Effects on functional outcome after IORT-containing multimodality treatment for locally advanced primary and locally recurrent rectal cancer

Int. J. Radiation Oncology Biol. Phys., Vol. 54, No. 4, pp. 1082–1088, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/02/$–see front matter

PII S0360-3016(02)03012-2

CLINICAL INVESTIGATION

Rectum

EFFECTS ON FUNCTIONAL OUTCOME AFTER IORT-CONTAINING MULTIMODALITY TREATMENT FOR LOCALLY ADVANCED PRIMARY AND LOCALLY RECURRENT RECTAL CANCER GUIDO H. H. MANNAERTS, M.D., PH.D.,* HARM J. T. RUTTEN, M.D., PH.D., F.R.C.S.,* HENDRIK MARTIJN, M.D., PH.D.,† PATRICK E. J. HANSSENS, M.D.,‡ AND THEO WIGGERS, M.D., PH.D., F.R.C.S.§ Departments of *Surgery and †Radiotherapy, Catharina Hospital, Eindhoven, The Netherlands; Departments of ‡Radiotherapy and § Surgical Oncology, Daniel den Hoed Cancer Center, University Hospital Rotterdam, Rotterdam, The Netherlands Purpose: In the treatment of patients with locally advanced primary or locally recurrent rectal cancer, much attention is focused on the oncologic outcome. Little is known about the functional outcome. In this study, the functional outcome after a multimodality treatment for locally advanced primary and locally recurrent rectal cancer is analyzed. Methods and Materials: Between 1994 and 1999, 55 patients with locally advanced primary and 66 patients with locally recurrent rectal cancer were treated with high-dose preoperative external beam irradiation, followed by extended surgery and intraoperative radiotherapy. To assess long-term functional outcome, all patients still alive (n ⴝ 97) were asked to complete a questionnaire regarding ongoing morbidity, as well as functional and social impairment. Seventy-six of the 79 patients (96%) returned the questionnaire. The median follow-up was 14 months (range: 4 – 60 months). Results: The questionnaire revealed fatigue in 44%, perineal pain in 42%, radiating pain in the leg(s) in 21%, walking difficulties in 36%, and voiding dysfunction in 42% of the patients as symptoms of ongoing morbidity. Functional impairment consisted of requiring help with basic activities in 15% and sexual inactivity in 56% of the respondents. Social handicap was demonstrated by loss of former lifestyle in 44% and loss of professional occupation in 40% of patients. Conclusions: As a result of multimodality treatment, the majority of these patients have to deal with long-term physical morbidity, the need for help with daily care, and considerable social impairment. These consequences must be weighed against the chance of cure if the patient is treated and the disability eventually caused by uncontrolled tumor progression if the patient is not treated. These potential drawbacks should be discussed with the patient preoperatively and taken into account when designing a treatment strategy. © 2002 Elsevier Science Inc. Functional outcome, Quality of life, IORT, Locally advanced, Locally recurrent rectal cancer.

INTRODUCTION

aggressive multimodality treatment may have an important bearing on the patient’s functional outcome, however, has received little attention in the medical literature. The purpose of this study is to assess the effect of multimodality treatment on long-term functional outcome for locally advanced primary or locally recurrent rectal cancer.

Conventional treatment with radiotherapy and/or surgery for locally advanced primary or locally recurrent rectal cancer results in high local recurrence and low survival rates (The 5-year survival range is 10%–26% for locally advanced and 7%–24% for locally recurrent rectal cancer) (1– 4). Multimodality treatment combining preoperative external beam radiotherapy (EBRT) with extended surgery that aims at a complete tumor resection, followed by intraoperative radiotherapy (IORT) to boost the area at risk for tumor residue, has been reported to achieve 5-year survival rates in the range 46%– 62% in patients with locally advanced primary and 19%–21% in patients with locally recurrent rectal cancer (4 –13). The possibility that this more

PATIENTS AND METHODS Between February 1994 and August 1999, 121 patients (55 patients with locally advanced rectal cancer and 66 with locally recurrent rectal cancer) underwent multimodality treatment with curative intent at the Catharina Hospital in Eindhoven and the Daniel den Hoed Cancer Center in Rotterdam.

Reprint requests to: H.J.T. Rutten, M.D., Ph.D., F.R.C.S., Department of Surgery, Catharina Hospital, Michelangelolaan 2, 5631EJ Eindhoven, The Netherlands. Tel: (⫹31) 402397155; Fax:

(⫹31) 402443370; E-mail: [email protected] Received Mar 6, 2002, and in revised form May 29, 2002. Accepted for publication Jun 10, 2002. 1082

Functional outcome after multimodality treatment for rectal cancer

Table 1. Patient and treatment characteristics Locally advanced primary

Total number of patients Age (years) Median Range Gender Male Female Prior treatment Irradiation Mean (Gy) Range (Gy) Surgical procedure Low anterior res. Abdominoperineal res. Multimodality treatment Irradiation (n) Median (Gy) Range (Gy) Surgical procedure Low anterior res. Abdominoperineal res. Abdominosacral res. Exenteration Ileum conduit Radicality resection Neg. margins Microscopic pos. margins Macroscopic pos. margins IORT IOERT (n) 10 Gy 12.5 Gy 15 Gy 17.5 Gy IOHDR 10 Gy

Locally recurrent

No.

(%)

No.

(%)

37

(49)

39

(51)

62 36–86

– –

62 41–84

– –

22 15

(59) (41)

24 15

(62) (38)

– – –

– – –

12 50.4 25–63

(31) – –

– –

– –

25 14

(64) (36)

37 50.4 25–61

(100) – –

*36 50.4 25–50.4

(92) – –

11 10 9 7 3

(30) (27) (24) (19) (8)

6 10 17 6 5

(15) (26) (44) (15) (13)

32 3 2

(87) (8) (5)

23 12 4

(59) (31) (10)

24 2 2 2

(65) (5) (5) (5)

18 – 5 4

(46) – (10) (10)

7

(19)

12

(31)

* Seven locally recurrent cancer patients had 30.6 Gy reirradiation, and 3 patients received no irradiation. Abbreviations: res. ⫽ resection; neg. ⫽ negative; pos. ⫽ positive; IORT ⫽ intraoperative radiotherapy; IOERT ⫽ intraoperative electron beam radiotherapy; IOHDR ⫽ intraoperative highdose-rate brachytherapy.

The multimodality treatment consisted of high-dose preoperative radiotherapy (50.4 Gy or 30.6 Gy after previous irradiation), extended circumferential margin excision, and IORT (10 –17.5 Gy) (11). IORT was delivered either as intraoperative electron beam radiotherapy at the Catharina Hospital (n ⫽ 94) or as intraoperative high-dose-rate brachytherapy at the Daniel den Hoed Cancer Center (n ⫽ 27). Long-term effects on functional outcome were evaluated by means of a questionnaire that was sent to all surviving patients (n ⫽ 79). The response rate was 96%, yielding 76 evaluable patients (Table 1). If a question was not answered, fewer than the total number of 76 patients were analyzed.

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The same questions were asked at two different times, the first time to cover the period of 6 months before the treatment, and the second time to evaluate the current situation. The details of patient and treatment characteristics for the 76 patients are listed in Table 1. The groups were comprised of 37 patients with locally advanced primary rectal cancer (22 male, 15 female) and 39 patients with locally recurrent rectal cancer (24 male, 15 female). The median age was 62 years (range: 36 – 84 years). The minimal time between the operation as part of multimodality treatment and the questionnaire was 4 months; the maximal time was 60 months (median: 14 months). Functional outcome was assessed by the following criteria: 1. Morbidity: fatigue, perineal pain, signs of plexus neuropathy (radiating pain, numbness, or decreased strength), general walking disturbances, and urologic dysfunction. 2. Functional impairment: need of assistance with basic activities (getting dressed, washing, eating, and walking), anal incontinence, and sexual dysfunction. 3. Social handicap: lifestyle (hobbies, sports, and social contacts) and occupation. The questions, except those concerning working activity, former lifestyle, and anal incontinence, could be answered by the following: no, sometimes, regularly, often, or always. The question regarding working activity could be answered by the following: no job, resigned, alternative job, or the same job; the question regarding catching up with former lifestyle could be answered by yes or no. Anal incontinence—assessed by incontinence for gas, liquid/solid stools, urgency, frequency, and the need to wear a pad—was scored according to the scale of Prescatori et al. (14), as well as according to the Memorial Sloan-Kettering Cancer Center Sphincter Function Scale (15, 16). Patients with an ileum conduit (n ⫽ 10) were excluded for questions concerning urologic dysfunction. Patients indicating “sexually inactive” (n ⫽ 8) in the pretreatment status were excluded from the analysis of sexual dysfunction. Anal incontinence was analyzed in 8 of the 17 patients (6 locally advanced and 2 locally recurrent) who underwent a low anterior resection with restoration of bowel continuity. Statistical comparisons were performed using the Wilcoxon test for repeated measurements of an individual person; the chi-squared test was used for matching the p values of the different variables in multivariate analysis: i.e., age (ⱕ60 or ⬎60 years), gender, recurrent or primary tumor status, IORT doses (ⱕ12.5 Gy or ⬎12.5 Gy), type of resection (low anterior or other type of resection), and length of follow-up (ⱕ or ⬎ the median follow-up of 14 months). A p value less than 0.05 was considered statistically significant. p values were calculated for every category of debility. However, the percentages of functional impairment, for reasons of presentation in both the “Results” section and the

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Table 2. Questionnaire functional outcome in locally advanced primary and locally recurrent rectal cancer* Locally advanced primary rectal cancer Preoperative

Fatigue Perineal pain Perineal pain when sitting Radiating pain in leg(s) Numb sensation in leg(s) Decreased strength in leg(s) Walking difficulties Voiding dysfunction Sexual activity Help in basic activities of daily living Catching up former lifestyle Resumption of former job No job preoperatively No restart of working Restarted working same job Restarted working in lighter job

Postoperative

Locally recurrent rectal cancer Preoperative

Postoperative

n

%

n

%

p value

n

%

n

%

p value

11/36 12/35 9/36 4/37 4/37 4/37 5/36 1/34 27/34 1/36

31 34 25 11 11 11 14 3 79 3 18/34

22/36 19/35 20/36 9/37 7/37 16/37 13/36 15/34 11/34 3/36 53%

61 54 56 24 19 43 36 44 32 8

0.02 0.2 0.046 0.3 0.1 0.008 0.2 ⬍0.001 ⬍0.001 0.5

16/39 16/38 14/36 8/38 7/39 5/39 4/39 7/32 23/34 0/39

41 42 39 21 18 13 10 22 68 0 23/39

26/39 28/38 29/36 16/38 19/39 22/39 20/39 18/32 11/34 9/39 59%

67 74 81 42 49 56 51 56 32 23

0.001 0.08 0.01 0.01 0.006 ⬍0.001 ⬍0.001 0.001 ⬍0.001 0.004

19 7 4 5

54% 20% 12% 14%

20 7 7 5

51% 18% 18% 13%

* If a question was not answered, fewer than the total number of 76 patients were analyzed.

tables, were calculated in terms of having dysfunction in any degree vs. having no dysfunction. RESULTS Morbidity (Table 2) Fatigue was observed in 31% preoperatively vs. 61% postoperatively in the locally advanced group (p ⫽ 0.02) and in 41% vs. 67%, respectively, in the locally recurrent group (p ⫽ 0.001). Perineal pain while sitting was experienced by 25% preoperatively vs. 56% postoperatively in the locally advanced group (p ⫽ 0.046) and in 39% preoperatively vs. 81% postoperatively in the locally recurrent group (p ⫽ 0.01). Neuropathic pain in the leg(s) was observed in 11% preoperatively vs. 24% postoperatively in the locally advanced group (p ⫽ 0.3) and in 21% vs. 42%, respectively, in the locally recurrent group (p ⫽ 0.01). Walking difficulties were observed in 14% preoperatively vs. 36% postoperatively in the locally advanced group (p ⫽ 0.2) and in 10% vs. 51%, respectively, in the locally recurrent group (p ⬍ 0.001). Voiding dysfunction was observed in 3% preoperatively vs. 44% postoperatively in the locally advanced group (p ⬍ 0.001) and in 22% vs. 56%, respectively, in the locally recurrent patients (p ⫽ 0.001). Functional impairment Three percent of the locally advanced patients needed help with basic activities preoperatively vs. 8% postoperatively (p ⫽ 0.5). This difference was significantly greater (p ⫽ 0.03) in the locally recurrent patient group, with a percentage of 0% preoperatively vs. 23% postoperatively (p ⫽ 0.004). Sexual activity decreased from 79% preoperatively to 32% postoperatively in the locally advanced

group (p ⬍ 0.001) and from 68% to 32%, respectively, in the locally recurrent patients (p ⬍ 0.001). The results for anal incontinence after restoration of bowel continuity (n ⫽ 8) are summarized in Table 3. None of the patients were incontinent for solid stools preoperatively, whereas 63% (5/8) of the patients were incontinent postoperatively, 3/8 (38%) every day. Urgency was observed in 25% (2/8) of patients preoperatively and in 88% (7/8) postoperatively. One patient needed to wear a pad preoperatively; 4 patients (50%) needed to postoperatively. The mean incontinence score by Prescatori et al. (14) increased from 0.1 preoperatively (median: 0) to 4.6 postoperatively (median: 5). The Memorial Sloan-Kettering Cancer Center Sphincter Function Scale was excellent in 88% (7/8) preoperatively and was fair or poor in the same percentage postoperatively. Social handicap In the locally advanced group, 53% of patients could regain their former lifestyle; in the locally recurrent group, 59% of patients could. Of the 35 patients overall (48%) who had a job preoperatively, 21 (60%) started working postoperatively, with half of them (n ⫽ 10) in the same occupation. Multivariate analysis In general, female patients revealed more symptoms both preoperatively and postoperatively. In particular, decreased strength in the leg(s) was significantly higher in female patients (p ⫽ 0.03). Male patients had a significantly higher rate of resuming their former lifestyle in comparison to female patients (67% vs. 39%, p ⫽ 0.02). The rate at which male patients returned to work postoperatively (15/20) was

Functional outcome after multimodality treatment for rectal cancer

Incontinence of flatus Incontinence of liquid Incontinence of stool Urgency Multiple evacuations/day Use of pads Use of medications Prescatori incontinence scale (mean)* MSKCC SF score 1 ⫽ excellent (1–2 BN and no S) 2 ⫽ good (3–4 BM or mild S) 3 ⫽ fair (⬎4 BM or moderate S) 4 ⫽ poor (incontinence)

Postoperative

No.

(%)

No.

(%)

2/8 1/8 0/8 2/8 1/8 1/8 2/8

(25) (13) (0) (25) (13) (13) (25)

6/8 5/8 5/8 1/8 7/8 4/8 3/8

(75) (63) (63) (13) (88) (50) (38)

0.1

–

4.6

–

7/8

(88)

1/8

(13)

–

–

–

–

1/8

(13)

2/8

(25)

–

–

5/8

(63)

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type of resection), IORT doses (ⱕ12.5 Gy or ⬎12.5 Gy), or length of follow-up (shorter or longer than the median follow-up of 14 months) (Table 4).

Table 3. Incontinence after restoration of bowel continuity Preoperative

● G. H. H. MANNAERTS et al.

DISCUSSION

* The Prescatori incontinence scale gives 1 point for incontinence of flatus, 2 points for incontinence of liquid stools, and 3 points for incontinence of solid stools. An extra 1–3 points are added for frequency of incontinence less than once a week, at least once a week, or every day. Thus the minimum total score is 0, and the maximum total score is 6 points. Abbreviations: BM ⫽ bowel movements/day; S ⫽ soiling; MSKCC SF ⫽ Memorial Sloan-Kettering Cancer Center Sphincter Function Scale.

higher than that at which female patients returned to work (6/15). No significant differences could be found between age (ⱕ60 or ⬎60 years), type of resection (low anterior or other

Multimodality treatment consisting of preoperative highdose EBRT, extended surgery, and IORT is reported to have 3-year local control rates 70%– 85%, disease-free survival rates 45%– 48%, and survival rates 51%– 60% in locally advanced primary rectal cancer patients; in locally recurrent rectal cancer patients, the rates are, respectively, 30%–75%, 19%–33%, and 31%–56% (12, 17). The results of this multimodality treatment at our institution have been reported and show an overall 3-year local control, disease-free survival, and survival rate of, respectively, 74%, 63%, and 56% for the locally advanced group and, respectively, 63%, 35%, and 49% for the locally recurrent group (11, 12). Cure and local tumor control are the main goals for such patients, and treatment-related morbidity seems to be of less importance. This is reflected by the lack of data reported on morbidity after multimodality treatment. As far as we know, only one report has described functional outcome results, predominantly regarding anal sphincter function, in 18 rectal cancer patients treated with low anterior resection as part of an IORT-containing multimodality treatment (15). However, the outcome of multimodality treatment can be placed in proper perspective only if morbidity and effects on social functioning are also taken into account. Because these patients constitute a rather specific group, we focused on the particular variables that frequently affect their functional outcome. The causes of impairment are multifactorial: i.e., high-dose preoperative radio(chemo)therapy, extensive surgery, and IORT. Extensive surgery is

Table 4. Questionnaire regarding functional outcome in males and females* Male Preoperative

Fatigue Perineal pain Perineal pain when sitting Radiating pain in leg(s) Numb sensation in leg(s) Decreased strength in leg(s) Walking difficulties Voiding dysfunction Sexual activity Help in basic activities of daily living Catching up former lifestyle Resumption of former job No job preoperatively No restart of working Restarted working same job Restarted working in lighter job

Female

Postoperative

Preoperative

Postoperative

n

%

n

%

p value

n

%

n

%

p value

14/45 15/46 23/46 0/46 7/46 3/46 5/45 6/38 33/41 0/46

31 33 50 0 15 7 11 16 80 0 30/45

25/46 27/46 28/46 11/46 14/46 16/46 15/45 16/38 15/41 6/46 67%

54 59 61 24 30 35 33 42 37 13

0.002 0.09 0.04 0.05 0.1 0.002 0.01 0.02 ⬍0.001 0.03

13/30 13/27 10/29 8/29 4/30 6/30 4/30 2/28 17/27 1/29

43 48 34 28 13 20 13 7 63 3 11/29

23/30 20/27 21/29 14/29 12/30 22/30 18/30 17/28 7/27 6/29 39%

77 74 72 48 40 73 60 61 26 21

0.01 0.1 0.01 0.08 0.001 0.001 0.005 ⬍0.001 0.002 0.06

25 5 7 8

56% 11% 15% 18%

14 9 4 2

48% 31% 14% 7%

* If a question was not answered, fewer than the total number of 76 patients were analyzed.

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needed to achieve the most important negative margins (11, 12, 18), causing anatomic changes (i.e., excision, incision, fibrosis, and ischemia) that are likely to be major factors affecting functional outcome. The IORT boost, which is equivalent to two to three times its nominal value in fractionated EBRT form, can increase the total (EBRT plus IORT) local effective dose to above 80 Gy (19, 20), to eliminate possible tumor residue. Peripheral nerves are the main dose-limiting structures for IORT, because it can induce plexus neuropathy (21–23). EBRT is known for its effects on bowel and urogenital function (24 –28). The use of small radiation fields, fractionation, and exclusion of bowel and bladder from the radiation volume, as well as lower total doses in case of reirradiation (⫾30 Gy), can reduce damage to the peripheral nerves (29). In this study, where both preoperative status and status after multimodality treatment were assessed with the same questionnaire, a major effect on the functional outcome was observed. As a new complaint, 44% of patients developed fatigue, 42% perineal pain (overall 50% while sitting), 43% decreased strength in the leg(s), and 36% walking difficulties. The neuropathic plexus symptoms are a major cause of these effects, which were observed in about one-fourth of patients and which correspond to the 3%–52% neuropathy rate reported by others (10, 13, 30 –32). Although IORT doses above 12.5 Gy are being held responsible for the increased rate of plexus neuropathy (33), such a relation could not be established in this study. Furthermore, plexopathy can be induced also by surgical damage to the sacral nerve plexus. Voiding dysfunction as a new complaint was observed in 42%, and decrease in sexual activity was observed in 56% of patients. The group of female patients had a remarkably higher percentage of voiding dysfunction compared to the male group. Such an observation was made also by Havenga et al. about a group of mobile rectal cancer patients treated with surgery only; this was explained by the larger bladder capacity but shorter length of the urethra in women (28). Women also had both preoperatively and postoperatively a lower rate of sexual activity compared to that for men. Very few data can be found about this effect in females, because more attention is focused on erectile and ejaculation disturbances in male patients after rectal surgery (34). Shibata et al. found in all 4 female patients treated with IORT-containing multimodality treatment for locally advanced primary or recurrent rectal cancer some lack of sensation or dyspareunia (15). Havenga et al. reported sexual activity in 70% of male and in 86% of female patients after total mesorectal excision surgery for mobile rectal cancer, with a reduction to 53% after abdominoperineal resection in males; however, there is no report on females after abdominoperineal resection (28). The difference in sexual dysfunction between the studies can be explained by the larger effect of multimodality treatment on sexual activity in female patients and by the fact that the median age of the patients in this study is 6 years older. Moreover, 56% of patients could not regain their former

Volume 54, Number 4, 2002

style of living. However, this should be placed in the perspective that uncontrolled tumor progression would decrease the quality of life and result in similar symptoms, such as fatigue, perineal pain, plexopathy, and urogenital dysfunction (35). Shibata et al. reported some degree of social restriction in two-thirds of patients treated with low anterior resection and IORT (15). Urgency of stools was the most limiting factor responsible for social restriction. This relation was not analyzed in this study, because most patients had a colostomy. However, for patients in whom bowel continuity had been restored (n ⫽ 8), both a high percentage of daily incontinence for solid stools (38%) and a dramatic increase in urgency of stools (from 25% to 88%) were observed. The postoperative Memorial Sloan-Kettering Cancer Center Sphincter Function Scale was fair or poor in 6 of the 7 patients (86%) who had an excellent sphincter function preoperatively and in whom bowel continuity was restored. This is less favorable in comparison to the 56% of locally advanced or locally recurrent rectal cancer patients given multimodality treatment in the study by Shibata et al. (15). The median postoperative anal incontinence score was 5, which is worse than the median score of 4 in a study of total mesorectal excision surgery with or without preoperative irradiation for mobile rectal cancer (36). For this reason and because 2 patients experienced postoperative sepsis as a result of anastomotic leakage, restoration of bowel continuity is questionable and should be studied more closely in these patient groups. Furthermore, in this study there were no significant differences in functional outcome parameters after low anterior resection vs. other types of resection. Twenty-one of the 35 patients (60%) who had an occupation resumed working postoperatively. This is less than the 86% rate in the functional outcome study by Frigell et al., in which patients received surgery only for primary mobile rectal cancer (37). Our figures are more favorable than those of Williams and Johnston, who reported that more than 50% of patients were unable to work after abdominoperineal resection (38). Women were less able to resume their former life-style in comparison to men (39% vs. 67%, p ⫽ 0.02), and women returned to work less frequently (40% vs. 75%). Social, financial, and family obligations and expectations are different for men and women; this might explain the difference in who returns to work. In the locally recurrent group, a 10% higher preoperative, as well as 20%–25% higher postoperative, complaint rate was found in comparison to the complaint rates for the locally advanced rectal cancer patient group. Age was not found to have a significant correlation with the level of functional outcome postoperatively. This study did not show any significant change in treatment-induced morbidity after a longer follow-up (ⱕ14 vs. ⬎14 months follow-up), which seems to imply that the relative short-term morbidity remains, effectively, the long-term morbidity. In this study, only those patients who had a chance to be cured were included, because they are the patients for whom this mul-

Functional outcome after multimodality treatment for rectal cancer

timodality treatment was initiated, and they are the ones who will have to bear the burden in the long run. Furthermore, it should be considered that differences in socioeconomic characteristics around the globe might have a substantial influence on the results of treatment. In conclusion, IORT-containing multimodality treatment improves local control and survival for patients with locally advanced primary and locally recurrent rectal cancer, but at the

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cost of a major impact on quality of life in more than half the patients. This compromise in lifestyle must be weighed against the mortality and morbidity due to uncontrolled tumor growth if rectal cancer is not treated accordingly. Therefore, preoperative counseling about treatment-related morbidity is mandatory. Evaluations of functional outcome should be an integral part of multimodality treatment strategies.

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