Late Side Effects of Short-Course Preoperative Radiotherapy Combined With Total Mesorectal Excision for Rectal Cancer: Increased Bowel Dysfu
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《临床肿瘤学》
the Departments of Surgery and Clinical Oncology, Leiden University Medical Center, Leiden
Department of Radiotherapy, St. Radboud University Medical Center, Nijmegen
Departments of Radiotherapy and Surgery, Catharina Ziekenhuis, Eindhoven
Department of Surgery, Leyenburg Hospital, The Hague
Department of Surgical Oncology, Groningen University Hospital, Groningen, the Netherlands
ABSTRACT
PURPOSE: Preoperative short-term radiotherapy improves local control in patients treated with total mesorectal excision (TME). This study was performed to assess the presence and magnitude of long-term side effects of preoperative 5 x 5 Gy radiotherapy and TME. Also, hospital treatment was recorded for diseases possibly related to late side effects of rectal cancer treatment.
PATIENTS AND METHODS: Long-term morbidity was assessed in patients from the prospective randomized TME trial, which investigated the efficacy of 5 x 5 Gy before TME surgery for mobile rectal cancer. Dutch patients without recurrent disease were sent a questionnaire.
RESULTS: Results were obtained from 597 patients, with a median follow-up of 5.1 years. Stoma function, urinary function, and hospital treatment rates did not differ significantly between the treatment arms. However, irradiated patients, compared with nonirradiated patients, reported increased rates of fecal incontinence (62% v 38%, respectively; P < .001), pad wearing as a result of incontinence (56% v 33%, respectively; P < .001), anal blood loss (11% v 3%, respectively; P = .004), and mucus loss (27% v 15%, respectively; P = .005). Satisfaction with bowel function was significantly lower and the impact of bowel dysfunction on daily activities was greater in irradiated patients compared with patients who underwent TME alone.
CONCLUSION: Although preoperative short-term radiotherapy for rectal cancer results in increased local control, there is more long-term bowel dysfunction in irradiated patients than in patients who undergo TME alone. Rectal cancer patients should be informed on late morbidity of both radiotherapy and TME. Future strategies should be aimed at selecting patients for radiotherapy who are at high risk for local failure.
INTRODUCTION
Surgery is the key to cure for patients with rectal cancer. In the past, local recurrence rates after conventional surgery averaged 30% and varied considerably between institutions from 15% to 45%.1-3 The acknowledgment of the importance of circumferential lateral spread in the occurrence of local failure4 has led to the introduction of total mesorectal excision (TME).5 This surgical technique ensures resection of the complete mesorectum in contrast to conventional blunt dissection, which is known to leave behind fragments of mesorectal tissue that frequently contain non-nodal foci of metastatic disease.6 TME has proven its superiority with regard to local control and survival when compared with historical controls.7-9
Apart from surgery, the benefit of radiotherapy, administered either pre- or postoperatively, has been established in several randomized trials.10-15 The only randomized trial comparing pre- and postoperative radiotherapy clearly showed the superiority of preoperative radiotherapy regarding side effects and local control.16 These results were confirmed in a large meta-analysis, including 8,507 patients from 22 randomized trials, that concluded that preoperative radiotherapy is superior to postoperative radiotherapy in terms of cancer-specific death (45% and 50%, respectively; P = .0003) and reduction of local recurrence risk (46% and 37%, respectively; P = .002).17 Furthermore, in the Swedish Rectal Cancer Trial, it was shown that a short-term regimen of high-dose preoperative radiotherapy (5 x 5 Gy) administered in 1 week, compared with surgery alone, was capable of not only reducing local recurrence rates (11% v 27%, respectively; P < .001), but also improving the 5-year overall survival rate (58% v 48%, respectively; P = .004).15
The benefit of this radiotherapy regimen in combination with TME surgery was also suggested in the prospective randomized TME trial. After a median follow-up of 2 years, irradiated patients had lower local recurrence rates than patients who underwent radiotherapy alone (2.4% v 8.2%, respectively; P < .001); no difference in overall survival could be detected (81.8% v 82%, respectively; P = .84).18 In a previous report reporting acute side effects and complications of 5 x 5 Gy followed by TME surgery within 1 week, we showed that radiotherapy was a safe procedure despite a slight increase in complications when compared with TME alone.19 Although acute toxicity of short-term radiotherapy has been examined in several other trials as well,12,13,20 reports on long-term morbidity are remarkably scarce. The aim of this study was to evaluate the effect of short-term preoperative radiotherapy and TME surgery on long-term side effects in patients with operable rectal cancer.
PATIENTS AND METHODS
Study Population
January 1996 until December 2000, 1,861 patients were randomly assigned to either preoperative radiotherapy (5 x 5 Gy) followed by TME or TME alone. Eligibility criteria for trial participation included histologically confirmed adenocarcinoma of the rectum without evidence of distant metastases. The inferior margin of the tumor had to be located not farther than 15 cm from the anal verge and below the level of S1 and S2. Patients with fixed tumors and patients with locally treated (transanal resected) tumors were excluded.
Most patients (n = 1,530) were Dutch. The remaining patients were included by Swedish, other European, and Canadian centers. Only Dutch patients were considered in the present analysis because accurate collection and verification of data on late side effects was, for logistical reasons, feasible for these patients only. In addition, only patients who were present in the analysis of acute toxicity were included. Inclusion and exclusion criteria for this analysis have been reported previously.19 Patients had to be free of local or distant recurrent disease to avoid confounding as a result of symptoms caused by disease recurrence. Finally, only patients who had responded to the quality-of-life questionnaires, which were sent 18 and 24 months after surgery, received a questionnaire about toxicity.
Treatment
Radiotherapy consisted of a total dose of 25 Gy administered in five fractions over 5 to 7 days. A three- or four-portal technique was used, and the clinical target volume included the primary tumor and the mesentery containing the perirectal, presacral, and internal iliac nodes up to the S1/S2 junction. The anal sphincter was included in the clinical target volume only if an abdominoperineal resection was planned. This resulted in an upper border at the level of the promontory and lateral borders 1.5 cm over the pelvic inlet. In the lateral fields, the entire sacrum had to be included, and the anterior border included the posterior part of the prostate or the vagina. Treatment was delivered with a three- or four-portal box technique, depending on the institutes' preference. The protocol prescribed an overall treatment time of a maximum of 10 days. It was advised to administer the radiotherapy on 5 consecutive days. Other details on radiotherapy have been described previously.19
All patients underwent surgery according the principles of TME surgery. Workshops, symposia, and video instructions were organized to ensure quality controlled surgery. Moreover, in each participating center, the first five TME procedures had to be supervised by an instructing surgeon. Both radiotherapy and surgical procedures have been reported in detail previously.18,20
Measurements
Late morbidity was assessed using a questionnaire that was mailed to all patients in April and May of 2003. The questionnaire was accompanied by a letter that explained the purpose of the study. In a pilot study, the questionnaire was tested for readability and understanding among 20 eligible patients. Patients who did not respond initially were sent one reminder. Table 1 lists the items of the questionnaire regarding bowel, stoma, and urinary function. Patients could indicate the severity of dysfunction on a 4-point scale ranging from "no, never" to "sometimes" (less than once a week), "often" (more than once a week but not every day), and "yes, always" (every day) for time-dependent symptoms and from "no, not at all" to "a little," "pretty much," and "very seriously" for time-independent symptoms. Data from 4-point scale answers were transformed into binary outcome measures (ie, signs present v no signs present). If there were no complaints at all, the item was scored as not present. Level of satisfaction with bowel and urinary function was assessed using a 3-point verbal scale including satisfied, neutral feelings, or unsatisfied. Because of previously reported neurogenic pain and subacute nerve damage using a fraction size of 5 Gy,21 questions regarding neurologic function were included. Patients were asked whether they had presence of back or buttock ache or pain in one or both legs, hip stiffness or pain, and walking difficulties and whether they used walking aids. In addition, patients were asked to rate their overall perceived health during the week before receipt of the questionnaire by means of a visual analog scale (a 100-mm horizontal line that was anchored at the extremes by "best imaginable quality of life" and "worst imaginable quality of life").22
Patients were further asked whether they were treated in the hospital (either on an in- or outpatient basis) since rectal cancer surgery for any of the following disorders: bowel obstruction, hernia cicatricales, delayed wound healing, anastomotic stenosis, stoma problems like parastomal hernia, stenosis and prolapse, chronic cystitis, fracture of hip and/or pelvis, and finally, myocardial infarction or stroke. Only those groups of diseases that were considered possible late side effects of treatment were specifically mentioned. In addition, patients were requested to report any other treatment in the hospital. Data on hospital treatment were added with information obtained from the regular follow-up of the TME trial.
Data Collection and Statistics
All questionnaires were sent to the central data center in Leiden, the Netherlands. Data were entered in a database and analyzed with Statistical Package for the Social Sciences statistical software (version 11.5 for Windows; SPSS Inc, Chicago, IL). 2 tests were used to compare proportions. The Student t test was applied for testing differences between continuous variables. A two-sided P = .05 was considered significant. No correction for multiple testing was applied.
RESULTS
Patients
Of all 1,530 randomly assigned Dutch patients, 116 were excluded from the assessment of acute radiotherapy toxicity.19 These patients were also excluded from the present analysis. Other reasons for exclusion were death (n = 517), recurrent disease (n = 83), and no compliance with the completion of a previous quality-of-life questionnaire (n = 106). Thus, 708 patients remained assessable. The median follow-up time since surgery of these patients was 5.09 years and did not differ significantly between irradiated and nonirradiated patients. Of these patients, 597 returned the questionnaire, resulting in a response rate of 84%. Distribution of patients and clinical characteristics were well balanced between irradiated and nonirradiated patients (Table 2).
At the time of filling out the questionnaires, 362 patients did not have a stoma. Of these patients, mean bowel frequency during the day was significantly higher in irradiated patients compared with patients who underwent surgery alone (3.69 v 3.02 times a day, respectively; P = .011); mean bowel frequency during the night did not differ statistically between the two arms (0.48 v 0.35 times a night, respectively; P = .207). Figure 1 shows significantly increased rates in irradiated patients of fecal incontinence at day and night and anal blood and mucus loss and higher rates of pad wearing as a result of fecal incontinence. The severity of fecal incontinence for the two arms is shown in Figure 2. Irradiated patients reported more signs of severe incontinence; daily incontinence was 5% in TME alone patients and 14% in irradiated patients. Figure 3 shows the degree of fecal incontinence depending on tumor distance from the anal verge; daytime incontinence was reported significantly more often after radiotherapy for patients with tumors between 5 and 10 cm from the anal verge. The difference was not statistically significant for proximal lesions up to 15 cm.
More irradiated patients, compared with TME alone patients, reported an impact of bowel dysfunction on daily activities like work and/or household activities (34% v 22%, respectively; P = .01) and activities outside the house (52% v 40%, respectively; P = .04). Although statistical significance was not reached, there was an increased impact on social activities in irradiated versus nonirradiated patients (46% v 37%, respectively; P = .15).
Two hundred thirty-five patients had a stoma at the time of completing the questionnaire. There were no statistical significant differences in stoma-related difficulties, although slightly more problems were seen in irradiated patients (Table 3). Overall, 87% of irradiated patients and 82% of TME-alone patients reported stoma complaints (P = .06). Between the irradiated and nonirradiated treatment arms, the impact of stoma dysfunction on work and household activities (31% v 33%, respectively; P = .77), activities outside the house (35% v 28%, respectively; P = .27), and social activities (35% v 28%, respectively; P = .29) did not differ significantly, but this impact was much lower than for patients without a stoma.
Patients with a stoma were more satisfied with their bowel functioning than patients without a stoma, whether they had received radiotherapy or not (Fig 4). In stoma patients, there was no difference in satisfaction between the randomization arms. In patients without a stoma, irradiated patients were less satisfied than nonirradiated patients (50% v 60%, respectively; P = .008).
Table 4 lists the results from urinary function assessment and shows no significant differences in voiding problems between the two treatment arms. However, approximately 39% of patients reported to be incontinent for urine in both groups, and 57% of the patients wore pads because of urine incontinence.
There was no increase in the readmission rates in irradiated patients for the indications as displayed in Figure 5. In particular, the number of cardiovascular accidents was not increased in irradiated patients. Moreover, angina pectoris complaints did not increase after radiotherapy (12% in irradiated patients v 16% in nonirradiated patients; P = .17).
Back or buttock ache or pain in one or both legs was reported by 52% of the irradiated patients and 58% of the patients who underwent TME alone (P = .20). Hip stiffness or pain and walking difficulties occurred in 34% and 43% of patients, respectively, who underwent radiotherapy compared with 37% and 46% of patients, respectively, who underwent TME alone (P = .423 and .79, respectively).
Median score on the visual analog scale for overall perceived health was 82.0 for irradiated patients (range, 13 to 100) and 81.0 for patients without radiotherapy (range, 4 to 100; P = .38). For patients with fecal incontinence, the median score on the visual analog scale was 79.0 (range, 16 to 100) compared with 84.0 (range, 13 to 100) for patients who were continent (P < .001). Of the continent patients, 68% were satisfied with their bowel function. Of the incontinent patients, 44% were satisfied with their bowel function (P < .001).
DISCUSSION
Short-term preoperative radiotherapy has been successfully used to reduce local recurrence rates in TME-treated rectal cancer patients.18 This benefit of radiotherapy has to be balanced against the acute and late side effects of irradiation. We previously demonstrated that there is hardly an increase of acute toxicity after preoperative hypofractionated radiotherapy.19 Concerning late side effects, there are only few reports available.23,24 This study evaluated, for the first time, the late sequelae of radiotherapy and TME surgery within the framework of a randomized prospective trial. There were no significant differences in voiding and stoma function or in symptoms possibly related to pelvic surgery or late side effects of radiotherapy. However, there were clear differences in bowel function between irradiated patients and patients who underwent TME alone.
In contrast to earlier radiotherapy studies,19,24,25 we detected no increased rates in irradiated patients of small bowel obstruction, urinary tract disease, femoral neck and pelvic fractures, and arterial disease. The only randomized trial comparing pre- with postoperative radiotherapy in rectal cancer reported an increase in bowel obstruction in patients assigned to postoperative irradiation.16 We now demonstrate that short-term preoperative radiotherapy does not lead to an increase in small bowel obstruction compared with surgery alone. This might be explained by the fact that, in preoperative radiotherapy, the pelvic cavity is still occupied by the large bowel, thus creating a natural spacer for the small bowel, which consequently is not exposed to irradiation. This is in contrast to radiotherapy after pelvic surgery, in which case the small bowel descends into the small pelvis because of the created open space.
Also, there was no difference in the number of femoral head or pelvic fractures. This is in contrast with data from the Stockholm trials, which showed a 5.3% rate of femoral neck or pelvic fractures after radiotherapy compared with a rate of 2.4% in patients without radiotherapy (P = .03).24 In the Stockholm I trial, a two-field technique was used, which was replaced in the Stockholm II trial by a four-field box technique. Concomitant with this change in radiotherapy technique, there was a decrease in the incidence of femoral neck and pelvic fractures. In our study, a three- or four-field technique was routinely used, which most likely explains the nonsignificant difference in fractures in our study population.
Long-term urinary function did not deteriorate in irradiated patients compared with TME alone patients, which is in agreement with results from the Stockholm I and II trials, in which there was no statistical difference in urinary function between irradiated and nonirradiated patients. A small study (n = 42) in male rectal cancer patients undergoing TME with or without preoperative radiotherapy demonstrated no significant difference in urinary function between irradiated and nonirradiated patients.26 Although there is no statistical significant difference between both treatment arms in urinary incontinence rates, it is noteworthy that incontinence was reported in as many as 40% of patients in both groups. However, in the present study, loosing urine involuntarily once a week or less was scored as urinary incontinence. Yet, there was an impact of urinary incontinence on overall perceived health; patients with urinary incontinence had a median visual analog scale score of 77 (range, 11 to 100) compared with 84 (range, 4 to 100) in patients without urinary incontinence (P < .001).
Despite the indisputable improvements in radiotherapy technique and application over time, the adverse effect on long-term bowel function and its impact on daily activities remains an important issue for concern. Dahlberg et al23 retrospectively investigated the effect of preoperative high-dose radiotherapy in the Swedish Rectal Cancer Trial15 and showed increased bowel frequency, incontinence, urgency, and emptying difficulties in irradiated patients. In a recent report involving 124 patients undergoing anterior rectal resection, Welsh et al27 showed higher incontinence scores in patients undergoing radiation of 5 x 5 Gy before TME. Data of these studies are in line with our results and indicate that there is a price to pay for increased local control, even with adjusted radiotherapy technique. According to the TME radiotherapy protocol, the clinical target volume excluded the anal sphincter in case of an anterior resection, with the lower border being 3 cm above the anal verge. Despite sparing of the anal sphincter, fecal incontinence rates were increased in irradiated patients. Apart from anal sphincter function, compliance of the rectal remnant is probably important for fecal continence as well. The latter might be decreased by radiotherapy as a result of aspecific changes in surrounding tissues.
As shown in Figure 2, the proportion of patients expressing signs of fecal incontinence is considerable, especially in case of irradiation. A 62% rate of fecal incontinence in irradiated patients might seem unsurpassed when compared with previous studies. However, it needs to be stressed that, even when the patient reported soiling once a week or less, the patient was considered as incontinent for the present study. Thus, comparison with previous reports should be made with care. Nevertheless, 14% of the irradiated patients reported suffering from fecal incontinence every day compared with 5% of the TME alone patients, making the additional toxic effect of radiotherapy significant.
On the basis of subgroup analyses from the TME trial at a median follow-up of 2 years, radiotherapy is most effective for patients with tumors between 5.1 and 10 cm, with local recurrence rates decreasing from 10.1% to as low as 1.0% after preoperative radiotherapy (P < .001).18 Figure 3 shows that the increase in incontinence rates caused by radiotherapy is statistically significant in patients with midrectal carcinomas. This is not the case for patients with proximal lesions 10 to 15 cm from the anal verge. Thus, late-term bowel dysfunction caused by irradiation is more explicit in patients who seem to benefit most from radiotherapy.
It is not clear to what extent patients' quality of life is affected by impaired bowel function. In a concomitant study of our group that measured health-related quality of life at different time points up to 24 months after surgery, there were only a few differences in quality of life between patients with and without preoperative radiotherapy, despite the presence of significantly more fecal incontinence and sexual dysfunction in irradiated patients.28 The current analysis of functional outcome was performed later in time and did not include a complete quality-of-life assessment. Nevertheless, overall perceived health was measured in this study; the median score of the visual analog scale was not significantly different between irradiated and nonirradiated patients without a stoma (83.0 v 80.5, respectively; P = .374), indicating that the increased rate of bowel dysfunction after radiotherapy is not expressed in a significantly worse visual analog scale score for the whole population. However, we showed that impairment of bowel function had a significant effect on daily and social activities, and this difference was translated in the overall perceived health because the median visual analog scale score was significantly lower for incontinent patients compared with continent patients (79.0 v 84.0, respectively; P = .05). In addition, we demonstrated a statistically significant difference in satisfaction between irradiated and nonirradiated patients without a stoma (50% v 60%, respectively; P = .008).
We found no significant increase in stoma-related problems in irradiated patients. In the analysis of acute radiotherapy toxicity, there was no increase of anastomotic dehiscence in irradiated patients.19 Apparently, anastomotic bowel healing is not influenced by radiotherapy. In parallel to this finding, in the long run, stoma healing and function were not affected adversely by radiotherapy. As shown in Figure 4, 74% of irradiated stoma patients were satisfied with bowel function compared with 75% of nonirradiated patients (P = .753). Apart from the effect of radiotherapy, it is remarkable to note the distinction in satisfaction rates between patients with and without a stoma; 74% of patients with a stoma (n = 173) and 55% of patients without a stoma (n = 199) reported to be satisfied with bowel function (P < .001). Sphincter-saving rectal surgery, which is often accompanied with long-term bowel dysfunction, does not seem to be the ultimate goal that should be aimed for in every rectal cancer patient.
In conclusion, late-term adverse effects of hypofractionated preoperative radiotherapy and TME surgery on functional outcome are considerable, using our strict criteria for dysfunction. However, an age-matched control group without a history of pelvic disease and treatment is lacking in the current study. Studying a control group would possibly reveal a certain degree of dysfunction as well, making the real contribution of radiotherapy and surgery to functional outcome clearer. However, the results of our study enable physicians to inform their patients reliably about the side effects of both radiotherapy and surgery in rectal cancer. Compared with radiotherapy, TME surgery is the main contributor to late bowel dysfunction. However, surgery is the only option that can lead to cure in contrast to radiotherapy, which has merely benefits in terms of increased local control. The substantial additional long-term side effects of radiotherapy on bowel dysfunction indicate that radiotherapy should be administered to those patients who are most likely to benefit from it. In this way, unnecessary exposure to the described late side effects would be avoided. However, the pretreatment staging modalities that are presently used are incapable of accurately identifying patients at risk for local failure. Considering the significant increase in local control after preoperative radiotherapy for TME-treated rectal cancer patients, the 5 x 5 Gy radiotherapy schedule remains a valuable treatment regimen.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant No. CKVO 95-04 from the Dutch Cancer Society, grant No. OWG 97/026 from the Dutch National Health Council, and the Swedish Cancer Society.
C.J.H. van de Velde was the principal investigator of this study/
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Kapiteijn E, Marijnen CA, Colenbrander AC, et al: Local recurrence in patients with rectal cancer diagnosed between 1988 and 1992: A population-based study in the West Netherlands. Eur J Surg Oncol 24:528-535, 1998
Phillips RK, Hittinger R, Blesovsky L, et al: Local recurrence following ‘curative’ surgery for large bowel cancer: II. The rectum and rectosigmoid. Br J Surg 71:17-20, 1984
Porter GA, Soskolne CL, Yakimets WW, et al: Surgeon-related factors and outcome in rectal cancer. Ann Surg 227:157-167, 1998
Quirke P, Durdey P, Dixon MF, et al: Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: Histopathological study of lateral tumour spread and surgical excision. Lancet 2:996-999, 1986
Heald RJ: A new approach to rectal cancer. Br J Hosp Med 22:277-281, 1979
Reynolds JV, Joyce WP, Dolan J, et al: Pathological evidence in support of total mesorectal excision in the management of rectal cancer. Br J Surg 83:1112-1115, 1996
Aitken RJ: Mesorectal excision for rectal cancer. Br J Surg 83:214-216, 1996
Enker WE: Total mesorectal excision: The new golden standard of surgery for rectal cancer. Ann Med 29:127-133, 1997
Kapiteijn E, Putter H, van de Velde CJ: Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in The Netherlands. Br J Surg 89:1142-1149, 2002
Gerard A, Buyse M, Nordlinger B, et al: Preoperative radiotherapy as adjuvant treatment in rectal cancer: Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg 208:606-614, 1988
O'Connell MJ, Martenson JA, Wieand HS, et al: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331:502-507, 1994
Cedermark B, Johansson H, Rutqvist LE, et al: The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma: A prospective randomized trial—Stockholm Colorectal Cancer Study Group. Cancer 75:2269-2275, 1995
Goldberg PA, Nicholls RJ, Porter NH et al: Long-term results of a randomised trial of short-course low-dose adjuvant pre-operative radiotherapy for rectal cancer: Reduction in local treatment failure. Eur J Cancer 30A:1602-1606, 1994
Medical Research Council Rectal Cancer Working Party: Randomised trial of surgery alone versus surgery followed by radiotherapy for mobile cancer of the rectum. Lancet 348:1610-1614, 1996
Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-987, 1997
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
Colorectal Cancer Collaborative Group: Adjuvant radiotherapy for rectal cancer: A systematic overview of 8,507 patients from 22 randomised trials. Lancet 358:1291-1304, 2001
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
Marijnen CA, Kapiteijn E, van de Velde CJ, et al: Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: Report of a multicenter randomized trial. J Clin Oncol 20:817-825, 2002
Kapiteijn E, Kranenbarg EK, Steup WH, et al: Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer: Prospective randomised trial with standard operative and histopathological techniques—Dutch Colorectal Cancer Group. Eur J Surg 165:410-420, 1999
Frykholm GJ, Sintorn K, Montelius A, et al: Acute lumbosacral plexopathy during and after preoperative radiotherapy of rectal adenocarcinoma. Radiother Oncol 38:121-130, 1996
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
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
Holm T, Singnomklao T, Rutqvist LE, et al: Adjuvant preoperative radiotherapy in patients with rectal carcinoma: Adverse effects during long term follow-up of two randomized trials. Cancer 78:968-976, 1996
Pahlman L, Glimelius B, Graffman S: Pre- versus postoperative radiotherapy in rectal carcinoma: An interim report from a randomized multicentre trial. Br J Surg 72:961-966, 1985
Bonnel C, Parc YR, Pocard M, et al: Effects of preoperative radiotherapy for primary resectable rectal adenocarcinoma on male sexual and urinary function. Dis Colon Rectum 45:934-939, 2002
Welsh FK, McFall M, Mitchell G, et al: Pre-operative short-course radiotherapy is associated with faecal incontinence after anterior resection. Colorectal Dis 5:563-568, 2003
Marijnen CA, van de Velde CJH, Putter H, et al: Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: Report of a multicenter randomized trialJ Clin Oncol 23:1847-1858, 2005(K.C.M.J. Peeters, C.J.H. )
Department of Radiotherapy, St. Radboud University Medical Center, Nijmegen
Departments of Radiotherapy and Surgery, Catharina Ziekenhuis, Eindhoven
Department of Surgery, Leyenburg Hospital, The Hague
Department of Surgical Oncology, Groningen University Hospital, Groningen, the Netherlands
ABSTRACT
PURPOSE: Preoperative short-term radiotherapy improves local control in patients treated with total mesorectal excision (TME). This study was performed to assess the presence and magnitude of long-term side effects of preoperative 5 x 5 Gy radiotherapy and TME. Also, hospital treatment was recorded for diseases possibly related to late side effects of rectal cancer treatment.
PATIENTS AND METHODS: Long-term morbidity was assessed in patients from the prospective randomized TME trial, which investigated the efficacy of 5 x 5 Gy before TME surgery for mobile rectal cancer. Dutch patients without recurrent disease were sent a questionnaire.
RESULTS: Results were obtained from 597 patients, with a median follow-up of 5.1 years. Stoma function, urinary function, and hospital treatment rates did not differ significantly between the treatment arms. However, irradiated patients, compared with nonirradiated patients, reported increased rates of fecal incontinence (62% v 38%, respectively; P < .001), pad wearing as a result of incontinence (56% v 33%, respectively; P < .001), anal blood loss (11% v 3%, respectively; P = .004), and mucus loss (27% v 15%, respectively; P = .005). Satisfaction with bowel function was significantly lower and the impact of bowel dysfunction on daily activities was greater in irradiated patients compared with patients who underwent TME alone.
CONCLUSION: Although preoperative short-term radiotherapy for rectal cancer results in increased local control, there is more long-term bowel dysfunction in irradiated patients than in patients who undergo TME alone. Rectal cancer patients should be informed on late morbidity of both radiotherapy and TME. Future strategies should be aimed at selecting patients for radiotherapy who are at high risk for local failure.
INTRODUCTION
Surgery is the key to cure for patients with rectal cancer. In the past, local recurrence rates after conventional surgery averaged 30% and varied considerably between institutions from 15% to 45%.1-3 The acknowledgment of the importance of circumferential lateral spread in the occurrence of local failure4 has led to the introduction of total mesorectal excision (TME).5 This surgical technique ensures resection of the complete mesorectum in contrast to conventional blunt dissection, which is known to leave behind fragments of mesorectal tissue that frequently contain non-nodal foci of metastatic disease.6 TME has proven its superiority with regard to local control and survival when compared with historical controls.7-9
Apart from surgery, the benefit of radiotherapy, administered either pre- or postoperatively, has been established in several randomized trials.10-15 The only randomized trial comparing pre- and postoperative radiotherapy clearly showed the superiority of preoperative radiotherapy regarding side effects and local control.16 These results were confirmed in a large meta-analysis, including 8,507 patients from 22 randomized trials, that concluded that preoperative radiotherapy is superior to postoperative radiotherapy in terms of cancer-specific death (45% and 50%, respectively; P = .0003) and reduction of local recurrence risk (46% and 37%, respectively; P = .002).17 Furthermore, in the Swedish Rectal Cancer Trial, it was shown that a short-term regimen of high-dose preoperative radiotherapy (5 x 5 Gy) administered in 1 week, compared with surgery alone, was capable of not only reducing local recurrence rates (11% v 27%, respectively; P < .001), but also improving the 5-year overall survival rate (58% v 48%, respectively; P = .004).15
The benefit of this radiotherapy regimen in combination with TME surgery was also suggested in the prospective randomized TME trial. After a median follow-up of 2 years, irradiated patients had lower local recurrence rates than patients who underwent radiotherapy alone (2.4% v 8.2%, respectively; P < .001); no difference in overall survival could be detected (81.8% v 82%, respectively; P = .84).18 In a previous report reporting acute side effects and complications of 5 x 5 Gy followed by TME surgery within 1 week, we showed that radiotherapy was a safe procedure despite a slight increase in complications when compared with TME alone.19 Although acute toxicity of short-term radiotherapy has been examined in several other trials as well,12,13,20 reports on long-term morbidity are remarkably scarce. The aim of this study was to evaluate the effect of short-term preoperative radiotherapy and TME surgery on long-term side effects in patients with operable rectal cancer.
PATIENTS AND METHODS
Study Population
January 1996 until December 2000, 1,861 patients were randomly assigned to either preoperative radiotherapy (5 x 5 Gy) followed by TME or TME alone. Eligibility criteria for trial participation included histologically confirmed adenocarcinoma of the rectum without evidence of distant metastases. The inferior margin of the tumor had to be located not farther than 15 cm from the anal verge and below the level of S1 and S2. Patients with fixed tumors and patients with locally treated (transanal resected) tumors were excluded.
Most patients (n = 1,530) were Dutch. The remaining patients were included by Swedish, other European, and Canadian centers. Only Dutch patients were considered in the present analysis because accurate collection and verification of data on late side effects was, for logistical reasons, feasible for these patients only. In addition, only patients who were present in the analysis of acute toxicity were included. Inclusion and exclusion criteria for this analysis have been reported previously.19 Patients had to be free of local or distant recurrent disease to avoid confounding as a result of symptoms caused by disease recurrence. Finally, only patients who had responded to the quality-of-life questionnaires, which were sent 18 and 24 months after surgery, received a questionnaire about toxicity.
Treatment
Radiotherapy consisted of a total dose of 25 Gy administered in five fractions over 5 to 7 days. A three- or four-portal technique was used, and the clinical target volume included the primary tumor and the mesentery containing the perirectal, presacral, and internal iliac nodes up to the S1/S2 junction. The anal sphincter was included in the clinical target volume only if an abdominoperineal resection was planned. This resulted in an upper border at the level of the promontory and lateral borders 1.5 cm over the pelvic inlet. In the lateral fields, the entire sacrum had to be included, and the anterior border included the posterior part of the prostate or the vagina. Treatment was delivered with a three- or four-portal box technique, depending on the institutes' preference. The protocol prescribed an overall treatment time of a maximum of 10 days. It was advised to administer the radiotherapy on 5 consecutive days. Other details on radiotherapy have been described previously.19
All patients underwent surgery according the principles of TME surgery. Workshops, symposia, and video instructions were organized to ensure quality controlled surgery. Moreover, in each participating center, the first five TME procedures had to be supervised by an instructing surgeon. Both radiotherapy and surgical procedures have been reported in detail previously.18,20
Measurements
Late morbidity was assessed using a questionnaire that was mailed to all patients in April and May of 2003. The questionnaire was accompanied by a letter that explained the purpose of the study. In a pilot study, the questionnaire was tested for readability and understanding among 20 eligible patients. Patients who did not respond initially were sent one reminder. Table 1 lists the items of the questionnaire regarding bowel, stoma, and urinary function. Patients could indicate the severity of dysfunction on a 4-point scale ranging from "no, never" to "sometimes" (less than once a week), "often" (more than once a week but not every day), and "yes, always" (every day) for time-dependent symptoms and from "no, not at all" to "a little," "pretty much," and "very seriously" for time-independent symptoms. Data from 4-point scale answers were transformed into binary outcome measures (ie, signs present v no signs present). If there were no complaints at all, the item was scored as not present. Level of satisfaction with bowel and urinary function was assessed using a 3-point verbal scale including satisfied, neutral feelings, or unsatisfied. Because of previously reported neurogenic pain and subacute nerve damage using a fraction size of 5 Gy,21 questions regarding neurologic function were included. Patients were asked whether they had presence of back or buttock ache or pain in one or both legs, hip stiffness or pain, and walking difficulties and whether they used walking aids. In addition, patients were asked to rate their overall perceived health during the week before receipt of the questionnaire by means of a visual analog scale (a 100-mm horizontal line that was anchored at the extremes by "best imaginable quality of life" and "worst imaginable quality of life").22
Patients were further asked whether they were treated in the hospital (either on an in- or outpatient basis) since rectal cancer surgery for any of the following disorders: bowel obstruction, hernia cicatricales, delayed wound healing, anastomotic stenosis, stoma problems like parastomal hernia, stenosis and prolapse, chronic cystitis, fracture of hip and/or pelvis, and finally, myocardial infarction or stroke. Only those groups of diseases that were considered possible late side effects of treatment were specifically mentioned. In addition, patients were requested to report any other treatment in the hospital. Data on hospital treatment were added with information obtained from the regular follow-up of the TME trial.
Data Collection and Statistics
All questionnaires were sent to the central data center in Leiden, the Netherlands. Data were entered in a database and analyzed with Statistical Package for the Social Sciences statistical software (version 11.5 for Windows; SPSS Inc, Chicago, IL). 2 tests were used to compare proportions. The Student t test was applied for testing differences between continuous variables. A two-sided P = .05 was considered significant. No correction for multiple testing was applied.
RESULTS
Patients
Of all 1,530 randomly assigned Dutch patients, 116 were excluded from the assessment of acute radiotherapy toxicity.19 These patients were also excluded from the present analysis. Other reasons for exclusion were death (n = 517), recurrent disease (n = 83), and no compliance with the completion of a previous quality-of-life questionnaire (n = 106). Thus, 708 patients remained assessable. The median follow-up time since surgery of these patients was 5.09 years and did not differ significantly between irradiated and nonirradiated patients. Of these patients, 597 returned the questionnaire, resulting in a response rate of 84%. Distribution of patients and clinical characteristics were well balanced between irradiated and nonirradiated patients (Table 2).
At the time of filling out the questionnaires, 362 patients did not have a stoma. Of these patients, mean bowel frequency during the day was significantly higher in irradiated patients compared with patients who underwent surgery alone (3.69 v 3.02 times a day, respectively; P = .011); mean bowel frequency during the night did not differ statistically between the two arms (0.48 v 0.35 times a night, respectively; P = .207). Figure 1 shows significantly increased rates in irradiated patients of fecal incontinence at day and night and anal blood and mucus loss and higher rates of pad wearing as a result of fecal incontinence. The severity of fecal incontinence for the two arms is shown in Figure 2. Irradiated patients reported more signs of severe incontinence; daily incontinence was 5% in TME alone patients and 14% in irradiated patients. Figure 3 shows the degree of fecal incontinence depending on tumor distance from the anal verge; daytime incontinence was reported significantly more often after radiotherapy for patients with tumors between 5 and 10 cm from the anal verge. The difference was not statistically significant for proximal lesions up to 15 cm.
More irradiated patients, compared with TME alone patients, reported an impact of bowel dysfunction on daily activities like work and/or household activities (34% v 22%, respectively; P = .01) and activities outside the house (52% v 40%, respectively; P = .04). Although statistical significance was not reached, there was an increased impact on social activities in irradiated versus nonirradiated patients (46% v 37%, respectively; P = .15).
Two hundred thirty-five patients had a stoma at the time of completing the questionnaire. There were no statistical significant differences in stoma-related difficulties, although slightly more problems were seen in irradiated patients (Table 3). Overall, 87% of irradiated patients and 82% of TME-alone patients reported stoma complaints (P = .06). Between the irradiated and nonirradiated treatment arms, the impact of stoma dysfunction on work and household activities (31% v 33%, respectively; P = .77), activities outside the house (35% v 28%, respectively; P = .27), and social activities (35% v 28%, respectively; P = .29) did not differ significantly, but this impact was much lower than for patients without a stoma.
Patients with a stoma were more satisfied with their bowel functioning than patients without a stoma, whether they had received radiotherapy or not (Fig 4). In stoma patients, there was no difference in satisfaction between the randomization arms. In patients without a stoma, irradiated patients were less satisfied than nonirradiated patients (50% v 60%, respectively; P = .008).
Table 4 lists the results from urinary function assessment and shows no significant differences in voiding problems between the two treatment arms. However, approximately 39% of patients reported to be incontinent for urine in both groups, and 57% of the patients wore pads because of urine incontinence.
There was no increase in the readmission rates in irradiated patients for the indications as displayed in Figure 5. In particular, the number of cardiovascular accidents was not increased in irradiated patients. Moreover, angina pectoris complaints did not increase after radiotherapy (12% in irradiated patients v 16% in nonirradiated patients; P = .17).
Back or buttock ache or pain in one or both legs was reported by 52% of the irradiated patients and 58% of the patients who underwent TME alone (P = .20). Hip stiffness or pain and walking difficulties occurred in 34% and 43% of patients, respectively, who underwent radiotherapy compared with 37% and 46% of patients, respectively, who underwent TME alone (P = .423 and .79, respectively).
Median score on the visual analog scale for overall perceived health was 82.0 for irradiated patients (range, 13 to 100) and 81.0 for patients without radiotherapy (range, 4 to 100; P = .38). For patients with fecal incontinence, the median score on the visual analog scale was 79.0 (range, 16 to 100) compared with 84.0 (range, 13 to 100) for patients who were continent (P < .001). Of the continent patients, 68% were satisfied with their bowel function. Of the incontinent patients, 44% were satisfied with their bowel function (P < .001).
DISCUSSION
Short-term preoperative radiotherapy has been successfully used to reduce local recurrence rates in TME-treated rectal cancer patients.18 This benefit of radiotherapy has to be balanced against the acute and late side effects of irradiation. We previously demonstrated that there is hardly an increase of acute toxicity after preoperative hypofractionated radiotherapy.19 Concerning late side effects, there are only few reports available.23,24 This study evaluated, for the first time, the late sequelae of radiotherapy and TME surgery within the framework of a randomized prospective trial. There were no significant differences in voiding and stoma function or in symptoms possibly related to pelvic surgery or late side effects of radiotherapy. However, there were clear differences in bowel function between irradiated patients and patients who underwent TME alone.
In contrast to earlier radiotherapy studies,19,24,25 we detected no increased rates in irradiated patients of small bowel obstruction, urinary tract disease, femoral neck and pelvic fractures, and arterial disease. The only randomized trial comparing pre- with postoperative radiotherapy in rectal cancer reported an increase in bowel obstruction in patients assigned to postoperative irradiation.16 We now demonstrate that short-term preoperative radiotherapy does not lead to an increase in small bowel obstruction compared with surgery alone. This might be explained by the fact that, in preoperative radiotherapy, the pelvic cavity is still occupied by the large bowel, thus creating a natural spacer for the small bowel, which consequently is not exposed to irradiation. This is in contrast to radiotherapy after pelvic surgery, in which case the small bowel descends into the small pelvis because of the created open space.
Also, there was no difference in the number of femoral head or pelvic fractures. This is in contrast with data from the Stockholm trials, which showed a 5.3% rate of femoral neck or pelvic fractures after radiotherapy compared with a rate of 2.4% in patients without radiotherapy (P = .03).24 In the Stockholm I trial, a two-field technique was used, which was replaced in the Stockholm II trial by a four-field box technique. Concomitant with this change in radiotherapy technique, there was a decrease in the incidence of femoral neck and pelvic fractures. In our study, a three- or four-field technique was routinely used, which most likely explains the nonsignificant difference in fractures in our study population.
Long-term urinary function did not deteriorate in irradiated patients compared with TME alone patients, which is in agreement with results from the Stockholm I and II trials, in which there was no statistical difference in urinary function between irradiated and nonirradiated patients. A small study (n = 42) in male rectal cancer patients undergoing TME with or without preoperative radiotherapy demonstrated no significant difference in urinary function between irradiated and nonirradiated patients.26 Although there is no statistical significant difference between both treatment arms in urinary incontinence rates, it is noteworthy that incontinence was reported in as many as 40% of patients in both groups. However, in the present study, loosing urine involuntarily once a week or less was scored as urinary incontinence. Yet, there was an impact of urinary incontinence on overall perceived health; patients with urinary incontinence had a median visual analog scale score of 77 (range, 11 to 100) compared with 84 (range, 4 to 100) in patients without urinary incontinence (P < .001).
Despite the indisputable improvements in radiotherapy technique and application over time, the adverse effect on long-term bowel function and its impact on daily activities remains an important issue for concern. Dahlberg et al23 retrospectively investigated the effect of preoperative high-dose radiotherapy in the Swedish Rectal Cancer Trial15 and showed increased bowel frequency, incontinence, urgency, and emptying difficulties in irradiated patients. In a recent report involving 124 patients undergoing anterior rectal resection, Welsh et al27 showed higher incontinence scores in patients undergoing radiation of 5 x 5 Gy before TME. Data of these studies are in line with our results and indicate that there is a price to pay for increased local control, even with adjusted radiotherapy technique. According to the TME radiotherapy protocol, the clinical target volume excluded the anal sphincter in case of an anterior resection, with the lower border being 3 cm above the anal verge. Despite sparing of the anal sphincter, fecal incontinence rates were increased in irradiated patients. Apart from anal sphincter function, compliance of the rectal remnant is probably important for fecal continence as well. The latter might be decreased by radiotherapy as a result of aspecific changes in surrounding tissues.
As shown in Figure 2, the proportion of patients expressing signs of fecal incontinence is considerable, especially in case of irradiation. A 62% rate of fecal incontinence in irradiated patients might seem unsurpassed when compared with previous studies. However, it needs to be stressed that, even when the patient reported soiling once a week or less, the patient was considered as incontinent for the present study. Thus, comparison with previous reports should be made with care. Nevertheless, 14% of the irradiated patients reported suffering from fecal incontinence every day compared with 5% of the TME alone patients, making the additional toxic effect of radiotherapy significant.
On the basis of subgroup analyses from the TME trial at a median follow-up of 2 years, radiotherapy is most effective for patients with tumors between 5.1 and 10 cm, with local recurrence rates decreasing from 10.1% to as low as 1.0% after preoperative radiotherapy (P < .001).18 Figure 3 shows that the increase in incontinence rates caused by radiotherapy is statistically significant in patients with midrectal carcinomas. This is not the case for patients with proximal lesions 10 to 15 cm from the anal verge. Thus, late-term bowel dysfunction caused by irradiation is more explicit in patients who seem to benefit most from radiotherapy.
It is not clear to what extent patients' quality of life is affected by impaired bowel function. In a concomitant study of our group that measured health-related quality of life at different time points up to 24 months after surgery, there were only a few differences in quality of life between patients with and without preoperative radiotherapy, despite the presence of significantly more fecal incontinence and sexual dysfunction in irradiated patients.28 The current analysis of functional outcome was performed later in time and did not include a complete quality-of-life assessment. Nevertheless, overall perceived health was measured in this study; the median score of the visual analog scale was not significantly different between irradiated and nonirradiated patients without a stoma (83.0 v 80.5, respectively; P = .374), indicating that the increased rate of bowel dysfunction after radiotherapy is not expressed in a significantly worse visual analog scale score for the whole population. However, we showed that impairment of bowel function had a significant effect on daily and social activities, and this difference was translated in the overall perceived health because the median visual analog scale score was significantly lower for incontinent patients compared with continent patients (79.0 v 84.0, respectively; P = .05). In addition, we demonstrated a statistically significant difference in satisfaction between irradiated and nonirradiated patients without a stoma (50% v 60%, respectively; P = .008).
We found no significant increase in stoma-related problems in irradiated patients. In the analysis of acute radiotherapy toxicity, there was no increase of anastomotic dehiscence in irradiated patients.19 Apparently, anastomotic bowel healing is not influenced by radiotherapy. In parallel to this finding, in the long run, stoma healing and function were not affected adversely by radiotherapy. As shown in Figure 4, 74% of irradiated stoma patients were satisfied with bowel function compared with 75% of nonirradiated patients (P = .753). Apart from the effect of radiotherapy, it is remarkable to note the distinction in satisfaction rates between patients with and without a stoma; 74% of patients with a stoma (n = 173) and 55% of patients without a stoma (n = 199) reported to be satisfied with bowel function (P < .001). Sphincter-saving rectal surgery, which is often accompanied with long-term bowel dysfunction, does not seem to be the ultimate goal that should be aimed for in every rectal cancer patient.
In conclusion, late-term adverse effects of hypofractionated preoperative radiotherapy and TME surgery on functional outcome are considerable, using our strict criteria for dysfunction. However, an age-matched control group without a history of pelvic disease and treatment is lacking in the current study. Studying a control group would possibly reveal a certain degree of dysfunction as well, making the real contribution of radiotherapy and surgery to functional outcome clearer. However, the results of our study enable physicians to inform their patients reliably about the side effects of both radiotherapy and surgery in rectal cancer. Compared with radiotherapy, TME surgery is the main contributor to late bowel dysfunction. However, surgery is the only option that can lead to cure in contrast to radiotherapy, which has merely benefits in terms of increased local control. The substantial additional long-term side effects of radiotherapy on bowel dysfunction indicate that radiotherapy should be administered to those patients who are most likely to benefit from it. In this way, unnecessary exposure to the described late side effects would be avoided. However, the pretreatment staging modalities that are presently used are incapable of accurately identifying patients at risk for local failure. Considering the significant increase in local control after preoperative radiotherapy for TME-treated rectal cancer patients, the 5 x 5 Gy radiotherapy schedule remains a valuable treatment regimen.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant No. CKVO 95-04 from the Dutch Cancer Society, grant No. OWG 97/026 from the Dutch National Health Council, and the Swedish Cancer Society.
C.J.H. van de Velde was the principal investigator of this study/
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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