34 Pelvic Radiotherapy

Introduction

Radiation injury is a well-known complication after external radiotherapy of cancers within the pelvic cavity. Radiation therapy might be the primary treat- ment for such cancers (prostate, uterine, cervical, bladder, and anal cancers), or it might be combined with surgery (rectal cancer).

Side Effects of Pelvic Radiation Therapy

Radiotherapy can cause both acute and chronic seque- lae. Side effects can be related to functional impairment (bladder, sexual, and bowel), pain and local fractures. If the small bowels are included, this might lead to stric- tures, fistulation, and increased risk of adhesions requiring surgical management. Furthermore, radio- therapy might increase the risk of postoperative car- diopulmonary problems and secondary malignancy.

This chapter focuses on the risk of long-term fecal incontinence when radiation (or chemoradiation) is used as a single modality or combined with surgery.

Interpretation of Risk of Fecal Incontinence after Pelvic Radiotherapy

The interpretation of the risk and the degree of fecal incontinence after pelvic radiotherapy is difficult for several reasons. First, the classification of fecal incontinence strongly depends on the method used.

Second, chronic radiation damage progresses with time, and the risk and degree of fecal incontinence is therefore directly related to the observational period.

Third, not only the total dose but also the fractiona- tion scheme, the number of fields, and the total irra- diated volume will influence the risk of fecal inconti- nence. Thus, the commonly used preoperative neoadjuvant fractionation scheme of 5 ×5 Gy before surgery for rectal cancer is equivalent to a biological dose of approximately 50 Gy when fractions of 1.8–2 Gy is used. Fourth, with modern techniques with

shielding and use of many fields, the dose to struc- tures near the target field is reduced. Finally, the anal sphincters are now excluded from the radiation field whenever possible. It is therefore likely that the risk of fecal incontinence using modern radiation therapy will be less than the risk with traditional methods.

For rectal cancer, surgery has also improved, with much more focus on sparing the autonomic nerves [1] and with reconstruction of a neorectum when total mesorectal excision is combined with a coloanal anas- tomosis [2, 3]. As both surgery and radiotherapy have improved, it is likely that modern combination of sur- gery and radiotherapy will create fewer functional problems [3, 4]. However, this must be evaluated in high-quality prospective observational studies.

Fecal Incontinence and Rectal Cancer

Surgery Alone

It is well established that surgical resection of the rec- tum with anastomosis can lead to the anterior resec- tion syndrome in about 25–50% of patients after tradi- tional restorative resection [3]. This syndrome is char- acterized by urgency, frequent bowel movements, and some degree of fecal incontinence. The syndrome is related to the loss of rectal reservoir function, and it is more frequent after a total mesorectal excision. If a small neorectal reservoir is constructed, either using a colonic J-pouch or the Baker type side-to-end anasto- mosis, the symptoms will be less severe [3]. The func- tional bowel problems are most pronounced initially, decrease within the first year, and then become stable.

This is in contrast to the deficits after adjuvant thera- py, which progress with time.

Surgery and Long-Course Postoperative Radiotherapy

The risk of fecal incontinence after postoperative radiotherapy for rectal cancer has been studied in a randomized Danish trial where patients with Dukes B

Pelvic Radiotherapy

Soeren Laurberg, Mette M. Soerensen

34

and C cancers were randomized to surgery with or without postoperative radiotherapy (50 Gy) [5, 6]. In this trial, the addition of postoperative radiotherapy was followed by a substantially increased risk of bowel problems, with a high risk of multiple defeca-

tions per day, urgency, fecal incontinence, and use of pads (Table 1). Similar impaired anal function has been described in other non-randomized and ran- domized studies [7].

The physiological studies suggest that the high

No radiotherapy Radiotherapy P

(n = 44) (n = 49)

Patients

Median age 73 (73–90) 77 (42–90) ns

Male/female 15/29 22/27 ns

Duke B/C 36/8 32/17 ns

Low/high resection 32/12 27/22 ns

Years since surgery 13 (11–17) 14 (11–17) ns

Symptoms % %

Stool frequency _⭓5 /day 2 18 < 0.001

Loose/liquid stool 2 25 0.024

Fecal urgency 12 41 0.003

Fecal incontinence 5 49 < 0.001

Use of pads 0 26 < 0.001

Differentiated stool/gas 95 77 0.014

Impaired social function 15 29 0.893

Antidiarrhoea medication 11 25 0.132

Abdominal pain 14 27 0.208

Tenesmus 3 13 0.122

Figures in parentheses are ranges.

Fig. 1.Pressure/cross-sectional area (CSA) relationship in patients treated with adjuvant radiotherapy (+RT) and patients treated with surgery alone (–RT) (p=0.0001). Reprinted with permission from [5]

risk of fecal incontinence after postoperative radio- therapy was due to a substantial reduction in rectal capacity and distensibility [5] (Fig. 1). In addition, there was a reduction in anal sphincter function, with a reduction in squeeze pressure and a thinning of the internal anal sphincter.

Strength and Limitation of the Danish Study

The main strength of the Danish study is that it was a randomized study, and the functional deficits were classified without knowledge of whether the patients had radiotherapy. The observational period was long, and it was therefore possible to describe the long-term detrimental effects of radiotherapy. How- ever, the study also has several limitations, as old- fashion irradiation and surgery was used. The radia- tion field included the sphincter in all cases. It is therefore likely that the study overestimated the risk of long-term anorectal dysfunction with modern techniques.

Surgery Combined with Short-Course Preoperative Radiotherapy

The risk of fecal incontinence after preoperative short-course radiotherapy (5 ×5 Gy) has been stud- ied in both Swedish [8, 9] and Dutch trials [4, 10].

Patients with respectable rectal cancer were random- ized to surgery alone or surgery combined with pre- operative radiotherapy. In both trials, the addition of short-course radiotherapy reduced the risk of local recurrence [4, 10, 11], and in the Swedish trial, sur- vival was improved. However, the addition of short- course radiotherapy substantially increased the risk of bowel problems, with a higher risk of fecal incon-

tinence, urgency, and use of pads (Table 2) [12, 13].

Furthermore, radiotherapy decreased sexual func- tion in both men and women [11, 14].

In the Dutch trial, this substantial increase in risk of fecal incontinence had no or only minor effect on health-related quality of life [4]. Overall perceived health, measured by the visual analog scale (VAS), did not differ significantly between irradiated patients and patients without radiotherapy [4, 10].

However, impaired social life because of bowel dys- function was more frequent in irradiated patients compared with surgery alone [4, 10, 13, 15]. It is notable that patients with a stoma were more satis- fied with their bowel function than were patients without a stoma, whether they had received radio- therapy or not [10].

Strength and Limitation of the Swedish and the Dutch Studies

The main strength of these studies was their ran- domized design. However, suboptimal irradiation therapy was used, and the radiation field included the sphincter in the majority of cases. Thus, it is like- ly that risk of long-term anorectal dysfunction is less with modern treatment. Compared with the study using postoperative radiotherapy, the functional deficit was apparently less. This should, however, be interpreted with caution. One reason for the differ- ence might be that the outcome was evaluated differ- ently. Another possibility is that the observational period was longer in the Danish study, and the Dan- ish technique was more “old-fashioned” [1, 5, 6].

However, theoretically, it is likely that preopera- tive adjuvant therapy would cause less functional problems than postoperative therapy. First, the radi- ation-induced damage might be greater when per- formed after surgery. Second, with postoperative

Table 2.Adverse events and symptoms in patients treated with and without preoperative radiotherapy Radiotherapy No radiotherapy

(n = 65) (n = 74) P**

Any adverse event 45 (69) 32 (43) 0.002

Cardiovascolar disease 23 (35) 14 (19) 0.032

Venous thromboebolism 4 (6) 5 (7) 0.823

Faecal incontinence* 12 (57) 11 (26) 0.013

Small-bowel obstruction 19 (29) 13 (18) 0.074

Urinary incontinence 29 (45) 20 (27) 0.023

Incomplete bladder emptying 17 (26) 13 (18) 0.193

Fractures (all types) 11 (17) 6 (8) 0.118

Hip and pelvic fractures 3 (5) 1 (1) 0.227

Values in parentheses are percentages. *Assessed only in patients who had anterior resection. **Fisher’s exact test. Reproduced with per- mission from [12]

radiotherapy, the rectal remnant or neorectum is irradiated, and this irradiation might severely impair the function of the reservoir, leading to a narrow rigid conduit. With preoperative adjuvant therapy, the neorectum would be outside the irradiated field, and with low anastomosis, there would be no irradi- ated rectum remnant. This is supported by Welsh et al. [16]. Preoperative short-course irradiation had lit- tle effect on risk of fecal incontinence in patients with anastomosis <6 cm from the anal verge, though the risk of incontinence was much higher than with a high anastomosis. In the latter patients, neoadjuvant short-course irradiation increased the risk of fecal incontinence, suggesting that irradiation of a rectal remnant might increase the risk of fecal incontinence after preoperative radiotherapy.

Long-Course Preoperative (Chemo)Radiotherapy for Rectal Cancer

It is now generally accepted that preoperative radio- therapy is more effective than postoperative radio- therapy and that the addition of chemotherapy decreases the risk of local recurrence [17–19]. Unfor- tunately, description of the functional deficit follow- ing long-course chemoradiation has not been studied scientifically. Therefore, we do not know the effect of long-course chemoradiation on function. However, the addition of chemotherapy might potentially increase the risk of side effects. On the other hand, the larger fractions that are used in short-course radiation, 5 ×5 Gy, may induce more damage to the normal tissue.

Only one study has compared short-course radio- therapy with long-course preoperative chemoradia- tion [20]. There were no significant difference in sur- vival and risk of local recurrence, but functional problems have not yet been evaluated in the Polish trial [20].

Conclusion: Pelvic Radiotherapy for Rectal Cancer

There is no doubt that the addition of (chemo)radia- tion increases the risk of fecal incontinence and other sequelae. On the other hand, this treatment modality decreases the risk of local recurrence and may also increase survival [11]. Further studies are needed to clarify which rectal cancer patient needs neoadjuvant therapy and how functional outcome can be improved by improving the quality of both radiother- apy and surgery. Hopefully, in the future, we will have much more specific methods to select patients who will benefit from neoadjuvant therapy and identify patients with the highest risk of functional problems.

Fecal Incontinence Associated with Radiotherapy for other Cancers

Several studies have shown that radical radiotherapy for both prostate cancer and bladder cancer is asso- ciated with an increased risk of fecal incontinence [21–24]. After 2 years, bowel frequency, fecal ur- gency, and fecal incontinence were increased in 50%, 47%, and 26% of patients, respectively [24]. These functional deficits were associated with a reduction in resting anal pressures, squeeze pressure, and rec- tal compliance [24].

With a medium observation time of 29 months after radical radiotherapy for urinary bladder cancer, about 55% of the patients experienced impairment in bowel function, including urgency, incontinence, and use of pads [22]. These changes had a moderate or severe impact on the performance of daily activity in 29% of patients. Physiological studies suggest that the impaired function, also for bladder cancer, is due to a combination of sphincter weakness and changes in rectal function.

For patients with cervical cancer treated with sur- gery and external radiotherapy, overall bowel dys- function was the most important source of distress of any degree in a Swedish study [25]. In an Australian study, ten out of 15 patients who had pelvic irradia- tion for a gynecological cancer had urgency of defe- cation, and four suffered from fecal incontinence [26]. This dysfunction was also associated with reduction in anal canal pressures and changes in rec- tal function. There is a relationship between late anorectal dysfunction and dose-volume parameters from the rectum and anal canal [27].

Interpretation of Studies

All the studies were observational studies. They all show that late anorectal dysfunction was common and related to a change in rectal function and weak- nesses of the anal sphincters. The changes progressed with time. The studies suggest that pelvic irradiation fields should be optimized, excluding the anal canal from the high-dose volume and applying rectal shielding whenever possible.

Treatment of Fecal Incontinence after Pelvic Radiotherapy

There is little knowledge on how to treat fecal incon-

tinence in these patients, and patients have, in gener-

al, been treated empirically with constipating agen-

cies or suppositories. Two new treatment modalities,

however, may be attractive to use in these patients:

transanal irrigation and percutaneous nerve evalua- tion (PNE)/sacral nerve stimulation (SNS).

Transanal Irrigation

This conservative management has proven very effective in certain groups of patients with bowel problems [28], with improvement in incontinence, constipation, and quality of life in a randomized trial on spinal cord patients [29, 30]. Small observational studies also suggest that this treatment can be very effective in patients with irradiation-related fecal incontinence [31] (Fig. 2).

PNE/SNS

Sacral nerve stimulation has been shown repeatedly to be a very effective treatment modality for various patient groups with fecal incontinence [32]. Small observational studies suggest that this can be very effective in patients with incontinence after pelvic irradiation. Further studies are, however, needed to evaluate the effectiveness of this treatment and how it influences the physiology in these patients.

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