Impact of Short-Term Preoperative Radiotherapy on Health-Related Quality of Life and Sexual Functioning in Primary Rectal Cancer: Report of
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《临床肿瘤学》
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
Department of Radiotherapy, University Medical Center Nijmegen, Nijmegen, the Netherlands
ABSTRACT
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 x 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.
INTRODUCTION
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 x 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 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
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.
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 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 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).
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.
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 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.
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 (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).
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 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 disorders, 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 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 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 x 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.
Appendix. List of Cooperative Clinical Investigators
NOTES
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.
REFERENCES
Heald RJ, Ryall RD: Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1:1479-1482, 1986
Martling AL, Holm T, Rutqvist LE, et al: Effect of a surgical training program on outcome of rectal cancer in the County of Stockholm: Stockholm Colorectal Cancer Study Group, Basingstoke Bowel Cancer Research Project. Lancet 356:93-96, 2000
Enker WE, Thaler HT, Cranor ML, et al: Total mesorectal excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 181:335-346, 1995
Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001
Allal AS, Bieri S, Pelloni A, et al: Sphincter-sparing surgery after preoperative radiotherapy for low rectal cancers: Feasibility, oncologic results and quality of life outcomes. Br J Cancer 82:1131-1137, 2000
Grumann MM, Noack EM, Hoffmann IA, et al: Comparison of quality of life in patients undergoing abdominoperineal extirpation or anterior resection for rectal cancer. Ann Surg 233:149-156, 2001
Jess P, Christiansen J, Bech P: Quality of life after anterior resection versus abdominoperineal extirpation for rectal cancer. Scand J Gastroenterol 37:1201-1204, 2002
Heald RJ: Rectal cancer: The surgical options. Eur J Cancer 31A:1189-1192, 1995
Putter H, Marijnen CAM, Klein Kranenbarg E, et al: Missing values and dropout: The TME quality of life substudy. Qual Life Res (in press)
de Haes JC, van Knippenberg FC, Neijt JP: Measuring psychological and physical distress in cancer patients: Structure and application of the Rotterdam Symptom Checklist. Br J Cancer 62:1034-1038, 1990
Frykholm GJ, Glimelius B, Pahlman L: Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 36:564-572, 1993
Marijnen CAM, Kapiteijn E, van de Velde CJH, et al: Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer. J Clin Oncol 20:817-825, 2002
Caffo O, Amichetti M, Romano M, et al: Evaluation of toxicity and quality of life using a diary card during postoperative radiotherapy for rectal cancer. Dis Colon Rectum 45:459-465, 2002
Camilleri-Brennan J, Steele RJ: Quality of life after treatment for rectal cancer. Br J Surg 85:1036-1043, 1998
Guren MG, Dueland S, Skovlund E, et al: Quality of life during radiotherapy for rectal cancer. Eur J Cancer 39:587-594, 2003
Whynes DK, Neilson AR: Symptoms before and after surgery for colorectal cancer. Qual Life Res 6:61-66, 1997
Saxena S, Carlson D, Billington R: The WHO quality of life assessment instrument (WHOQOL-Bref): The importance of its items for cross-cultural research. Qual Life Res 10:711-721, 2001
Havenga K, Maas CP, DeRuiter MC, et al: Avoiding long-term disturbance to bladder and sexual function in pelvic surgery, particularly with rectal cancer. Semin Surg Oncol 18:235-243, 2000
Dahlberg M, Glimelius B, Graf W, et al: Preoperative irradiation affects functional results after surgery for rectal cancer: Results from a randomized study. Dis Colon Rectum 41:543-549, 1998
Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al: Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomized trial comparing short-term radiotherapy versus conventionally fractionated radiochemotherapy. Radiother Oncol 72:15-24, 2004
Gerard JP, Chapet O, Nemoz C, et al: Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: The Lyon R96-02 randomized trial. J Clin Oncol 22:2404-2409, 2004
Engel J, Kerr J, Schlesinger-Raab A, et al: Quality of life in rectal cancer patients: A four-year prospective study. Ann Surg 238:203-213, 2003
Di Betta E, D'Hoore A, Filez L, et al: Sphincter saving rectum resection is the standard procedure for low rectal cancer. Int J Colorectal Dis 18:463-469, 2003
Kuzu MA, Topcu O, Ucar K, et al: Effect of sphincter-sacrificing surgery for rectal carcinoma on quality of life in Muslim patients. Dis Colon Rectum 45:1359-1366, 2002
Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 16:139-144, 1998(Corrie A.M. Marijnen, Cor)
Departments of Radiotherapy and Surgery, Catharina Ziekenhuis, Eindhoven
Department of Surgery, Groningen University Hospital, Groningen
Department of Radiotherapy, University Medical Center Nijmegen, Nijmegen, the Netherlands
ABSTRACT
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 x 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.
INTRODUCTION
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 x 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 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
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.
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 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 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).
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.
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 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.
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 (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).
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 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 disorders, 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 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 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 x 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.
Appendix. List of Cooperative Clinical Investigators
NOTES
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.
REFERENCES
Heald RJ, Ryall RD: Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1:1479-1482, 1986
Martling AL, Holm T, Rutqvist LE, et al: Effect of a surgical training program on outcome of rectal cancer in the County of Stockholm: Stockholm Colorectal Cancer Study Group, Basingstoke Bowel Cancer Research Project. Lancet 356:93-96, 2000
Enker WE, Thaler HT, Cranor ML, et al: Total mesorectal excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 181:335-346, 1995
Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001
Allal AS, Bieri S, Pelloni A, et al: Sphincter-sparing surgery after preoperative radiotherapy for low rectal cancers: Feasibility, oncologic results and quality of life outcomes. Br J Cancer 82:1131-1137, 2000
Grumann MM, Noack EM, Hoffmann IA, et al: Comparison of quality of life in patients undergoing abdominoperineal extirpation or anterior resection for rectal cancer. Ann Surg 233:149-156, 2001
Jess P, Christiansen J, Bech P: Quality of life after anterior resection versus abdominoperineal extirpation for rectal cancer. Scand J Gastroenterol 37:1201-1204, 2002
Heald RJ: Rectal cancer: The surgical options. Eur J Cancer 31A:1189-1192, 1995
Putter H, Marijnen CAM, Klein Kranenbarg E, et al: Missing values and dropout: The TME quality of life substudy. Qual Life Res (in press)
de Haes JC, van Knippenberg FC, Neijt JP: Measuring psychological and physical distress in cancer patients: Structure and application of the Rotterdam Symptom Checklist. Br J Cancer 62:1034-1038, 1990
Frykholm GJ, Glimelius B, Pahlman L: Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 36:564-572, 1993
Marijnen CAM, Kapiteijn E, van de Velde CJH, et al: Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer. J Clin Oncol 20:817-825, 2002
Caffo O, Amichetti M, Romano M, et al: Evaluation of toxicity and quality of life using a diary card during postoperative radiotherapy for rectal cancer. Dis Colon Rectum 45:459-465, 2002
Camilleri-Brennan J, Steele RJ: Quality of life after treatment for rectal cancer. Br J Surg 85:1036-1043, 1998
Guren MG, Dueland S, Skovlund E, et al: Quality of life during radiotherapy for rectal cancer. Eur J Cancer 39:587-594, 2003
Whynes DK, Neilson AR: Symptoms before and after surgery for colorectal cancer. Qual Life Res 6:61-66, 1997
Saxena S, Carlson D, Billington R: The WHO quality of life assessment instrument (WHOQOL-Bref): The importance of its items for cross-cultural research. Qual Life Res 10:711-721, 2001
Havenga K, Maas CP, DeRuiter MC, et al: Avoiding long-term disturbance to bladder and sexual function in pelvic surgery, particularly with rectal cancer. Semin Surg Oncol 18:235-243, 2000
Dahlberg M, Glimelius B, Graf W, et al: Preoperative irradiation affects functional results after surgery for rectal cancer: Results from a randomized study. Dis Colon Rectum 41:543-549, 1998
Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al: Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomized trial comparing short-term radiotherapy versus conventionally fractionated radiochemotherapy. Radiother Oncol 72:15-24, 2004
Gerard JP, Chapet O, Nemoz C, et al: Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: The Lyon R96-02 randomized trial. J Clin Oncol 22:2404-2409, 2004
Engel J, Kerr J, Schlesinger-Raab A, et al: Quality of life in rectal cancer patients: A four-year prospective study. Ann Surg 238:203-213, 2003
Di Betta E, D'Hoore A, Filez L, et al: Sphincter saving rectum resection is the standard procedure for low rectal cancer. Int J Colorectal Dis 18:463-469, 2003
Kuzu MA, Topcu O, Ucar K, et al: Effect of sphincter-sacrificing surgery for rectal carcinoma on quality of life in Muslim patients. Dis Colon Rectum 45:1359-1366, 2002
Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 16:139-144, 1998(Corrie A.M. Marijnen, Cor)