J Clin Oncol 23: by American Society of Clinical Oncology INTRODUCTION

VOLUME

23

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NUMBER

9

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MARCH

20

2005

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

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 Corrie A.M. Marijnen, Cornelis J.H. van de Velde, Hein Putter, Mandy van den Brink, Cornelis P. Maas, Hendrik Martijn, Harm J. Rutten, Theo Wiggers, Elma Klein Kranenbarg, Jan-Willem H. Leer, and Anne M. Stiggelbout From the Departments of Clinical Oncology, Surgical Oncology, Medical Statistics, and Medical Decision Making, Leiden University Medical Center, Leiden; Departments of Radiotherapy and Surgery, Catharina Ziekenhuis, Eindhoven; Department of Surgery, Groningen University Hospital, Groningen; and Department of Radiotherapy, University Medical Center Nijmegen, Nijmegen, the Netherlands. Submitted November 14, 2004; accepted December 13, 2004. Supported by the National Health Council (Ontwikkelingsgeneeskunde OWG 97/026) and the Dutch Digestive Diseases Foundation (SWO 02-15). Presented at the European Society of Therapeutic Radiology and Oncology (ESTRO), Amsterdam, the Netherlands, October 19, 2004 and at the 2nd Multidisciplinary ColoRectal Cancer Congress of the Dutch Colorectal Cancer Group, the Netherlands, February 16, 2004. Authors’ disclosures of potential conflicts of interest are found at the end of this article. Address reprint requests to C.A.M. Marijnen, MD, Department of Clinical Oncology, Leiden University Medical Center, K1-P, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail: [email protected].

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Background Few prospective studies have been performed about the impact of preoperative radiotherapy (PRT) or total mesorectal excision (TME) on health-related quality of life (HRQL) and sexual functioning in patients with resectable rectal cancer. This report describes the HRQL and sexual functioning of 990 patients who underwent TME and were randomly assigned to short-term PRT (5 ⫻ 5 Gy). Patients and Methods The Rotterdam Symptom Check List supplemented with additional items was used with questionnaires before treatment and at 3, 6, 12, 18, and 24 months after surgery. Patients without a recurrence the first 2 years were analyzed (n ⫽ 990). Results Few differences were found in HRQL between patients treated with or without PRT. Daily activities were significantly less for PRT patients 3 months postoperatively. Irradiated patients recovered slower from defecation problems than TME-only patients (P ⫽ .006). PRT had a negative effect on sexual functioning in males (P ⫽ .004) and females (P ⬍ .001). Irradiated males had more ejaculation disorders (P ⫽ .002), and erectile functioning deteriorated over time (P ⬍ .001). PRT had similar effects in patients who underwent a low anterior resection (LAR) versus an abdominoperineal resection (APR). Patients with an APR scored better on the physical (P ⫽ .004) and psychologic dimension (P ⫽ .007) than LAR patients, but worse on voiding (P ⫽ .0007). Conclusion Short-term PRT leads to more sexual dysfunction, slower recovery of bowel function, and impaired daily activity postoperatively. However, this does not seriously affect HRQL. The comparison between LAR and APR patients demonstrates that the existence of a permanent stoma is not the only determinant of HRQL. J Clin Oncol 23:1847-1858. © 2005 by American Society of Clinical Oncology

© 2005 by American Society of Clinical Oncology 0732-183X/05/2309-1847/$20.00

R

INTRODUCTION

DOI: 10.1200/JCO.2005.05.256

In the treatment of rectal cancer, local recurrences are a major problem that cause severe disabling symptoms and are difficult to treat. With the introduction of total mesorectal excision (TME), the number of local

failures has decreased significantly.1-3 We demonstrated an additional beneficial effect of 5 ⫻ 5 Gy preoperative radiotherapy (PRT) in a large randomized multicenter trial (TME study) with a reduction of the local recurrence rate from 8.2% to 2.4% after 2 years, but no survival benefit so far.4 1847

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The advantage of the treatment should outweigh the negative impact of the treatment on patients’ functioning and quality of life. Consequently, information of the health-related quality of life (HRQL) after treatment is needed. However, these data cannot be found in the literature, and there exists a general lack of large longitudinal studies. Data on the effects of PRT have not yet been investigated in a prospective randomized fashion. Because little is known about HRQL in general, even less is known about specific aspects, such as defecation and sexual functioning. The influence of the type of surgery (abdominoperineal resection [APR]) versus low anterior resection [LAR]) on the HRQL of patients with rectal cancer has only been investigated in small retrospective studies.5-7 Therefore, we studied the effects of PRT on the HRQL and sexual functioning in patients treated in a randomized trial with an additional stratification for the two types of surgery for rectal cancer. PATIENTS AND METHODS Study Population and Treatment From January 1996 until December 1999, 1,861 patients were randomly assigned to PRT followed by standardized TME surgery or to TME surgery only in a large, international, multicenter trial. Details of the TME study have been described elsewhere.4 All patients were required to give informed consent before randomization. All patients underwent surgery according to the TME principle.4,8 Patients assigned to PRT received a total dose of 25 Gy in five fractions over 5 to 7 days. Surgery had to take place within 10 days of the start of PRT. HRQL was evaluated in Dutch patients only (n ⫽ 1,530) after informed consent was obtained. To determine the so-called price to be paid for the reduction of local recurrences, patients with any recurrence during the period of evaluation were excluded. Quality-of-Life Assessment Patients were asked to fill out an HRQL questionnaire before treatment and at 3, 6, 12, 18, and 24 months after surgery. Patients who failed to return two consecutive questionnaires were considered as withdrawn from the study and did not receive further questionnaires. Pretreatment forms filled in after start of radiotherapy or after surgery were considered missing, as were forms for which the date was missing.9 For the different time points, the following time windows were defined: 1.5 to 4.5 (3 months), 4.5 to 9 (6 months), 9 to 15 (12 months), 15 to 21 (18 months), and 21 to 27 (24 months). Patients with a missing form at a certain time point were still included in the other time points. Measures The HRQL questionnaire consisted of a measure of overall perceived health of the Rotterdam Symptom Check List (RSCL),10 a cancer-specific questionnaire, supplemented with questions on voiding and defecation problems and sexual functioning, because the RSCL did not include all specific symptoms related to rectal cancer. The time frame of the questionnaire is the past week. Overall perceived health was measured by a 100-mm horizontal visual analog scale (VAS), anchored by perfect health and death. The score is the number of millimeters from the death anchor to the mark, with higher scores indicating better health. 1848

The RSCL is a validated questionnaire with three subscales: physical symptom distress (23 items), psychologic distress (seven items), and activity level (eight items; Table 1). Responses were given on four-point scales. For physical and psychologic items, responses range from “not at all” to “very much,” and for the

Table 1. Items in RSCL and Self-Created Scales 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 Self-created voiding scale (3 items) 1 Pain during urinating 2 Problems with emptying bladder 3 Incontinence for urine Self-created defecation scale (9 items) 1 Flatulence 2 Pain during defecation 3 Anal pain, not during defecation 4 Incontinence for feces 5 Tenesmus 6 Blood or mucus from anus 7 Diarrhea 8 Constipation 9 Irregular defecation Abbreviation: RSCL, Rotterdam Symptom Check List.

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activity items, responses range from being unable to perform an activity up to being able to do so without help. In the activity subscale, the item about work was often missing because of the average age of the study population (65 years) and has therefore been excluded. As recommended in the RSCL scoring manual, personal scale means of the patients were substituted for missing values in cases where less than 50% of items were missing for that scale. Otherwise, the subscale was regarded as missing. Items within a scale were summed and linearly transformed to fit a range from 0 to 100, with lower scores representing better levels of functioning. The voiding scale contained three items, and the defecation scale contained nine items, including two items that were already included in the RSCL physical symptom scale (Table 1). Postoperatively, patients with a stoma did not fill out the defecation scale. Patients with a temporary diverting stoma filled out these items only after their stoma had been converted. The reliability of all self-created scales was determined by Cronbach’s ␣ coefficient at 24 months. For the defecation scale, ␣ was .92, and for the voiding scale, ␣ was .80, demonstrating good reliability. The questions on sexual functioning included an item on feeling sexually attractive and an item on sexual activity. Further, the questionnaire consisted of one general sexual functioning scale (three items: interest, pleasure, satisfaction; Cronbach’s ␣ for females ⫽ .88 and for males ⫽ .85); for females a scale on dyspareunia (two items: ␣ ⫽ .87) and an item on vaginal dryness were also included, and for males a scale on erectile dysfunction (three items: ␣ ⫽ .98) and one on ejaculatory problems (two items: ␣ ⫽ .86) were included. For the voiding, defecation, and sexual scales, summed scores were calculated as for the RSCL. Statistics For the voiding and defecation scale and the subscales of the RSCL, linear mixed models with random patient intercepts and time (categoric) and treatment group as fixed factors were used to obtain estimates of each of the scheduled time points, to account for random drop-out. In a preliminary study, it was shown that it was not necessary to incorporate nonignorable drop-out.9 At each time point, the difference in quality of life between the two treatment groups was tested by Wald’s tests. For this analysis, the function linear mixed-effects model (lme) of S-plus 2000 for Windows (version 3.3; Statistical Sciences, Insightful, Seattle, WA) was used. For sexual functioning, male and female patients were analyzed separately. To correct for multiple testing, a P value of .01 was considered statistically significant; 99% CIs were used in the figures. RESULTS

Study Population and Compliance Of the 1,530 Dutch patients, patients were excluded from analysis for the following reasons: ineligible at randomization (n ⫽ 50), no operation (n ⫽ 37), in-hospital deaths (n ⫽ 52), no informed consent for HRQL study (n ⫽ 89), and no HRQL forms returned (n ⫽ 30). In addition, 282 patients had a local or distant recurrence within the first 2 years, leaving 990 patients. Patient and treatment characteristics are listed in Table 2. The following pretreatment forms were missing: filled in after start of radiotherapy (n ⫽ 53), after surgery (n ⫽ 68), no date (n ⫽ 25), and not filled out at all (n ⫽ 58). Consequently, 786 pretreatment forms were adequately www.jco.org

Table 2. Patients Characteristics for the Evaluated Group PRT⫹ (n ⫽ 497) No. of Patients Median age, years Sex Male Female Operation type LAR APR Hartmann TNM stage 0/I II III Distance to anal verge 0-5 5-10 10-15 Unknown

%

PRT⫺ (n ⫽ 493) No. of Patients

64.0

%

64.0

P .61 .58

318 179

64.0 36.0

307 186

62.3 37.7

323 147 27

65.0 29.6 5.4

334 146 13

67.7 29.6 2.6

203 149 145

40.8 30.0 29.2

169 140 157

34.3 28.4 31.8

139 210 145 3

28.0 42.3 29.2 0.6

159 189 143 2

32.3 38.3 29.0 0.4

.08

.5

.36

Abbreviations: PRT⫹, radiotherapy and surgery; PRT⫺, surgery only; LAR, low anterior resection; APR, abdominoperineal resection.

filled in, a response rate of 78%. For the postoperative forms, response rates varied between 83% and 89%. HRQL With and Without PRT The HRQL for all patients is displayed in Figure 1. Overall perceived health, measured by the VAS, improved over time but did not differ significantly between treatment arms (Fig 1A). The observed differences for the VAS (range, ⫺1.4 to ⫹1.8) are negligible against the magnitude of the scale (0 to 100), the smallest possible increment (1.0), and the standard deviation of the PRT⫺ group (17.4). Few differences were found on the subscales of HRQL in patients treated with or without PRT (Figs 1B through 1F). The only significant difference between the treatment arms was the activity level at 3 months, with a worse score for PRT⫹ patients compared with PRT⫺ patients (mean, 11.3 v 8.5; P ⫽ .006; Fig 1B). No other significant differences were found at any time point in any scale. However, compared with baseline, PRT⫹ patients did worse at 3 months for both VAS score and physical symptom scale (Fig 1C), whereas this was not the case for PRT⫺ patients. From 6 months onwards this difference no longer existed, suggesting it takes PRT⫹ patients longer to recuperate from surgery. No treatment effect was observed in the defecation scale postoperatively. Because this was in contrast with the clinical impression that radiotherapy might impair anal sphincter function, we compared the items of the defecation scale separately. The only significant difference was observed in the incidence of fecal incontinence (considered present even when patient answered “sometimes” on question of fecal incontinence), which was at 24 months observed in 51.3% of the PRT⫹ patients and in 36.5% of the PRT⫺ patients (P ⫽ .002). 1849

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Fig 1. Health-related quality of life for preoperative radiotherapy (PRT)⫹ and PRT⫺ patients. Ninety-nine percent CIs of the mean are displayed on the y axis. P values represent overall differences between randomization arms. (*) P ⬍ .01 for the difference between the randomization arms at a specific time point.

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patients were sexually active. Postoperatively, a decline in sexual activity was observed both for male and female patients, which was larger in PRT⫹ patients than PRT⫺ patients (Fig 2). At 24 months, 76% of the PRT⫺ and 67% of the PRT⫹ male patients who were previously active were still sexually active (P ⫽ .06). For female patients, these figures were 90% and 72%, respectively (P ⫽ .01). For male patients, sexual functioning deteriorated postoperatively and more for PRT⫹ than PRT⫺ patients (Fig 3A). In the functioning scales, both erection (Fig 3B) and ejaculation problems (Fig 3C) increased after treatment, with especially ejaculation disorders more pronounced in PRT⫹ patients (P ⫽ .002). For female patients, postoperative sexual functioning was significantly worse for PRT⫹ patients at all time points compared with PRT⫺ patients (Fig 3D; P ⬍ .001). Postoperatively, both vaginal dryness (Fig 3E) and pain during intercourse (Fig 3F) worsened for all patients, but for these items no differences between the two treatment arms were seen. Subgroup analyses for APR and LAR patients demonstrated a similar overall outcome. All results on sexual functioning are summarized in Table 4.

For the psychologic distress scale, a significant improvement postoperatively was observed for both arms (Fig 1E), mainly resulting from an improvement in the items on anxiety, nervousness, stress, and worrying. In contrast, the voiding scale demonstrated a significant deterioration for all patients compared with baseline, which was still worse at 24 months (Fig 1F). The effects of time, randomization, and the difference in time by randomization group are listed in Table 3. We analyzed the influence of PRT on the HRQL separately for APR and LAR patients. The pattern between irradiated and nonirradiated patients for either APR or LAR patients was not different from the pattern for all patients together. In particular, patients who underwent an LAR did not have significantly more defecation problems after PRT⫹. Although irradiated patients tended to have an increase in defecation problems postoperatively (from 28.7 to 29.6), whereas defecation problems decreased in PRT⫺ patients (from 29.3 to 25.8), the score at 24 months was 20.8 for PRT⫹ and 19.5 for PRT⫺. All patients had significantly fewer complaints 2 years postoperatively compared with baseline (20.1 v 29.0; P ⬍ .0001). In APR patients, the results concerning voiding problems were similar to overall results, with no significant differences between the randomization groups. Results of these subgroup analyses are also listed in Table 3.

HRQL by Type of Surgery The stratification for APR versus LAR enabled us to compare the HRQL for patients with a permanent stoma (APR) versus patients with a temporary or no stoma (LAR; Fig 4). The VAS score, representing overall perceived health, was constantly somewhat lower in LAR patients

Sexual Functioning With and Without PRT Before treatment, 81% of PRT⫹ and 78% of the PRT⫺ male patients and 53% of PRT⫹ and 50% of PRT⫺ female

Table 3. Health-Related Quality-of-Life Scores by Randomization Group and by Operation Type PRT⫹

PRT⫺

P

Randomization

3

6

12

18

24

3

6

12

18

24

Time

Randomization

Time by Randomizationⴱ

Overall health† Activity level Physical scale Psychological scale Voiding scale Defecation scale‡ LAR Overall health† Activity level Physical scale Psychological scale Voiding scale Defecation scale‡ APR Overall health† Activity level Physical scale Psychological scale Voiding scale

73.9 11.3 14.4 16.3 11.7 28.9

76.4 7.8 12.4 13.8 10.4 24.5

77.2 7.3 12.0 14.1 10.2 22.1

77.1 7.7 12.0 13.5 10.1 19.9

77.1 8.0 12.3 13.0 10.4 20.7

75.6 8.5 13.0 15.5 11.8 25.2

76.9 6.8 12.5 14.6 10.5 23.8

78.9 5.6 11.9 14.0 9.3 19.6

78.7 5.9 12.1 12.5 10.0 19.8

78.7 5.6 12.0 12.4 9.7 19.3

⬍ .001 ⬍ .001 ⬍ .001 ⬍ .001 ⬍ .001 ⬍ .001

.18 .04 .57 .76 .63 .12

.53 .26 .03 .66 .73 .006

72.9 12.1 14.9 17.5 9.8 29.6

75.6 7.4 12.7 15.4 9.3 24.9

77.1 7.5 11.9 14.5 9.3 22.6

76.8 7.4 12.3 15.1 8.8 20.2

77.7 7.7 12.2 14.2 9.4 20.8

74.8 8.7 13.8 16.2 11.1 25.8

76.5 7.2 13.4 14.9 10.1 24.0

78.3 5.8 12.7 14.5 8.6 19.7

78.3 6.6 12.8 12.5 9.8 20.0

78.0 5.7 12.9 13.3 9.0 19.5

⬍ .001 ⬍ .001 ⬍ .001 ⬍ .001 .04 ⬍ .001

.33 .14 .81 .43 .84 .10

.64 .05 .03 .49 .21 .007

77.0 9.2 12.8 13.4 15.3

79.3 7.0 11.2 10.8 12.0

78.5 5.3 11.8 12.5 11.3

78.7 6.7 10.7 9.9 11.2

77.9 7.3 11.6 9.6 10.9

77.6 7.8 11.5 14.0 13.4

77.8 5.8 10.5 13.8 11.7

80.8 5.2 10.3 12.8 11.1

79.8 4.5 10.5 12.2 10.4

79.3 5.4 10.2 10.1 11.3

.15 ⬍ .001 .005 ⬍ .001 ⬍ .001

.69 .40 .34 .38 .76

.35 .80 .45 .30 .63

Abbreviations: PRT⫹, radiotherapy and surgery; PRT⫺, surgery alone; LAR, low anterior resection; APR, abdominoperineal resection. ⴱ Difference in time effect between randomization groups. †For overall perceived health, a higher score indicates a better health; for all other scales, a higher score indicates more problems. ‡For patients without a stoma.

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Fig 2. Sexual activity of (A) male and (B) female patients who were sexually active preoperatively. P values represent the difference between the randomization arms at each time point.

(P ⫽ .04). No difference in activity level was observed between types of resection (P ⫽ .30). Postoperatively, APR patients had fewer physical (P ⫽ .004) and psychologic (P ⫽ .007) problems but had more voiding problems (P ⫽ .007) compared with LAR patients. At 24 months, male and female LAR patients were slightly more sexually active (75% and 90%, respectively) than male and female APR patients (63% and 72%, respectively; P ⫽ .03 and P ⫽ .01). Erection disorders in males and pain during intercourse in females were significantly worse for APR patients (P ⬍ .001 and P ⫽ .006, respectively; Table 5). 1852

DISCUSSION

Patients treated for rectal cancer may experience a wide range of problems affecting their physical, psychological, social, and emotional functioning. Although the occurrence and incidence of postoperative complications is well documented,11,12 the impact of rectal cancer and its treatment on quality of life has only been studied in small series.13-16 Even less is known about the impact of rectal cancer and its treatment on sexual functioning. Our study is the first prospective randomized study addressing both HRQL and sexual functioning. The JOURNAL OF CLINICAL ONCOLOGY

QOL/Sexual Functioning and Rectal Cancer Treatment

Fig 3. Sexual functioning of preoperative radiotherapy (PRT)⫹ and PRT⫺ male and female patients. Ninety-nine percent CIs of the mean are displayed on the y axis. P values represent overall differences between randomization arms. *P ⬍ .01 for the difference between the randomization arms at a specific time point.

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Table 4. Sexual Function Scores by Randomization Group and by Operation Type PRT⫹

Male Sexual functioning Erection disorders Ejaculation disorders Female Sexual functioning Vaginal dryness Pain during intercourse LAR Male Sexual functioning Erection disorders Ejaculation disorders Female Sexual functioning Vaginal dryness Pain during intercourse APR Male Sexual functioning Erection disorders Ejaculation disorders Female Sexual functioning Vaginal dryness Pain during intercourse

PRT⫺

P Randomization

Time by Randomizationⴱ

3

6

12

18

24

3

6

12

18

24

Time

46.2 43.4 34.1

47.2 48.9 36.4

46.4 52.6 39.1

47.6 52.7 43.6

47.4 53.9 42.5

40.3 44.2 32.7

38.6 42.0 28.7

39.4 45.3 28.6

41.5 44.6 30.0

40.8 47.1 31.7

.18 ⬍ .001 .09

.004 .03 .002

51.8 35.5 23.6

48.3 35.7 21.3

48.2 39.5 21.5

49.5 36.8 21.3

50.0 38.8 20.7

35.2 33.3 22.9

33.1 32.3 17.7

30.3 29.9 16.9

32.4 25.8 18.7

29.9 35.1 20.0

.005 .36 .16

⬍ .001 .21 .67

.67 .27 .82

43.9 38.4 32.9

45.7 44.2 32.6

44.2 49.6 39.0

46.3 50.1 42.9

46.5 50.8 42.5

38.9 37.4 30.7

36.5 35.6 26.8

36.5 38.8 25.8

41.0 39.1 28.0

38.2 43.6 29.3

.12 ⬍ .001 .02

.01 .05 .01

.37 .005 .02

49.6 35.3 17.6

43.7 35.6 18.9

44.1 37.9 18.3

46.5 34.2 15.9

48.1 36.6 15.4

32.6 30.8 21.0

32.5 30.7 15.1

27.5 29.2 16.4

33.3 26.8 15.4

28.6 33.3 18.5

.01 .47 .17

⬍ .001 .26 .89

.47 .99 .66

52.2 51.6 39.2

51.5 57.3 45.0

49.3 56.6 39.3

49.0 57.1 44.4

47.5 59.4 41.7

42.3 57.1 35.6

42.2 52.0 31.0

45.6 57.3 32.9

42.4 52.7 33.4

45.7 53.1 35.2

.77 .45 .95

.21 .33 .07

.74 .29 .59

53.0 30.3 37.5

59.2 39.4 30.6

56.4 43.6 34.5

57.7 46.7 37.8

53.0 50.0 41.7

43.6 41.0 39.5

38.1 37.3 26.0

35.3 33.3 17.5

27.8 24.1 23.7

33.2 37.9 23.8

.17 .73 .67

⬍ .001 .65 .19

.40 .01 .93

.62 .002 .002

NOTE. A higher score indicates more problems. Abbreviations: PRT⫹, radiotherapy and surgery; PRT⫺, surgery alone; LAR, low anterior resection; APR, abdominoperineal resection. ⴱ Difference in time effect between randomization arms.

results of this study enable physicians and patients to weigh the beneficial effect of PRT on local recurrence against the price to be paid in terms of HRQL and sexual functioning. We demonstrate that for patients without recurrence, sexual activity declines postoperatively for both male and female patients. The clear difference between the randomization arms in sexual functioning was not reflected in the values patients assigned to their general health. Nevertheless, patients who were no longer sexually active postoperatively demonstrated a lower VAS score (five points) than patients who remained sexually active (data not shown). The only significant difference in HRQL scales concerned the activity level at 3 months postoperatively, with a worse score for the PRT⫹ group. In addition, the differences in VAS score, activity level, and physical problems between irradiated and nonirradiated patients were consistently larger at 3 months compared with 6 months, suggesting that patients who undergo radiotherapy have more difficulties in recuperating after surgery than patients who do not. For female patients, sexual activity and functioning deteriorated significantly more in PRT⫹ patients, suggesting that radiotherapy is the most influencing factor. A negative influence of PRT was also observed in males for ejaculation disor1854

ders, with a further deterioration over time, which can be explained by the fact that the seminal vesicles have been irradiated and may stop functioning. Irradiated men show a decrease in erectile function for up to 2 years, suggesting late radiation damage to the small vessels. We therefore conclude that short-term PRT does lead to a significant deterioration in sexual functioning, but this is not reflected in a worse valuation of HRQL. An explanation for this might be the fact that patients consider sexual functioning least important for their HRQL, as has been demonstrated in studies in the WHO quality of life (WHOQOL).17 Postoperative worsening of voiding was observed both for patients who underwent radiotherapy and those who did not. These results demonstrate that with TME surgery, damage to the hypogastric plexus still occurs, resulting in reduced bladder function. APR patients have more difficulties with voiding and erection and report more pain during intercourse compared with LAR patients. This can be explained by the fact that more plexus damage occurs in APR patients, especially during the perineal phase, where the distal branches of the pelvic autonomic nerves are at risk.18 We found no significant differences in defecation problems between the treatment arms. This was in contrast with JOURNAL OF CLINICAL ONCOLOGY

QOL/Sexual Functioning and Rectal Cancer Treatment

Fig 4. Health-related quality of life for patients who underwent abdominoperineal resection or low anterior resection. (A) Overall perceived health, (B) daily activity, (C) physical, (D) psychological, (E) voiding. Ninety-nine percent CIs of the mean are displayed on the y axis. P values represent overall differences between resection types. (*) P ⬍ .01 for the difference between the resection types at a specific time point.

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Table 5. Health-Related Quality-of-Life and Sexual Functioning for the Different Operation Types Abdominoperineal Resection

Overall health† Activity level Physical scale Psychologic scale Voiding scale Male Sexual functioning Erection disorders Ejaculation disorders Female Sexual functioning Vaginal dryness Pain during intercourse

Low Anterior Resection

P

3

6

12

18

24

3

6

12

18

24

Time

Surgery

77.3 8.5 12.1 13.7 14.4

78.6 6.4 10.8 12.3 11.9

79.6 5.3 11.1 12.6 11.2

79.3 5.7 10.6 11.0 10.8

78.6 6.4 10.9 9.9 11.1

73.8 10.4 14.3 16.8 1.4

76.0 7.3 13.1 15.1 9.7

77.7 6.6 12.3 14.5 8.9

77.5 7.0 12.5 13.8 9.3

77.8 6.7 12.5 13.7 9.2

⬍ .001 ⬍ .001 ⬍ .001 ⬍ .001 ⬍ .001

.04 .30 .004 .007 .007

46.8 54.6 37.3

46.6 54.4 37.2

47.3 57.0 35.9

45.6 54.7 38.4

46.5 56.1 38.4

41.4 37.8 31.3

41.1 39.6 29.5

40.2 44.0 32.1

43.7 44.7 35.6

42.5 47.2 36.0

.52 ⬍ .001 .64

.02 ⬍ .001 .13

47.8 36.1 33.3

48.1 38.1 28.0

43.9 37.4 24.5

42.8 34.3 29.9

41.7 42.2 30.3

40.7 32.9 19.5

37.4 33.0 16.8

36.1 33.3 17.3

39.8 30.1 15.7

38.4 34.8 17.2

.006 .42 .12

.24 .46 .006

Time by Surgeryⴱ .23 .71 .42 .47 .12 .39 ⬍ .001 .27 .66 .90 .78

ⴱ

Difference in time effect between types of surgery. †For overall perceived health, a higher score indicates a better health; for all other scales, a higher score indicates more problems.

clinical experiences and with the report of Dahlberg et al, in which all surviving patients previously treated in a randomized trial were sent a questionnaire. They demonstrated a deterioration in anal sphincter function in patients randomized for short-term preoperative radiotherapy.19 We therefore analyzed each item of the defecation scale separately and found significantly more fecal incontinence in the PRT⫹ patients. The avoidance of a permanent stoma is generally regarded as a favorable strategy, as recently underlined by several randomized trials, in which the number of sphincter saving procedures was an important outcome measure.20-22 However, patients undergoing sphincter-saving surgery (SSS) may develop a number of distressing symptoms, typically fecal soiling and urgency, especially with low anastomoses. Many studies on HRQL in SSS have been performed, but most were small and retrospective.5,6,23 A recent review of 34 studies and 6,570 patients concluded that SSS should always be the procedure of choice, unless the tumor invades the anal sphincter.24 We found no significant difference in the overall perceived health between patients who underwent APR versus LAR. APR patients had fewer physical and psychological problems but more voiding problems. These results suggest that SSS may not always improve the HRQL and illustrate the complexity of the discussion about sphincter-saving procedures. The desirability of avoiding a permanent stoma is mainly determined by patients’ preferences and sociodemographic characteristics. For example, in countries where stoma care is insufficient or difficult because of climatologic circumstances, SSS may be preferable. Muslim patients who underwent an APR instead of SSS more often stopped praying and fasting during Ramadan.25 Therefore, we believe that SSS must

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be discussed with patients and patients’ personal situation should be taken into consideration. In general, analysis and interpretation of HRQL results remains a topic of discussion. Small numeric differences in mean scores may give statistically significant results in large samples sizes, but the interpretation of these differences is uncertain. In a study to determine the significance of observed changes in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, it was found that a change in mean score between five and 10 on a scale running from zero to 100 was interpreted as small, a change between 10 and 20 was interpreted as moderate, and a change greater than 20 was interpreted as large.26 Although we have to be careful to assume that a similar approach can be used for our results, the observed differences in our study cannot even be considered small. In conclusion, HRQL is not significantly affected by short-term 5 ⫻ 5 Gy PRT, although patients need more time to recover after PRT and PRT negatively affects sexual functioning. In addition, the HRQL does not significantly differ for LAR or APR patients. We believe that the impact of radiotherapy and the type of surgery should be discussed with the patient and the choice of treatment should be based on staging as well as patients’ characteristics and preferences. ■ ■ ■

Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.

JOURNAL OF CLINICAL ONCOLOGY

QOL/Sexual Functioning and Rectal Cancer Treatment

Appendix. List of Cooperative Clinical Investigators Surgeons: A.B. Bijnen, P. de Ruiter, Medisch Centrum Alkmaar, Alkmaar; B. van Ooijen, Algemeen Christelijk Ziekenhuis Eemland Locatie de Lichtenberg, Amersfoort; D. van Geldere, R.P.A. Boom, Ziekenhuis Amstelveen, Amstelveen; R.P. Bleichrodt, S. Meyer, Academisch Ziekenhuis Vrije Universiteit, Amsterdam; R.M.J.M. Butzelaar, E.Ph. Steller, Sint Lucas Andreas Ziekenhuis, Locatie Lucas, Amsterdam; W.F. van Tets, A.C.H. Boissevain, Sint Lucas Andreas Ziekenhuis, Locatie Andreas, Amsterdam; F.J. Sjardin, BovenIJ Ziekenhuis, Amsterdam; J.F.M. Slors, Academisch Medisch Centrum, Amsterdam; W.H. Bouma, J.G.J. Roussel, Gelre Ziekenhuizen, Apeldoorn; J.H.G. Klinkenbijl, E.J. Spillenaar Bilgen, Ziekenhuis Rijnstate, Arnhem; Ph.M. Kruyt, W.K. de Roos, Stichting Ziekenhuisvoorzieningen Gelderse Vallei Locatie Ziekenhuis Gelderse Vallei Bennekom, Bennekom; E.J.R. Slingenberg, P.D. de Rooij, Sint Ziekenhuis Lievensberg, Bergen op Zoom; M.A.J.M. Hunfeld, Rode Kruis Ziekenhuis, Beverwijk; A.L.A. Meersman, Maasziekenhuis Boxmeer, Boxmeer; J.K.S. Nuytinck, Ignatius Ziekenhuis Breda, Breda; R.M.P.H. Crolla, Ziekenhuis de Baronie, Breda; J. van der Bijl, Atrium Brunssum, Atrium Heerlen, Brunssum, Heerlen; G.W.M. Tetteroo, IJsselland Ziekenhuis, Capelle A/D Ijssel; L.P.S. Stassen, P.W. de Graaf, Reinier de Graaf Groep Loc. Reinier de Graaf Gasthuis, Delft; W.A.H. Gelderman, F.G.J. Willekens, Bosch Medicentrum Locatie Groot Ziekengasthuis, Den Bosch; I.P.T. van Bebber, E.J. Carol, Stichting Carolus-Liduina-Lindelust Ziekenhuis Locatie Carolus Ziekenhuis, Den Bosch; G.W. Kastelein, H. Boutkan, Rode Kruis Ziekenhuis, Den Haag; Ch. Ulrich, B.C. de Vries, Medisch Centrum Haaglanden Locatie Westeinde, Den Haag; H.J. Smeets, J.M. Heslinga, Stichting Bronovo-Nebo, Ziekenhuis Bronovo, Den Haag; W.H. Steup, P.V.M. Pahlplatz, Ziekenhuis Leyenburg, Den Haag; P. Heres, J.A. van Oijen, Stichting het van Weel-Bethesda Ziekenhuis, Dirksland; M. van Hillo, Stichting Talma Sionsberg, Dokkum; R.J. Oostenbroek, K.G. Tan, Albert Schweitzer Ziekenhuis Locatie Dordwijk, Dordrecht; H.C.J. van der Mijle, Christelijk Ziekenhuis Nij Smellinghe, Drachten; R. Looijen, Christelijk Ziekenhuis Nij Smellinghe, Drachten; J.J. Jakimowicz, Catharina Ziekenhuis, Eindhoven; O.J. Repelaer van Driel, P.H.M. Reemst, Diaconessenhuis Eindhoven, Eindhoven; E.J.Th. Luiten, R.F.T.A. Assmann, Sint Annaziekenhuis, Geldrop; C.M. Dijkhuis, Oosterscheldeziekenhuis, Goes; R.T. Ottow, Het Groene Hart Ziekenhuis Locatie Bleuland, Gouda; J.T.M. Plukker, Academisch Ziekenhuis Groningen, Groningen; E.J. Boerma, R. Silvis, Kennemer Gasthuis Locatie Deo, Haarlem; J.H. Tomee, Stichting Streekziekenhuis Coevorden-Hardenberg, Hardenberg; G.J.M. Akkersdijk, Spaarne Ziekenhuis, Heemstede; C.G.B.M. Rupert, de Tjongerschans, Ziekenhuis Heerenveen, Heerenveen; G.J.C.M. Niessen, G. Verspui, Elkerliek Ziekenhuis Locatie Helmond, Helmond; J.H. Kroesen, J.W. Juttmann, Ziekenhuis Hilversum, Hilversum; J.W.D. de Waard, M.W.C. de Jonge, Westfries Gasthuis Locatie Sint Jan, Hoorn; D.B.W. de Roy van Zuidewijn, W. Dahmen, Medisch Centrum Leeuwarden, Leeuwarden; R. Vree, J.A. Zonnevylle, Diaconessenhuis Leiden, Leiden; C.J.H. van de Velde (Principal Investigator), R.A.E.M. Tollenaar, Leiden University Medical Center, Leiden; P.A. Neijenhuis, S.A. da Costa, S.K. Adhin, Rijnland Ziekenhuis Locatie Sint Elisabeth, Leiderdorp; F.J. Idenburg, Medisch Centrum Haaglanden Locatie Antoniushove, Leidschendam; H. van der Veen, IJsselmeerziekenhuizen Loc. Zuiderzeeziekenhuis, Lelystad; C.E.A.M. Hoynck van Papendrecht, IJsselmeerziekenhuizen Locatie Zuiderzeeziekenhuis, Lelystad; C.G.M.I. Baeten, M.F. von Meyenfeldt, G.L. Beets, Academisch Ziekenhuis Maastricht, Maastricht; T. Wobbes, Academisch Ziekenhuis Nijmegen Sint Radboud, Nijmegen; E.D.M. Bruggink, L.J.A. Strobbe, Canisius-Wilhelmina Ziekenhuis Nijmegen, Nijmegen; O.J. van West, R.A.J. Dörr, Pasteurziekenhuis, Oosterhout; C.D. van Duyn, Ziekenhuis Bernhoven Locatie Oss, Oss; J.W.M. Bol, Th.A.A. van den Broek, Waterlandziekenhuis, Purmerend; J.M.H. Debets, R.J.A. Estourgie, Laurentius Ziekenhuis, Roermond; H.W.P.M. Kemperman, Ziekenhuis Franciscus, Roosendaal; H.F. Veen, W.F. Weidema, C.J. van Steensel, Ikazia Ziekenhuis, Rotterdam; F. Logeman, A.A.E.A. de Smet, Sint Clara Ziekenhuis, Rotterdam; A.W.K.S. Marinelli, Academisch Ziekenhuis Rotterdam, Daniel den Hoed Kliniek, Rotterdam; J.H. Driebeek-van Dam, Havenziekenhuis, Rotterdam; W.R. Schouten, P.P.L.O. Coene, Academisch Ziekenhuis Rotterdam, Dijkzigt, Rotterdam; M.A. Paul, Zuiderziekenhuis, Rotterdam; J.J. van Bruggen, Schieland Ziekenhuis, Schiedam; E.J. Mulder, Antonius Ziekenhuis, Sneek; R. den Toom, A.J. van Beek, Ruwaard van Putten Ziekenhuis, Spijkenisse; S.J. Brenninkmeyer, G.P. Gerritsen, TweeSteden ziekenhuis, Tilburg; H.J.M. Oostvogel, J.A. Roukema, Sint Elisabeth Ziekenhuis, Tilburg; E.B.M. Theunissen, Mesos, Medisch Centrum Locatie Overvecht, Utrecht; L.W.M. Janssen, A. Hennipman, Universitair Medisch Centrum Utrecht, Utrecht; A.J.M. van Wieringen, Mesos, Medisch Centrum Locatie Oudenrijn, Utrecht; A. Pronk, P. Leguit, Diakonessenhuis, Utrecht; F.A.A.M. Croiset van Uchelen, R.M.H. Roumen, Sint Joseph Ziekenhuis, Veldhoven; C.L.H. van Berlo, J.F.M. Reinders, Sint Maartens Gasthuis, Venlo; C.D.G.W. Verheij, Sint Elisabeth Ziekenhuis, Venray; J.H. ten Thije, Ziekenhuis Walcheren, Vlissingen; W. van Overhagen, I.H. Oei, Reinier de Graaf Groep Locatie Diaconessenhuis Voorburg, Voorburg; E.M.G. Leerkotte, J.W.A. van Luijt, TweeSteden ziekenhuis, Waalwijk; H.C.M. Verkooyen, J.A.L. Jansen, Sint Jans-Gasthuis, Weert; J. Merkx, J.P. Vente, Hofpoort Ziekenhuis, Woerden; H. de Morree, Stichting Oosterscheldeziekenhuizen, Zierikzee; P.J.J. van Rijn, ’t Lange Land Ziekenhuis, Zoetermeer; W.F. Blom, Albert Schweitzer Ziekenhuis Locatie Zwijndrecht, Zwijndrecht. Pathologists: J.P.A Baak, Medisch Centrum Alkmaar, Alkmaar; H. Barrowclough, Algemeen Christelijk Ziekenhuis Eemland Locatie de Lichtenberg, Amersfoort; E. Bloemena, Vrije Universiteit, Amsterdam; G.J.A. Offerhaus, Academisch Medisch Centrum, Amsterdam; G. Brutel de la Riviere, Sint Lucas Andreas Ziekenhuis Locatie Sint Lucas, Amsterdam; M.L.F. van Velthuysen, Antoni van Leeuwenhoekziekenhuis, Amsterdam; B.A. van de Wiel, Sint Lucas Andreas Ziekenhuis Locatie Andreas, Amsterdam; H.H. Oushoorn, BovenIJ Ziekenhuis, Amsterdam; Th.A.J.M. Manschot, Gelre Ziekenhuizen, Apeldoorn; J.M. Wiersma-van Tilburg, Ziekenhuis Rijnstate, Arnhem; V. Potters, Stichting Ziekenhuis Lievensberg, Bergen op Zoom; H.V. Stel, Ziekenhuis Gooi-Noord, Blaricum; J. Los, Ignatius Ziekenhuis Breda, Breda; G.W. Verdonk, Atrium Brunssum, Brunssum; C. van Krimpen, S.H. Sastrowijoto, E.M. van der Loo, Stichting Diagnostisch Centrum Stichting Samenwerkende Delftse Ziekenhuizen, Delft; H.A. Meijer, Bosch Medicentrum Locatie Groot Ziekengasthuis, Den Bosch; P. Blok, Ziekenhuis Leyenburg, Den Haag; C.J. Tinga, Stichting Bronovo-Nebo, Ziekenhuis Bronovo, Den Haag; E.C.M. Ooms, Medisch Centrum Haaglanden Locatie Westeinde, Den Haag; C.M. Bruijn-van Duinen, Ziekenhuis Leyenburg, Den Haag; J.W. Steffelaar, Rode Kruis Ziekenhuis, Den Haag; P.J. Westenend, Pathologisch Laboratorium voor Dordrecht en omstreken, Dordrecht; I.W.N. Tan-Go, H.M. Peters, Stichting Pathologische Anatomie en Medische Microbiologie, Eindhoven; E.J.M. Ahsmann, Stichting LaboratoriaGoudse Ziekenhuizen, Gouda; J.F. Keuning, Stichting Pathologisch Anatomisch Laboratorium Kennemerland, Haarlem; K. van Groningen, Spaarne Ziekenhuis, Heemstede; P.H.M.H. Theunissen, Atrium Heerlen, Heerlen; F.J.J.M. van Merrienboer, Elkerliek Ziekenhuis Locatie Helmond, Helmond; G. Freling, Ziekenhuis Bethesda, Hoogeveen; A.J.K. Grond, Laboratorium voor de Volksgezondheid in Friesland, Leeuwarden; M.C.B. Gorsira, Diaconessenhuis Leiden, Leiden; J.J. Calame, Rijnland Ziekenhuis Locatie Sint Elisabeth, Leiderdorp; E.A. Neefjes-Borst, IJsselmeerziekenhuizen Locatie Zuiderzeeziekenhuis, Lelystad; J.W. Arends, academisch ziekenhuis Maastricht, Maastricht; A.P. Runsink, Streeklaboratorium “Zeeland”, Middelburg; C.A. Seldenrijk, Stichting Sint Antonius Ziekenhuis, Nieuwegein; J.H.J.M. van Krieken, Academisch Ziekenhuis Nijmegen St Radboud, Nijmegen; M. Mravunac, Canisius-Wilhelmina Ziekenhuis Nijmegen, Nijmegen; W.S. Kwee, Laurentius Ziekenhuis, Roermond; H. van Dekken, Academisch Ziekenhuis Rotterdam, Daniel den Hoed Kliniek, Rotterdam; J.C. Verhaar, Stichting Pathan, Rotterdam; N.A.L. van Kaam, Stichting Pathan, Rotterdam; H. van Dekken, Academisch Ziekenhuis Rotterdam, Dijkzigt, Rotterdam; R.W.M. Giard, Sint Clara Ziekenhuis, Rotterdam; H. Beerman, Zuiderziekenhuis, Rotterdam; A.A.M. van der Wurff, Sint Elisabeth Ziekenhuis, Tilburg; M.E.I. Schipper, Universitair Medisch Centrum Utrecht, Utrecht; H.M. Ruitenberg, Diakonessenhuis, Utrecht; R.F.M. Schapers, Stichting Pathologisch Laboratorium, Venlo; A.P. Willig, Sint Jans-Gasthuis, Weert; A.G. Balk, Stichting Ziekenhuis De Heel, Zaandam. Radiation Oncologists: E.H.J.M. Rutten, Medisch Centrum Alkmaar, Alkmaar; D. Gonzalez Gonzalez, G. van Tienhoven, Academisch Medisch Centrum, Amsterdam; B.J. Slotman, J.A. Langendijk, Academisch Ziekenhuis Vrije Universiteit, Amsterdam; G.M.M. Bartelink, B.M.P. Aleman, Antoni van Leeuwenhoekziekenhuis, Amsterdam; A.H. Westenberg, Arnhems Radiotherapeutisch Instituur, Arnhem; J. Pomp, Reinier de Graaf Gasthuis, Delft; C.C.E. Koning, R.G.J. Wiggenraad, Medisch Centrum Haaglanden Locatie Westeinde, Den Haag; F.M. Gescher, Ziekenhuis Leyenburg, Den Haag; J.J.F.M. Immerzeel, A.C.A. Mak, Radiotherapeutisch Instituut Stedendriehoek en Omstreken, Deventer; J.G. Ribot, Catharina Ziekenhuis, Eindhoven; D.F.M. de Haas-Kock, Stichting Radiotherapeutisch Instituut Limburg, Heerlen; G. Botke, A. Slot, Radiotherapeutisch Instituut Friesland, Leeuwarden; E.M. Noordijk, Leids Universitair Medisch Centrum, Leiden; Ph. Lambin, Academisch Ziekenhuis Maastricht, Maastricht; J.W.H. Leer, J. Hoogenhout, Academisch Ziekenhuis Nijmegen Sint Radboud, Nijmegen; Academisch Ziekenhuis Nijmegen Sint Radboud, Nijmegen; P.C. Levendag, P.E.J. Hanssens, Academisch Ziekenhuis Rotterdam, Daniel den Hoed Kliniek, Rotterdam; G.S.J. Bunnik, K.A.J. de Winter, Bernard Verbeeten Instituut, Tilburg; J.J. Batterman, H.K. Wijrdeman, Universitair Medisch Centrum Utrecht, Utrecht.

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