound impact of RT on QoL16–20.

The primary aim of this study was to investigate long-term QoL after curative treatment of rectal cancer and to explore the impact of RT on QoL. Secondary aims were to investigate functional outcomes and to compare QoL between these patients and the general population.

Methods

LaTE (Langtid livskvalitet for Tykktarmskreft og Endetarmskreft; long-term QoL for colon and rectal cancer) is a nationwide cross-sectional retrospective cohort study based on data from the Norwegian Patient Registry (NPR), the CRN and a national online patient survey. The study was approved by the Regional Committees for Medical Research Ethics South East Norway (Reference 2018/1938 REC South East A). This is the second part of the study reporting the results of patients with rectal cancer; the results of patients with colon cancer have been reported previously21.

Participants and inclusion

All stage I–III patients with rectal cancer under the age of 75 years at the time of surgery and operated on in Norway between 30 September 2007 and 1 October 2020 were eligible. Exclusion criteria were distant metastasis at diagnosis, any recurrence and dementia. The CRN identified all eligible patients with either recto-sigmoidal or rectal cancer (ICD-10 codes: C19 and C20). Their national ID numbers were transferred to Tietoevry AS (contractor of the Norwegian tax administration) who identified the postal addresses in the Norwegian Population Registry and sent invitation letters to all eligible patients. First invitations were sent in October 2021 and a reminder was sent in December 2021. Patients who reported either distant metastasis or local recurrence were excluded. Based on whether the patients had or had not received RT the cohort was divided into two study groups.

Data collection

A webform provided by the TSD (Tjenester for Sensitive Data) service, which is a national platform for secure data collection, storage and analysis (developed and maintained by the University of Oslo) was used to collect data securely. Safe patient log in using two-factor authentication (bank ID) allowed patients to confirm their identity, give informed consent and answer the questionnaire online. A paper version of the consent form and questionnaire was sent to patients unable to fill in the electronic version. Sensitive data was stored pseudonymized. A separately stored code key linked the study ID to the patient ID. The code key was then used to match data from the questionnaire with data from the CRN and the NPR.

Outcome measures and covariates

The Gastrointestinal QoL Index (GIQLI) was the primary outcome measure. GIQLI consists of 36 items and each item generates a score from 0–4 (see Appendix). The total score ranges from 0–144, 0 indicating worst and 144 indicating best QoL22. GIQLI for all patients was further analysed for the four domains: symptoms, emotional items, physical items and social items. Secondary outcome measures were the Short Form Health Survey (SF-36), Low Anterior Resection Syndrome (LARS) and the Scale for Chemotherapy-Induced long-term Neurotoxicity (SCIN) questionnaires (see Appendix). SF-36 consists of 36 items and can be divided into eight domains and one question about health change. The score for all domains ranges from 0 to 100, where 0 is the worst and 100 is the best23. SCIN consists of six items, and each item has four similar options to choose from, where 1 is the best and 4 is the worst24. LARS consists of five items, each item with a different range of scores. A score from 0–20 is defined as no LARS, 21–29 as minor LARS and 30–42 as major LARS25.

The whole survey consisted of a maximum of 107 questions. In addition to the GIQLI, SF36, SCIN and LARS questionnaires, there were questions about RT, duration of RT, chemotherapy, co-morbidity, stoma, bladder function and optional questions about sexual function. Functional outcomes will be reported in detail elsewhere.

Covariates retrieved from the NPR and the CRN included sex, age, ASA (American Society of Anesthesiologists) classification26, operation date, time since surgery, surgical access, surgical method, tumour distance from anus, reoperations, whether surgery was performed as an emergency, and pathological tumour (pT) and lymph node (pN) staging. ICD-10 codes provided by the NPR were used to calculate the Charlson Co-morbidity Index (CCI)27,28.

Statistics

Patient characteristics in the total sample as well as for the two study groups (RT yes versus no) are presented as mean(s.d.) for continuous variables, and as frequencies and percentages for categorical variables. The groups were compared as appropriate by χ2 test or independent-samples t-test. Unlike in randomized clinical trials (RCTs), the patient characteristics in an observational study may not be balanced between the comparison groups, potentially causing bias in the assessed effects. To balance the groups, the authors thus generated propensity scores, i.e. the probability of belonging to one of the groups, for each patient by estimating a multiple logistic regression model for RT (yes versus no) as the outcome, and all covariates listed in Table 1 as independent variables, which were also thoroughly examined for multicollinearity issues, an approach widely used in observational studies29. For analyses, the propensity scores were transformed to inverse probability weights30. Two methodological issues are important to consider when applying this approach: it may produce extreme weights for small groups of patients with very low or very high probabilities, elevating the variance; in addition, the size of the pseudo-population generated through inverse probability weighting is always larger than the size of the original sample, consequently underestimating the variance and thus increasing the risk of type I error. These issues were handled by generating stabilized weights31. In addition, a sensitivity analysis of the main outcome was performed, using traditional multivariable linear regression analysis.

Table 1 Patient characteristics for all patients based on stabilized weights

Covariates	Participants
N = 2142	No RT
N = 1380	RT
N = 762	P	
Age (years) at time of surgery, mean(s.d.)	60.5(9.2)	60.3(9.3)	60.8(9.1)	0.271*	
Sex Female	(3 missing)
847 (39.5)	(2 missing)
566 (39.2)	(1 missing)
283 (40.2)	0.720†	
BMI, mean(s.d.)	26.1(4.5)	26.2(4.6)	25.9(4.2)	0.149*	
CCI at time of surgery, mean(s.d.)	0.65(1.38)	0.64(1.37)	0.68(1.41)	0.527*	
Surgical method	(4 missing)	(2 missing)	(2 missing)		
 Anterior resection	1558 (72.7)	1060 (73.7)	497 (70.7)	0.305†	
 Hartman	87 (4.0)	56 (3.9)	30 (4.3)		
 Rectum amputation	459 (21.4)	294 (20.4)	166 (23.6)		
 Other resections	38 (1.8)	29 (2.0)	9 (1.3)		
Surgical access	(14 missing)	(6 missing)	(8 missing)		
 Laparotomy	1019 (47.6)	696 (48.3)	323 (45.9)	0.366†	
 Laparoscopy	1123 (52.4)	743 (51.7)	380 (54.1)		
Reoperations	236 (11.0)	163 (11.3)	74 (10.5)	0.582†	
Emergency surgery	34 (1.6)	23 (1.6)	10 (1.5)	0.875†	
Tumour distance from anus (cm), mean(s.d.)	8.6(4.3)	8.7(4.3)	8.6(4.2)	0.592*	
	(505 missing)	(402 missing)	(103 missing)		
Time since surgery (years), mean(s.d.)	6.7(3.6)	6.8(3.5)	6.7(3.7)	0.567*	
Current co-morbidity affecting QoL, yes	372 (17.4)	251 (17.4)	121 (17.93)	0.937†	
Chemotherapy (not concomitant)‡	(2 missing)	(2 missing)	(0 missing)	0.008†	
 No	1877 (87.6)	1241 (86.2)	636 (90.5)		
 Yes	265 (12.4)	198 (13.8)	67 (9.5)		
Beyond TME, yes	64 (3.0)	37 (2.6)	27 (3.8)	0.355*	
Other characteristics	
Age at time of survey (years), mean(s.d.)	67.2(9.5)	67.1(9.5)	67.5(9.4)	0.390*	
CCI at time of survey, mean(s.d.)	1.09(1.71)	1.05(1.68)	1.16(1.77)	0.179*	
ASA score	(532 missing)	(342 missing)	(190 missing)	0.003†	
 I	489 (22.8)	374 (26.0)	118 (16.8)		
 II	1430 (66.8)	926 (64.3)	502 (71.4)		
 III	211 (9.8)	131 (9.1)	79 (11.2)		
 IV	11 (0.5)	7 (0.5)	4 (0.5)		
 V	1 (0.05)	1 (0.1)	0		
cT-stage	(967 missing)	(637 missing)	(330 missing)	<0.001*	
 1	254 (11.9)	250 (17.3)	15 (2.2)		
 2	508 (23.7)	469 (32.6)	56 (8.0)		
 3	1127 (52.6)	638 (44.3)	474 (67.4)		
 4	252 (11.7)	83 (5.8)	158 (22.4)		
pT-stage	(649 missing)	(122 missing)	(527 missing)	0.004†	
 1	317 (14.8)	223 (15.5)	71 (10.1)		
 2	841 (39.3)	579 (40.2)	232 (33.0)		
 3	944 (44.1)	607 (42.2)	391 (55.7)		
 4	41 (1.9)	29 (2.0)	8 (1.2)		
pN-stage	(592 missing)	(111 missing)	(481 missing)		
 0	1598 (74.6)	1077 (74.8)	516 (73.4)	0.879†	
 1	400 (18.7)	265 (18.4)	141 (20.0)		
 2	144 (6.7)	97 (6.7)	46 (6.6)		
Stoma after surgery				<0.001†	
 No	616 (28.8)	534 (37.1)	82 (11.7)		
 Yes, but not anymore	830 (38.7)	478 (33.2)	352 (50.1)		
 Yes, ileostomy	45 (2.1)	23 (1.6)	22 (3.2)		
 Yes, colostomy	635 (29.7)	395 (27.5)	240 (34.1)		
 Yes, not sure what type	16 (0.8)	10 (0.7)	6 (0.9)		
Stoma				<0.001†	
 No	1446 (67.5)	1011 (70.3)	434 (61.8)		
 Yes	696 (32.5)	428 (29.7)	269 (38.2)		
Values are n (%) unless otherwise stated. Bold values show statistically significant differences (P < 0.050). RT, radiotherapy; BMI, body mass index; CCI, Charlson co-morbidity index; QoL, quality of life; TME, total mesorectal excision; ASA, American Society of Anesthesiologists; cT-stage, radiological tumor stage; pT-stage, pathological tumor stage; pN, pathological nodal stage. *Independent samples t-test. †χ2 test. ‡Does not include chemotherapy given together with long-course radiotherapy.

Differences in continuous primary and secondary outcomes were presented as mean differences and 95% confidence intervals (95% c.i.). For the main outcome (GIQLI), the mean total score was calculated for all patients in the two study groups. A subgroup analysis was then performed for patients with and without a stoma. A sensitivity analysis was performed for patients with RT depending on whether they received SC-RT or LC-CRT. An additional subgroup analysis of primary outcome was performed including only patients with tumours ≤12 cm above the anus (patients with missing tumour height excluded). Results from a Norwegian general population survey were used to generate normative data stratified by age and sex for SF-36 domains32.

All tests were two-sided, and results were considered statistically significant when P values were lower than 0.05. Adjustment for the multiple testing was not performed, however, all inferences are presented for transparency. STATA v.17 (Stata Corp LLC, Texas, USA) was used to perform all statistical analyses.

Results

Demographics

The CRN identified 5014 patients operated on for rectal or recto-sigmoidal cancer during the study interval without distant metastases at diagnosis or any recurrence. A total of 2180 patients (43%) answered the questionnaire either online (n = 2052) or on paper (n = 128). Of these 38 were excluded, either for reporting recurrent disease in the questionnaire or for dementia based on NPR data, leaving 2142 patients in the study. There were 762 patients (36%) who received RT and 1380 (64%) who did not (Figure 1). The mean follow-up time was 6.4(3.5) and median follow-up time was 5.9 (1.1 to 14.5) years for the surgery alone group, and 7.4(3.7) and 7.4 (1.4 to 14.3) years for those who received RT respectively. The proportion of female participants was 38.6%, whereas the proportion of females among all invited patients was 40.4%. The mean age at time of surgery was 60.4 years for the participants and 62 years for all invited patients (Table S1).

Fig. 1 Study flow diagram with exclusions

NPR, Norwegian Patient Registry.

Baseline characteristics

Table S1 shows the descriptive statistics of patient characteristics for the entire sample and the two study groups, and Tables S2, S3 show the descriptive statistics of patient characteristics for patients with and without a stoma respectively. Statistically significant differences among the covariates for the entire sample between the two groups were found for age at time of surgery, CCI at time of surgery, surgical method, surgical access, reoperations, emergency surgery, tumour distance from anus, time since surgery, chemotherapy (not concomitant) and beyond TME. After adjustment with inverse probability weighting based on propensity score, a statistically significant difference was found only for the covariate ‘chemotherapy (not concomitant)’ (Table 1). The balance between the groups was assessed by the overidentification test and presented graphically (Fig. S1).

Primary endpoint

Among patients without a stoma the primary endpoint GIQLI score differed statistically significantly between the groups (RT, (mean(s.d.)) 102.8(18.6) versus no RT, 110.9(19.4); mean difference: −8.1 (95% c.i. −10.53 to −5.67); P < 0.001; Fig. 2a and Table S4). Among patients with a stoma this difference was also statistically significant (RT, 105.4(20.6) versus no RT, 111.0(20.4); mean difference: −5.7 (95% c.i. −8.73 to −2.59); P < 0.001; Fig. 2a and Table S4). Overall, the GIQLI score differed significantly between patients who had or had not received RT (RT, 103.8(19.4) versus no RT, 110.8(19.6); mean difference: −7.0 (95% c.i. −8.72 to −5.19); P < 0.001; Fig. 2a and Table S4), which was also the case for patients with tumours below 12 cm (RT, 104.1(19.8) versus no RT, 109.6(19.8); mean difference: −5.5 (95% c.i. −7.71 to −3.30); P < 0.001; Table S4). In the sensitivity analysis using multivariable linear regression analysis the difference in GIQLI score was also significant for all three cohorts (Table S5).

Fig. 2 Symbols: ♦ with number = mean values

a Boxplots with median (horizontal line in the box), interquartile range (box), 95% confidence intervals (whiskers) and outliers (dots) for the gastrointestinal QoL index (GIQLI) for all patients, patients without a stoma and patients with a stoma in the two study groups (radiotherapy: yes/no). All cohorts are weighted separately with the same prechosen covariates. b Mean GIQLI for patients who did or did not receive radiotherapy as a function of time from surgery. Nonoverlapping 95% confidence intervals (whiskers) imply significant differences between the groups at each time interval.

In Fig. 2b, the difference in total GIQLI between the groups is illustrated as a function of time from operation. There were significant differences in GIQLI for all the time intervals between the two groups, except at 1 year (Table S6). There was no statistically significant difference in GIQLI between patients who had received SC-RT and patients who had received LC-CRT for all patients, for those without a stoma and those with a stoma (Table S4). There were significant differences between the two groups in favour of no RT in all the GIQLI domains: ‘emotional items’ (P < 0.050 for 3 of 5 items), ‘physical items’ (P < 0.050 for 6 of 7 items), ‘social items’ (P < 0.050 for 5 of 5 items) and ‘symptoms’ (P < 0.050 for 11 of 19 items) (Table S7).

Secondary endpoints

In the SF-36 instrument, 7 of 8 domains showed significantly lower scores for patients who received RT compared with those who did not receive RT (Fig. 3a and Table S8). Figure 3b shows deviation from normative values in the background population adjusted for age and sex for all patients, for both groups stratified by those with and without a stoma. The scores for SF-36 domains depending on the time from operation are illustrated for those not receiving and receiving RT in Fig. 3c,d respectively. No significant differences were seen between the groups at 1 year. Statistically significant differences were seen for ‘role-limit physical health’, ‘energy fatigue’, ‘social function’ and ‘general health’ for the time interval 2–3 years and for 4–6 years. ‘Physical function’ also differed significantly for the time interval 4–6 years and 7+ years. Significant differences were also seen for ‘social function’ and ‘general health’ for the time interval 7+ years.

Fig. 3 Symbols: ○ on a line = mean values

a Mean difference for the Short Form Health Survey (SF-36) domains between patients who did or did not receive radiotherapy. Boxplots with median (horizontal line in the box), interquartile range (box), 95% confidence intervals (whiskers) and outliers (dots). b Deviation from normative SF-36 score in the Norwegian population (dashed line) adjusted for age and sex for all patients, patients without a stoma and patients with a stoma in the two study groups (radiotherapy: yes/no). c and d SF-36 scores for the 4 subcohorts depending on time from surgery (c: patients with no RT, d: patients after RT). RT, radiotherapy; PF, physical function; RP, role-limit physical health; RE, role-limit emotional; EF, emotional fatigue; EW, emotional wellbeing; SF, social function; PA, pain; GH, general health.

Among patients with no stoma, major LARS (30–42 points) was significantly more frequent after RT and surgery (75.9%) than after surgery alone (46.3%; P < 0.001; Table S8).

A statistically significant difference was found in favour of no RT for SCIN 2 (paraesthesia of feet; P < 0.001) and SCIN 4 (numbness and coldness of feet; P = 0.012) for all patients between the two groups, and no significant differences were found for the rest of the SCIN items (Table S9).

Discussion

Among the 2142 eligible responders of this nationwide cross-sectional cohort study of disease-free patients with rectal cancer, the patients who received RT reported significantly lower QoL scores as measured by the GIQLI instrument. On average, their scores were 7.0 points lower compared with patients who did not receive RT. The difference was most pronounced in patients without a stoma. In this group, patients after RT had, on average, a GIQLI that was 8.1 points lower than patients with no RT. The difference was smaller among patients with a stoma, on average 5.7 points lower after RT compared with no RT. In addition, the SF-36 scores were significantly lower in 7 of 8 domains for patients who received RT. Furthermore, when adjusted for age and sex, their scores in the SF-36 domains role-limit physical, role-limit emotional, social function and general health were lower than those of the general population.

There have been a few studies looking at the long-term impact of RT on QoL among rectal cancer patients. A Norwegian and a Dutch study with a median follow-up time of 4.8 and 5.1 years respectively showed that both LC-CRT and SC-RT for rectal cancer are associated with considerable long-term effects on bowel frequency and faecal incontinence affecting QoL19,33. The present results are in line with these studies as both bowel frequency and faecal incontinence are significantly impacted by RT, when measured separately with the GIQLI instrument. These two symptoms also contribute towards a higher proportion of major LARS among patients after RT.

The minimal clinically important difference (MCID)34 for GIQLI in rectal cancer patients has not been investigated. After elective laparoscopic sigmoid resection for diverticular disease the MCID was estimated to be 10 points35. One may therefore question whether the observed difference in GIQLI (7.0 points for all patients and 8.1 points for those with no stoma and 5.7 for those with a stoma) is clinically important. However, in GIQLI the largest mean differences were seen for sexual life, endurance, physical strength, feeling unfit, bowel frequency, incontinence, bothered by treatment and urgency items in descending order. As there was a considerable difference in some items and little or no difference in other items it seems that the mean differences of 7.0 and 8.1 points are of relevance. Furthermore, the difference in GIQLI is smaller for patients with a shorter follow-up interval, possibly due to a delayed stoma reversal. One may therefore assume that the long-term effect of RT on GIQLI is slightly larger. In addition, for SF-36, single domains were much more affected than others (largest mean differences: role-limit physical 8.3, social function 5.3 and physical function 4.7 points).

Among patients without a permanent stoma, major LARS occurred significantly more frequently after RT (76%) than after surgery alone (46.3%), which is in line with other studies36. The fact that major LARS symptoms do not exclusively occur after low anterior resection (LAR) illustrates that the development of LARS is multifactorial. In a Danish study, 9.6% of healthy men and 18.8% of healthy women between 50 and 79 years of age reported major LARS37. Likewise, 24% of patients with colon cancer reported major LARS symptoms after colon resection21,38. After RT with complete clinical response (cCR) in a watch-and-wait setting, 24.9% of patients reported major LARS after 2 years39. These findings indicate that the combination of RT and LAR has a larger impact on the development of major LARS than either RT or LAR alone.

The two rationales for RT in patients with rectal cancer are to reduce the local recurrence rate and to achieve cCR. Local recurrence also has a major impact on QoL40,41, whereas patients after cCR and a watch-and-wait strategy presumably have a much better QoL than operated on patients. The present results indicate, however, that RT comes at a price, especially for patients who do not achieve cCR and who would otherwise have had a low risk of local recurrence after LAR alone. One may argue that patients with early stage, low rectal cancers requiring abdominoperineal resection (APR) have less to lose from RT and more to gain from cCR, which might encourage a more liberal use of RT in this group. Patients opting for RT instead of direct surgery in this situation, need to be informed about the increased risk of impaired QoL if they end up with both RT and APR.

We know that the majority of patients receiving long-term RT in Norway also receive concomitant capecitabine. In the last decade, LC-CRT has been the mainstay neoadjuvant regimen for rectal cancer in Norway. The trend has changed somewhat during the last few years because of the introduction of total neoadjuvant treatment (TNT) especially RAPIDO (Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation) where SC-RT is combined with oxaliplatin-based neoadjuvant chemotherapy42–46. The authors could not find any significant differences between patients receiving SC-RT and LC-CRT for the main endpoint GIQLI (Table S2). The SCIN questionnaire was added to the survey mainly because of concomitant chemotherapy. Although there were statistically significant differences for paraesthesia and coldness and numbness of feet in favour of no RT, these were very small. This was expected, as concomitant chemotherapy does not contain neurotoxic oxaliplatin.

The strengths of this study include the large number of participants (N = 2142), which to the authors' knowledge makes it the largest cohort study investigating long-term QoL for patients with rectal cancer. The use of propensity score-based inverse probability of treatment weighting is a major strength in the present study as it allowed us to balance major covariates between the groups. Another strength is the use of GIQLI as the main outcome measure. Compared with other QoL questionnaires such as SF-36, GIQLI as a disease-specific QoL instrument has the advantage that it also includes gastrointestinal symptoms. The high proportion of online participation (94%) resulted in very little missing data for the outcome measures. Further, the cross-sectional design of the study allowed a very long median follow-up time. This is therefore the largest study with such a long follow-up in a real-world setting.

One of the main limitations of the study is the low response rate of 43%. The differences in main baseline characteristics such as age at time of operation and survey, sex and ASA score between all invited individuals and the participants were small. The main important difference between the invited individuals and the participants was a slightly lower percentage of ASA III patients among the participants. It is unclear what impact this may have on the results, but one would expect the results to be equally impacted in both groups. Another limitation is missing values for some of the variables from the registry data, although this has been minimized by combining data from the NPR and the CRN. To account for some reporting mistakes and coding errors in register data the authors have placed more emphasis on information from the patients when there were discrepancies between register data and what patients had reported. Missing values for tumour height are of particular concern, as patients with higher tumours are less likely to be irradiated and are usually treated with partial mesorectal excision rather than TME. However, a subanalysis including only patients with a known tumour height below 12 cm did not change the effect of RT on the primary outcome considerably. Register data for RT were reliable as only 13 (<2%) patients registered without RT reported to have received RT, whereas all patients registered with RT in the register data confirmed that they had received RT.

The findings of this study warrant a critical re-evaluation of frequent RT use in some countries, both in the traditional neoadjuvant setting and in the modern organ-preserving treatment regimens, especially for patients with a low risk of local recurrence after surgery alone (that is T1–T3 tumours with >2 mm distance from tumour or metastatic lymph nodes to MRF).

Supplementary Material

zrae091_Supplementary_Data

Funding

Internal funding from the hospital and the surgical department.

Disclosure

The authors declare no conflict of interest.

Supplementary material

Supplementary material is available at BJS Open online.

Data availability

Available upon request.

Author contributions

Yasir Gulzar Malik (Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Validation, Visualization, Writing—original draft, Writing—review & editing), Jūratė Šaltytė Benth (Formal analysis, Methodology, Visualization, Writing—review & editing), Hanne M. Hamre (Conceptualization, Writing—review & editing), Arne Færden (Conceptualization, Supervision, Writing—review & editing) and Johannes Schultz (Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing)
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