Original article
Survival after pelvic exenteration for T4 rectal cancer M. Kusters1,2 , K. K. S. Austin3,4 , M. J. Solomon3,4 , P. J. Lee3,4 , G. A. P. Nieuwenhuijzen1 and H. J. T. Rutten1,2 Departments of Surgery, 1 Catharina Hospital, Eindhoven, and 2 Maastricht University Medical Centre, Maastricht, The Netherlands, and 3 Department of Colorectal Surgery, Royal Prince Alfred Hospital, and 4 Surgical Outcome Research Centre (SOuRCe), Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia Correspondence to: Professor M. J. Solomon, Department of Colorectal Surgery, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia (e-mail: [email protected])
Background: The purpose of this study was to analyse retrospectively the pooled results after pelvic
exenteration for locally advanced T4 rectal cancer. Historically, patients with T4 rectal cancers requiring pelvic exenteration have been offered only palliative surgery or no operation. Methods: The basic treatment principle was preoperative (chemo)radiotherapy, radical surgery and, in some patients, adjuvant chemotherapy. Risk factors for local recurrence, distant metastases and overall survival were studied in univariable and multivariable analyses. Results: Ninety-five patients with T4 rectal cancer who underwent pelvic exenteration in two tertiary referral centres up to 2013 were studied. Clear margins (R0) were achieved in 87 per cent of patients. Adjuvant chemotherapy was administered in 33 per cent, independent of the resection margin, lymph node status and postoperative T category. The 5-year local recurrence rate was 17 per cent, with a distant metastasis rate of 16 per cent and overall survival rate of 62 per cent. In multivariable analysis the only factor associated with death was omission of adjuvant chemotherapy (P = 0⋅016). The effect of adjuvant chemotherapy was more pronounced in the elderly: patients aged over 70 years who had chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 39 per cent of elderly patients who did not receive chemotherapy (P = 0⋅019). Conclusion: Pelvic exenteration led to an R0 resection rate of 87 per cent for T4 rectal cancer, giving good local control and overall survival comparable to population-based colorectal cancer survival rates. Adjuvant chemotherapy may improve overall survival further, even in the elderly. Paper accepted 23 September 2014 Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9683
Introduction
The acceptance into surgical practice that the rectum should be removed within its enveloping mesorectal fascia has led to a decline in the local recurrence rate after rectal cancer treatment1 . However, when tumour invades adjacent organs, standard total mesorectal excision is not sufficient. For most T4 tumours an extended resection is sufficient with, for example, partial prostatectomy in men or resection of part of the vagina in women. However, when the tumour massively invades adjacent organs, extensive surgery with en bloc resection of other pelvic organs is the only possibility for complete resection. Resection with a clear margin (R0) is the key to local control, and neoadjuvant (chemo)radiation has been used to facilitate surgical resection by downsizing the tumour2 – 4 . © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Historically, the few patients with T4 rectal cancers requiring pelvic exenteration were offered surgery alone or no surgery5 – 7 . Pelvic exenteration is the only form of treatment that is potentially curative; without resection, patients have a very poor prognosis and substantial morbidity6 . Reported morbidity and mortality rates for pelvic exenteration used to be more than 50 and 10 per cent respectively5,7 . However, experience in the past decade has shown it can be performed with good long-term quality of life in expert centres with a multidisciplinary approach8,9 . Regarding adjuvant treatment, chemotherapy is used widely in colonic cancer treatment10 . However, there is no consensus among clinicians on whether use of chemotherapy should be standard in the treatment of rectal cancer11 . The aim of this study was to pool the results of patients with locally advanced T4 rectal cancer undergoing pelvic exenteration in two tertiary referral centres, in order to BJS 2015; 102: 125–131
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M. Kusters, K. K. S. Austin, M. J. Solomon, P. J. Lee, G. A. P. Nieuwenhuijzen and H. J. T. Rutten
study a relatively large number of patients who have undergone this uncommon type of extensive resection. This combined analysis allowed conclusions and decisions to be made about the risks and benefits of pelvic exenteration surgery, and also allowed multivariable analysis of factors influencing local control and survival.
Methods
Two national tertiary referral centres for locally advanced rectal cancer and recurrent rectal cancer, the Royal Prince Alfred Hospital (RPA) in Sydney, Australia, and the Catharina Hospital, Eindhoven (CHE), The Netherlands, have been following their patients prospectively since 1997. Tumour staging was obtained by cross-sectional imaging (endoscopic ultrasonography, CT and/or MRI). Only patients who underwent curative resection were selected; patients with stage IV disease were included only when they were eligible for a curative resection of synchronous metastases. Patients who underwent partial or complete exenteration, as defined previously8 , were identified from the operation reports. Patients with a T4 tumour with focal invasion requiring only an extended resection were excluded, leaving patients with primary locally advanced T4 rectal cancer treated with exenterative surgery for analysis. Methods of detection of local and distant recurrence have been described previously8,12,13 .
Exenteration definitions To simplify the types of resection, three categories of pelvic exenteration were defined: posterior pelvic exenteration (PPE), total pelvic exenteration (TPE) and supralevator exenteration (SLE). PPE included removal of the rectum and anus (abdominoperineal resection, APR) en bloc with the pelvic floor/side wall, including the posterior vaginal wall in women and part of the prostate/ureter/bladder in men, or an abdominal sacral resection with a high sacrectomy (defined as S3 or higher). TPE was defined as en bloc removal of the rectum and anus (APR), prostate in men, vagina, uterus and ovaries (if present) in women, and removal of the urinary bladder, with or without sacrectomy or coccygectomy. SLE included removal of the rectum, prostate in men, vagina, uterus and ovaries (if present) in women, and urinary bladder, with establishment of rectal continuity (low anterior resection). After resection of the bladder, a urinary diversion was formed by the urologist in the form of an ileal or colonic conduit. A rectus abdominis flap was used for closure of large defects and reconstruction of the vagina in women. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
(Neo)adjuvant treatment and intraoperative radiotherapy The standard neoadjuvant treatment was chemoradiotherapy. At RPA this was radiotherapy in the earlier years, but has switched to chemoradiotherapy more recently. The radiotherapy dose in both centres was typically in the range 45–50⋅4 Gy in fractions from 1⋅8 to 2⋅0 Gy; chemotherapy was based on 5-fluorouracil schemes. In CHE intraoperative radiotherapy (IORT) was delivered as an electron boost during open surgery, to the area at risk of having a narrow resection margin10,11 . The IORT dose was typically in the range 10–12⋅5 Gy, with energy ranging from 8 to 12 MeV. There was no consensus on the use of adjuvant chemotherapy in either treatment centre during the study interval.
Statistical analysis The t test and χ2 test were used for comparison of data on individual variables. Rates of local recurrence, distant metastasis, cancer-specific survival and overall survival were estimated using the Kaplan–Meier method, with differences assessed by means of the log rank test. Cancer-specific survival was defined as the time between rectal cancer surgery and death from rectal cancer. Overall survival was defined as the time between surgery and death from any cause. P values were two-sided and considered statistically significant at a value of 0⋅050 or less. For determination of risk factors, the effect of co-variables was first analysed by univariable Cox regression, stratifying for treatment centre. Co-variables with a trend towards significance (P < 0⋅100) were selected for multivariable analysis, again stratifying for treatment centre, using stepwise Cox proportional hazards regression modelling. Both forward and backward stepwise regression was used, and two-sided P < 0⋅050 was considered significant. Statistical analysis was performed using SPSS® version 16.0 for Windows® (IBM, Armonk, New York, USA). Results
Up to May 2013, 144 patients had had a curative resection for T4 rectal cancer at RPA and 384 at CHE. Patients with a T4 tumour with focal invasion requiring only an extended resection were excluded (104 and 329 patients from RPA and CHE respectively), leaving 40 patients from RPA and 55 from CHE with primary locally advanced T4 rectal cancer treated with exenterative surgery for analysis.
Comparison between centres Similarities and differences between patients and treatments at RPA and CHE are shown in Table 1. The age of the www.bjs.co.uk
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Table 1
127
Patients and treatments at the two institutes All patients (n = 95)
RPA (n = 40)
CHE (n = 55)
P†
63 (30–86) 48 : 47
61 (30–85) 25 : 15
63 (32–86) 23 : 32
0⋅625‡ 0⋅047 0⋅052
4 (4) 9 (9) 82 (86)
4 (10) 3 (8) 33 (82)
0 (0) 6 (11) 49 (89)
52 (55) 23 (24) 20 (21)
17 (43) 14 (35) 9 (22)
35 (64) 9 (16) 11 (20)
48 (51) 43 (45) 4 (4)
40 (100) 0 (0) 0 (0)
8 (15) 43 (78) 4 (7)
3 (3) 2 (2) 52 (55) 32 (34) 6 (6)
0 (0) 1 (3) 17 (43) 18 (45) 4 (10)
3 (5) 1 (2) 35 (64) 14 (25) 2 (4)
83 (87) 12 (13)
35 (87) 5 (13)
48 (87) 7 (13)
64 (67) 31 (33) 62 (2–191)
19 (48) 21 (52) 44 (2–191)
45 (82) 10 (18) 66 (5–155)
Age (years)* Sex ratio (M : F) Preoperative treatment None Radiotherapy alone Chemoradiotherapy Type of surgery Posterior pelvic exenteration Total pelvic exenteration Supralevator exenteration Intraoperative radiotherapy (Gy) None 10 12⋅5 Postoperative disease stage 0 I II III IV Surgical margins R0 R1/R2 Postoperative chemotherapy No Yes Follow-up (months)*
0⋅071
< 0⋅001
0⋅083
0⋅974
< 0⋅001
0⋅550‡
Values in parentheses are percentages unless indicated otherwise; *values are median (range). RPA, Royal Prince Alfred Hospital, Sydney, Australia; CHE, Catharina Hospital, Eindhoven, The Netherlands. †χ2 test, except ‡t test. Table 2
Differences between the exenteration types Posterior pelvic exenteration (n = 52)
Total pelvic exenteration (n = 23)
Supralevator exenteration (n = 20)
61 (30–86) 8 : 44
59 (35–78) 22 : 1
67 (44–81) 18 : 2
1 (2) 4 (8) 47 (90) 3595 (150–20 800)
0 (0) 4 (17) 19 (83) 4894 (200–25 000)
3 (15) 1 (5) 16 (80) 2955 (100–11 500)
33 (63) 6 (12) 3 (6) 6 (12) 4 (8)
12 (52) 5 (22) 1 (4) 4 (17) 1 (4)
20 (100) 0 (0) 0 (0) 0 (0) 0 (0)
30 (58) 1 of 8 21 of 44
18 (78) 4 of 22 1 of 1
20 (100) 0 (0) 0 (0)
44 (85) 8 (15)
20 (87) 3 (13)
19 (95) 1 (5)
50 (96) 2 (4)
23 (100) 0 (0)
18 (90) 2 (10)
Median age (years)* Sex ratio (M : F) Preoperative treatment None Radiotherapy alone Chemoradiotherapy Blood loss (ml)† Excision of coccyx/sacrum None Coccyx Sacrum at level S4 Sacrum at level S3 Sacrum at level S2 Reconstruction with flap None In men In women Surgical margins R0 R1/R2 Death within 1 month No Yes
P‡ 0⋅344§ < 0⋅001 0⋅050
0⋅071§ 0⋅073
< 0⋅001
0⋅493
0⋅261
Values in parentheses are percentages unless indicated otherwise; values are *median (range) and †mean (range). ‡χ2 test, except §t test.
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Table 3
M. Kusters, K. K. S. Austin, M. J. Solomon, P. J. Lee, G. A. P. Nieuwenhuijzen and H. J. T. Rutten
5 (10) 5 (10) 3 (6) 6 (12) 2 (4)
1 (4) 3 (13) 2 (9) 6 (26) 0 (0)
1 (5) 3 (15) 1 (5) 3 (15) 0 (0)
(P = 0⋅569). The R0 rate was similar in the intervals up to and after 2005 (both 87 per cent; P = 0⋅956). In the period up to 2005, ten (32 per cent) of 31 patients underwent bladder-resecting surgery (TPE or SLE), compared with 33 (52 per cent) of 64 after 2005 (P = 0⋅076). Adjuvant chemotherapy was administered in 33 per cent of the patients, independent of R0 margin (P = 0⋅475), lymph node status (P = 0⋅511), postoperative T category (P = 0⋅244) and treatment interval (P = 0⋅146).
0 (0)
2 (9)
1 (5)
Types of exenteration
1 (2)
3 (13)
2 (10)
4 of 22 (18)
0 (0)
0 (0)
2 (4)
0 (0)
1 (5)
4 (8) 2 (4) 2 (4) 1 (2) 1 (2)
3 (13) 2 (9) 1 (4) 2 (9) 0 (0)
6 (30) 5 (25) 1 (5) 4 (20) 0 (0)
n.a. n.a. n.a.
0 (0) 2 (9) 0 (0) 0 (0) 0 (0) 0 (0)
1 (5) 3 (15) 3 (15) 1 (5) 1 (5) 1 (5)
Table 2 summarizes demographic and treatment data in relation to the type of exenteration. There was no difference in the age of the patients. Women mainly underwent PPE (44 of 47), whereas most men had TPE (22 of 48) or SLE (18 of 48). A sacrectomy or coccygectomy was performed in 11 of 23 TPEs and 19 of 52 PPEs. Twenty-one of the 44 women who underwent PPE had reconstruction of the perineum and the vagina with a rectus abdominis flap. Flaps were used in one of eight and four of 22 men who had a PPE and TPE respectively. There was no difference in the percentage of R0 margins between the types of exenteration (P = 0⋅493). Four deaths within 30 days (4 per cent) were due to bleeding, anastomotic leakage, respiratory insufficiency and cardiac arrest. Complications by type of exenteration are listed in Table 3.
Complications Posterior pelvic Total pelvic Supralevator exenteration exenteration exenteration (n = 52) (n = 23) (n = 20)
Minor Wound infection midline Wound infection perineal Pulmonary infection Urinary tract infection Central venous line infection Major Bleeding requiring reoperation Wound dehiscence requiring reoperation Flap necrosis requiring reoperation Stoma retraction/leakage requiring reoperation Intra-abdominal abscess Treated with antibiotics Requiring drainage Urinary leakage Ureteric – stent placed From neobladder Requiring drainage Requiring reoperation Anastomotic leakage Managed with drain Requiring reoperation Leading to death
Values in parentheses are percentages. n.a., Not applicable.
patients (63 years) and follow-up time (62 months) did not differ between the institutions. Neoadjuvant chemoradiation was administered to 86 per cent of the patients. Splitting the cohort into two arbitrary time intervals (up to 2005 and after 2005), there was no overall difference in the use of neodjuvant chemoradiation between the two periods: 25 (81 per cent) of 31 versus 57 (89 per cent) of 64 (P = 0⋅263). At RPA, however, significantly more chemoradiotherapy was given after 2005: 27 of 30 versus six of 10 before 2005 (P = 0⋅031). Chemoradiotherapy resulted in downstaging of the T category in 43 (52 per cent) of 82 patients, compared with four (31 per cent) of 13 who had radiotherapy or no neoadjuvant treatment (P = 0⋅147). A significantly higher proportion of women underwent exenteration at CHE (32 of 55 versus 15 of 40 at RPA), probably explaining the higher percentage of PPEs performed at CHE. More TPEs were carried out at RPA. The R0 resection rate did not differ between the institutions (both 87 per cent). Neoadjuvant treatment and downstaging were not related to an R0 margin (P = 0⋅564 and P = 0⋅511 respectively). Lymph node status was not influenced by which neoadjuvant treatment was given © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Local and distant recurrence Overall, 11 patients developed a local recurrence (5-year local recurrence rate 17 per cent). No factors were significantly associated with local recurrence in univariable analysis (Table 4). The 5-year distant metastasis rate was 16 per cent among patients without previously metastasized disease. Univariable analysis identified no factors significantly associated with distant recurrence.
Survival The overall 5-year survival rate was 62 per cent. The only risk factor for death identified by univariable analysis was the omission of postoperative chemotherapy (Table 4). Patients who had adjuvant chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 53 per cent in those without chemotherapy (P = 0⋅016) (Fig. 1). The effect of adjuvant chemotherapy was even more pronounced in the elderly: patients older than 70 years who had chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 39 per cent of elderly patients who had no chemotherapy (P = 0⋅019). In patients www.bjs.co.uk
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Table 4
129
Univariable Cox regression analysis of factors affecting recurrence and survival Local recurrence Hazard ratio
Age (years) < 70 ≥70 Sex M F Preoperative treatment Chemoradiotherapy None/radiotherapy Type of surgery Bladder retained (PPE) Bladder removed (TPE/SLE) Intraoperative radiotherapy Yes No Any downstaging Yes No Node category N0 N+ Metastasis category M0 M1 Surgical margin R0 R1/R2 Postoperative chemotherapy Yes No
Distant metastasis P
Hazard ratio
Cancer-specific survival P
0⋅151
Hazard ratio
0⋅805
1⋅00 (reference) 2⋅42 (0⋅73, 8⋅07)
1⋅00 (reference) 1⋅17 (0⋅35, 3⋅91) 0⋅202 1⋅00 (reference) 0⋅43 (0⋅13, 1⋅47) 0⋅428 1⋅00 (reference) 2⋅08 (0⋅26, 16⋅66) 0⋅297
0⋅324
0⋅378
1⋅00 (reference) n.c. 0⋅917
0⋅528
1⋅00 (reference) 0⋅93 (0⋅30, 2⋅90) 0⋅733
0⋅427
1⋅00 (reference) 1⋅88 (0⋅59, 5⋅98)
0⋅290 1⋅00 (reference) n.c.
0⋅769 1⋅00 (reference) 1⋅15 (0⋅45, 2⋅94)
0⋅288
1⋅00 (reference) 1⋅24 (0⋅36, 4⋅35)
0⋅995 1⋅00 (reference) 1⋅00 (0⋅48, 2⋅08)
1⋅00 (reference) n.c. 0⋅895
1⋅00 (reference) 1⋅06 (0⋅32, 3⋅53)
0⋅408 1⋅00 (reference) 0⋅59 (0⋅17, 2⋅05)
1⋅00 (reference) 1⋅36 (0⋅53, 3⋅51) 0⋅507
1⋅00 (reference) 2⋅25 (0⋅45, 11⋅29)
0⋅921 1⋅00 (reference) 1⋅04 (0⋅51, 2⋅13)
1⋅00 (reference) 0⋅40 (0⋅05, 3⋅09)
1⋅00 (reference) 2⋅68 (0⋅78, 9⋅21)
0⋅101
0⋅799
0⋅117
1⋅00 (reference) 0⋅49 (0⋅13, 1⋅89)
0⋅604 1⋅00 (reference) 1⋅21 (0⋅59, 2⋅49)
0⋅050 1⋅00 (reference) 2⋅59 (1⋅00, 6⋅70)
0⋅667
0⋅669 1⋅00 (reference) 1⋅18 (0⋅56, 2⋅49)
0⋅078
1⋅00 (reference) n.c.
–
–
0⋅464
1⋅00 (reference) 4⋅01 (0⋅86, 18⋅70)
0⋅198
1⋅00 (reference) 1⋅79 (0⋅38, 8⋅49)
1⋅00 (reference) 2⋅39 (0⋅64, 8⋅95) 0⋅474 1⋅00 (reference) 1⋅17 (0⋅32, 4⋅31)
0⋅277 1⋅00 (reference) 2⋅27 (0⋅52, 9⋅94)
0⋅173 1⋅00 (reference) 2⋅20 (0⋅71, 6⋅85)
0⋅818
1⋅00 (reference) 1⋅63 (0⋅43, 6⋅15)
0⋅345 1⋅00 (reference) 1⋅60 (0⋅60, 4⋅26)
0⋅209 1⋅00 (reference) 2⋅15 (0⋅65, 7⋅09)
P
1⋅00 (reference) 1⋅91 (0⋅88, 4⋅16)
1⋅00 (reference) 0⋅89 (0⋅35, 2⋅27) 0⋅490
1⋅00 (reference) n.c.
Hazard ratio
0⋅194 1⋅00 (reference) 1⋅90 (0⋅72, 5⋅02)
0⋅181
1⋅00 (reference) 2⋅41 (0⋅62, 9⋅29)
P
Overall survival
0⋅018 1⋅00 (reference) 3⋅40 (1⋅23, 9⋅40)
Values in parentheses are 95 per cent c.i. n.c., Not calculable because the number of events in each group was too small for reliable analysis. PPE, posterior pelvic exenteration; TPE, total pelvic exenteration; SLE, supralevator exenteration.
up to 69 years of age the effect of adjuvant chemotherapy on survival was also evident, but not significant (P = 0⋅085). The overall cancer-specific survival rate was 72 per cent after 5 years. In univariable analysis factors associated with death from cancer were lymph node positivity and M1 status. Neither of these factors remained significant in the multivariable model (P = 0⋅115 and P = 0⋅180 respectively).
1·0
Survival
0·8
0·6
0·4 Adjuvant chemotherapy
Discussion
No adjuvant chemotherapy 0·2
0
24
12
36
48
60
Time after surgery (months) No. at risk Chemotherapy No chemotherapy
31 64
31 48
23 31
18 22
12 18
Overall survival in patients who did, or did not receive adjuvant chemotherapy. P = 0⋅016 (log rank test)
Fig. 1
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10 14
This was a pooled analysis of 95 patients who underwent exenterative surgery for locally advanced T4 tumours in two tertiary referral centres, representing 18 per cent of 528 curatively treated T4 tumours. The overall results showed successful treatment, with 87 per cent clear margins and a local recurrence rate of 17 per cent after 5 years. The overall survival rate was 62 per cent after 5 years, which is comparable to, or even better than, rates among patients with colorectal cancer in general in www.bjs.co.uk
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two population-based studies from Australia, Canada and Europe14,15 . The first of these studies14 reported an overall 5-year survival rate of between 45⋅7 and 66⋅4 per cent for colorectal cancer between 1995 and 2007, depending on the country and period, with an average of 57⋅8 per cent. For rectal cancer alone in Europe the 5-year survival rates were worse: 52⋅1 per cent for patients operated on between 1999 and 2001, and 57⋅6 per cent between 2005 and 200715 . Based on the present data, if referral to expert centres with a subspecialized multidisciplinary approach to exenteration surgery occurred, patients who in the past were treated palliatively could be offered long-term cure and a good quality of life8 . In the present study, the main factor that improved overall survival was the administration of adjuvant chemotherapy. Patients who had adjuvant chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 53 per cent in patients without chemotherapy. That this factor is significant even after multivariable analysis in this relatively small group of patients is striking. The results of this study, however, should be interpreted with caution, as patient numbers are small and there may be a selection bias resulting from the oncologists selecting physically more fit patients for chemotherapy. It should also be noted that use of adjuvant chemotherapy did not affect cancer-specific survival. Although it should be borne in mind that these are subgroup analyses, the fact that the effect of adjuvant chemotherapy was even more pronounced in patients aged over 70 years suggests that any elderly patient who is considered fit for this extensive surgery should also be strongly considered for adjuvant chemotherapy, despite their age. In the literature there is increasing evidence that chemotherapy can improve survival10,16 and local recurrence17 rates, at least in a selected group of patients with rectal cancer. In the absence of randomized trial data, the results of this study at least reinforce the need to consider adjuvant chemotherapy in physically fit patients with advanced primary rectal cancer. The definitions of pelvic exenteration vary in the literature, and many studies also included exenterations for locally recurrent rectal cancer or other pelvic cancers in their outcome data. This makes it difficult to compare morbidity and postoperative mortality rates. A recent review9 described a perioperative mortality rate ranging from 0 to 25 per cent (another 0–12 per cent died after the first 30 days) and a complication rate of 37–100 per cent in 19 studies. In the present cohort, the 30-day (and 90-day) mortality rate was 4 per cent. The main major complications were bleeding, wound dehiscence, and anastomotic and urinary leakage.
In recent decades preoperative imaging has improved with the introduction of MRI to determine the exact extent of invasion of T4 rectal cancers18 . Although in the early years of this study the surgeons could rely only on rectal examination and endoanal ultrasonography or CT, interestingly this had no influence on the radicality of resection, as the R0 rate was exactly the same in the two intervals (up to 2005 versus after 2005). The higher rate of bladder-resecting surgery after 2005 suggests that more confidence had been gained that such large resections would be curative and that the centres were becoming better at managing the complications. This study analysed a subgroup of patients with locally advanced tumours treated by exenterative surgery from a total of more than 500 T4 tumours. However, the number of patients was still too small to reach statistical significance in some analyses where clinically significant differences were apparent. It cannot be concluded from this study whether there is a quantitative effect of IORT in the treatment of locally advanced T4 rectal cancer. The present data suggest that patients with advanced T4 primary rectal cancers necessitating pelvic exenteration have survival rates comparable to those of all patients with colorectal cancer if they are treated in tertiary referral centres specialized in this type of surgery. Adjuvant chemotherapy might possibly play a role in improving survival, even in the elderly.
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Acknowledgements
At the time of this study M.K. was supported by a Clinical Fellowship Grant from the Dutch Cancer Society and worked as a Colorectal Fellow at the Royal Prince Alfred Hospital. Disclosure: The authors declare no conflict of interest. References 1 Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1986; 1: 1479–1482. 2 Sebag-Montefiore D, Glynne-Jones R, Falk S, Meadows HM, Maughan T. A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group (CCOG) study. Br J Cancer 2005; 93: 993–998. 3 Wong RK, Tandan V, De Silva S, Figueredo A. Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst Rev 2007; (2)CD002102. 4 Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R et al. Preoperative versus postoperative
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18
recurrence in locally advanced rectal cancer after intra-operative radiotherapy containing multimodality treatment. Radiother Oncol 2009; 92: 221–225. Coleman MP, Forman D, Bryant H, Butler J, Rachet B, Maringe C et al. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995–2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. Lancet 2011; 377: 127–138. De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D et al. Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5 – a population-based study. Lancet Oncol 2014; 15: 23–34. Collette L, Bosset JF, den Dulk M, Nguyen F, Mineur L, Maingon P et al. Patients with curative resection of cT3–4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 2007; 25: 4379–4386. Kusters M, Valentini V, Calvo FA, Krempien R, Nieuwenhuijzen GA, Martijn H et al. Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases. Ann Oncol 2010; 21: 1279–1284. Beets-Tan RG, Lambregts DM, Maas M, Bipat S, Barbaro B, Caseiro-Alves F et al. Magnetic resonance imaging for the clinical management of rectal cancer patients: recommendations from the 2012 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol 2013; 23: 2522–2531.
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Survival after pelvic exenteration for T4 rectal cancer M. Kusters1,2 , K. K. S. Austin3,4 , M. J. Solomon3,4 , P. J. Lee3,4 , G. A. P. Nieuwenhuijzen1 and H. J. T. Rutten1,2 Departments of Surgery, 1 Catharina Hospital, Eindhoven, and 2 Maastricht University Medical Centre, Maastricht, The Netherlands, and 3 Department of Colorectal Surgery, Royal Prince Alfred Hospital, and 4 Surgical Outcome Research Centre (SOuRCe), Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia Correspondence to: Professor M. J. Solomon, Department of Colorectal Surgery, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia (e-mail: [email protected])
Background: The purpose of this study was to analyse retrospectively the pooled results after pelvic
exenteration for locally advanced T4 rectal cancer. Historically, patients with T4 rectal cancers requiring pelvic exenteration have been offered only palliative surgery or no operation. Methods: The basic treatment principle was preoperative (chemo)radiotherapy, radical surgery and, in some patients, adjuvant chemotherapy. Risk factors for local recurrence, distant metastases and overall survival were studied in univariable and multivariable analyses. Results: Ninety-five patients with T4 rectal cancer who underwent pelvic exenteration in two tertiary referral centres up to 2013 were studied. Clear margins (R0) were achieved in 87 per cent of patients. Adjuvant chemotherapy was administered in 33 per cent, independent of the resection margin, lymph node status and postoperative T category. The 5-year local recurrence rate was 17 per cent, with a distant metastasis rate of 16 per cent and overall survival rate of 62 per cent. In multivariable analysis the only factor associated with death was omission of adjuvant chemotherapy (P = 0⋅016). The effect of adjuvant chemotherapy was more pronounced in the elderly: patients aged over 70 years who had chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 39 per cent of elderly patients who did not receive chemotherapy (P = 0⋅019). Conclusion: Pelvic exenteration led to an R0 resection rate of 87 per cent for T4 rectal cancer, giving good local control and overall survival comparable to population-based colorectal cancer survival rates. Adjuvant chemotherapy may improve overall survival further, even in the elderly. Paper accepted 23 September 2014 Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9683
Introduction
The acceptance into surgical practice that the rectum should be removed within its enveloping mesorectal fascia has led to a decline in the local recurrence rate after rectal cancer treatment1 . However, when tumour invades adjacent organs, standard total mesorectal excision is not sufficient. For most T4 tumours an extended resection is sufficient with, for example, partial prostatectomy in men or resection of part of the vagina in women. However, when the tumour massively invades adjacent organs, extensive surgery with en bloc resection of other pelvic organs is the only possibility for complete resection. Resection with a clear margin (R0) is the key to local control, and neoadjuvant (chemo)radiation has been used to facilitate surgical resection by downsizing the tumour2 – 4 . © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Historically, the few patients with T4 rectal cancers requiring pelvic exenteration were offered surgery alone or no surgery5 – 7 . Pelvic exenteration is the only form of treatment that is potentially curative; without resection, patients have a very poor prognosis and substantial morbidity6 . Reported morbidity and mortality rates for pelvic exenteration used to be more than 50 and 10 per cent respectively5,7 . However, experience in the past decade has shown it can be performed with good long-term quality of life in expert centres with a multidisciplinary approach8,9 . Regarding adjuvant treatment, chemotherapy is used widely in colonic cancer treatment10 . However, there is no consensus among clinicians on whether use of chemotherapy should be standard in the treatment of rectal cancer11 . The aim of this study was to pool the results of patients with locally advanced T4 rectal cancer undergoing pelvic exenteration in two tertiary referral centres, in order to BJS 2015; 102: 125–131
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M. Kusters, K. K. S. Austin, M. J. Solomon, P. J. Lee, G. A. P. Nieuwenhuijzen and H. J. T. Rutten
study a relatively large number of patients who have undergone this uncommon type of extensive resection. This combined analysis allowed conclusions and decisions to be made about the risks and benefits of pelvic exenteration surgery, and also allowed multivariable analysis of factors influencing local control and survival.
Methods
Two national tertiary referral centres for locally advanced rectal cancer and recurrent rectal cancer, the Royal Prince Alfred Hospital (RPA) in Sydney, Australia, and the Catharina Hospital, Eindhoven (CHE), The Netherlands, have been following their patients prospectively since 1997. Tumour staging was obtained by cross-sectional imaging (endoscopic ultrasonography, CT and/or MRI). Only patients who underwent curative resection were selected; patients with stage IV disease were included only when they were eligible for a curative resection of synchronous metastases. Patients who underwent partial or complete exenteration, as defined previously8 , were identified from the operation reports. Patients with a T4 tumour with focal invasion requiring only an extended resection were excluded, leaving patients with primary locally advanced T4 rectal cancer treated with exenterative surgery for analysis. Methods of detection of local and distant recurrence have been described previously8,12,13 .
Exenteration definitions To simplify the types of resection, three categories of pelvic exenteration were defined: posterior pelvic exenteration (PPE), total pelvic exenteration (TPE) and supralevator exenteration (SLE). PPE included removal of the rectum and anus (abdominoperineal resection, APR) en bloc with the pelvic floor/side wall, including the posterior vaginal wall in women and part of the prostate/ureter/bladder in men, or an abdominal sacral resection with a high sacrectomy (defined as S3 or higher). TPE was defined as en bloc removal of the rectum and anus (APR), prostate in men, vagina, uterus and ovaries (if present) in women, and removal of the urinary bladder, with or without sacrectomy or coccygectomy. SLE included removal of the rectum, prostate in men, vagina, uterus and ovaries (if present) in women, and urinary bladder, with establishment of rectal continuity (low anterior resection). After resection of the bladder, a urinary diversion was formed by the urologist in the form of an ileal or colonic conduit. A rectus abdominis flap was used for closure of large defects and reconstruction of the vagina in women. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
(Neo)adjuvant treatment and intraoperative radiotherapy The standard neoadjuvant treatment was chemoradiotherapy. At RPA this was radiotherapy in the earlier years, but has switched to chemoradiotherapy more recently. The radiotherapy dose in both centres was typically in the range 45–50⋅4 Gy in fractions from 1⋅8 to 2⋅0 Gy; chemotherapy was based on 5-fluorouracil schemes. In CHE intraoperative radiotherapy (IORT) was delivered as an electron boost during open surgery, to the area at risk of having a narrow resection margin10,11 . The IORT dose was typically in the range 10–12⋅5 Gy, with energy ranging from 8 to 12 MeV. There was no consensus on the use of adjuvant chemotherapy in either treatment centre during the study interval.
Statistical analysis The t test and χ2 test were used for comparison of data on individual variables. Rates of local recurrence, distant metastasis, cancer-specific survival and overall survival were estimated using the Kaplan–Meier method, with differences assessed by means of the log rank test. Cancer-specific survival was defined as the time between rectal cancer surgery and death from rectal cancer. Overall survival was defined as the time between surgery and death from any cause. P values were two-sided and considered statistically significant at a value of 0⋅050 or less. For determination of risk factors, the effect of co-variables was first analysed by univariable Cox regression, stratifying for treatment centre. Co-variables with a trend towards significance (P < 0⋅100) were selected for multivariable analysis, again stratifying for treatment centre, using stepwise Cox proportional hazards regression modelling. Both forward and backward stepwise regression was used, and two-sided P < 0⋅050 was considered significant. Statistical analysis was performed using SPSS® version 16.0 for Windows® (IBM, Armonk, New York, USA). Results
Up to May 2013, 144 patients had had a curative resection for T4 rectal cancer at RPA and 384 at CHE. Patients with a T4 tumour with focal invasion requiring only an extended resection were excluded (104 and 329 patients from RPA and CHE respectively), leaving 40 patients from RPA and 55 from CHE with primary locally advanced T4 rectal cancer treated with exenterative surgery for analysis.
Comparison between centres Similarities and differences between patients and treatments at RPA and CHE are shown in Table 1. The age of the www.bjs.co.uk
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Table 1
127
Patients and treatments at the two institutes All patients (n = 95)
RPA (n = 40)
CHE (n = 55)
P†
63 (30–86) 48 : 47
61 (30–85) 25 : 15
63 (32–86) 23 : 32
0⋅625‡ 0⋅047 0⋅052
4 (4) 9 (9) 82 (86)
4 (10) 3 (8) 33 (82)
0 (0) 6 (11) 49 (89)
52 (55) 23 (24) 20 (21)
17 (43) 14 (35) 9 (22)
35 (64) 9 (16) 11 (20)
48 (51) 43 (45) 4 (4)
40 (100) 0 (0) 0 (0)
8 (15) 43 (78) 4 (7)
3 (3) 2 (2) 52 (55) 32 (34) 6 (6)
0 (0) 1 (3) 17 (43) 18 (45) 4 (10)
3 (5) 1 (2) 35 (64) 14 (25) 2 (4)
83 (87) 12 (13)
35 (87) 5 (13)
48 (87) 7 (13)
64 (67) 31 (33) 62 (2–191)
19 (48) 21 (52) 44 (2–191)
45 (82) 10 (18) 66 (5–155)
Age (years)* Sex ratio (M : F) Preoperative treatment None Radiotherapy alone Chemoradiotherapy Type of surgery Posterior pelvic exenteration Total pelvic exenteration Supralevator exenteration Intraoperative radiotherapy (Gy) None 10 12⋅5 Postoperative disease stage 0 I II III IV Surgical margins R0 R1/R2 Postoperative chemotherapy No Yes Follow-up (months)*
0⋅071
< 0⋅001
0⋅083
0⋅974
< 0⋅001
0⋅550‡
Values in parentheses are percentages unless indicated otherwise; *values are median (range). RPA, Royal Prince Alfred Hospital, Sydney, Australia; CHE, Catharina Hospital, Eindhoven, The Netherlands. †χ2 test, except ‡t test. Table 2
Differences between the exenteration types Posterior pelvic exenteration (n = 52)
Total pelvic exenteration (n = 23)
Supralevator exenteration (n = 20)
61 (30–86) 8 : 44
59 (35–78) 22 : 1
67 (44–81) 18 : 2
1 (2) 4 (8) 47 (90) 3595 (150–20 800)
0 (0) 4 (17) 19 (83) 4894 (200–25 000)
3 (15) 1 (5) 16 (80) 2955 (100–11 500)
33 (63) 6 (12) 3 (6) 6 (12) 4 (8)
12 (52) 5 (22) 1 (4) 4 (17) 1 (4)
20 (100) 0 (0) 0 (0) 0 (0) 0 (0)
30 (58) 1 of 8 21 of 44
18 (78) 4 of 22 1 of 1
20 (100) 0 (0) 0 (0)
44 (85) 8 (15)
20 (87) 3 (13)
19 (95) 1 (5)
50 (96) 2 (4)
23 (100) 0 (0)
18 (90) 2 (10)
Median age (years)* Sex ratio (M : F) Preoperative treatment None Radiotherapy alone Chemoradiotherapy Blood loss (ml)† Excision of coccyx/sacrum None Coccyx Sacrum at level S4 Sacrum at level S3 Sacrum at level S2 Reconstruction with flap None In men In women Surgical margins R0 R1/R2 Death within 1 month No Yes
P‡ 0⋅344§ < 0⋅001 0⋅050
0⋅071§ 0⋅073
< 0⋅001
0⋅493
0⋅261
Values in parentheses are percentages unless indicated otherwise; values are *median (range) and †mean (range). ‡χ2 test, except §t test.
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Table 3
M. Kusters, K. K. S. Austin, M. J. Solomon, P. J. Lee, G. A. P. Nieuwenhuijzen and H. J. T. Rutten
5 (10) 5 (10) 3 (6) 6 (12) 2 (4)
1 (4) 3 (13) 2 (9) 6 (26) 0 (0)
1 (5) 3 (15) 1 (5) 3 (15) 0 (0)
(P = 0⋅569). The R0 rate was similar in the intervals up to and after 2005 (both 87 per cent; P = 0⋅956). In the period up to 2005, ten (32 per cent) of 31 patients underwent bladder-resecting surgery (TPE or SLE), compared with 33 (52 per cent) of 64 after 2005 (P = 0⋅076). Adjuvant chemotherapy was administered in 33 per cent of the patients, independent of R0 margin (P = 0⋅475), lymph node status (P = 0⋅511), postoperative T category (P = 0⋅244) and treatment interval (P = 0⋅146).
0 (0)
2 (9)
1 (5)
Types of exenteration
1 (2)
3 (13)
2 (10)
4 of 22 (18)
0 (0)
0 (0)
2 (4)
0 (0)
1 (5)
4 (8) 2 (4) 2 (4) 1 (2) 1 (2)
3 (13) 2 (9) 1 (4) 2 (9) 0 (0)
6 (30) 5 (25) 1 (5) 4 (20) 0 (0)
n.a. n.a. n.a.
0 (0) 2 (9) 0 (0) 0 (0) 0 (0) 0 (0)
1 (5) 3 (15) 3 (15) 1 (5) 1 (5) 1 (5)
Table 2 summarizes demographic and treatment data in relation to the type of exenteration. There was no difference in the age of the patients. Women mainly underwent PPE (44 of 47), whereas most men had TPE (22 of 48) or SLE (18 of 48). A sacrectomy or coccygectomy was performed in 11 of 23 TPEs and 19 of 52 PPEs. Twenty-one of the 44 women who underwent PPE had reconstruction of the perineum and the vagina with a rectus abdominis flap. Flaps were used in one of eight and four of 22 men who had a PPE and TPE respectively. There was no difference in the percentage of R0 margins between the types of exenteration (P = 0⋅493). Four deaths within 30 days (4 per cent) were due to bleeding, anastomotic leakage, respiratory insufficiency and cardiac arrest. Complications by type of exenteration are listed in Table 3.
Complications Posterior pelvic Total pelvic Supralevator exenteration exenteration exenteration (n = 52) (n = 23) (n = 20)
Minor Wound infection midline Wound infection perineal Pulmonary infection Urinary tract infection Central venous line infection Major Bleeding requiring reoperation Wound dehiscence requiring reoperation Flap necrosis requiring reoperation Stoma retraction/leakage requiring reoperation Intra-abdominal abscess Treated with antibiotics Requiring drainage Urinary leakage Ureteric – stent placed From neobladder Requiring drainage Requiring reoperation Anastomotic leakage Managed with drain Requiring reoperation Leading to death
Values in parentheses are percentages. n.a., Not applicable.
patients (63 years) and follow-up time (62 months) did not differ between the institutions. Neoadjuvant chemoradiation was administered to 86 per cent of the patients. Splitting the cohort into two arbitrary time intervals (up to 2005 and after 2005), there was no overall difference in the use of neodjuvant chemoradiation between the two periods: 25 (81 per cent) of 31 versus 57 (89 per cent) of 64 (P = 0⋅263). At RPA, however, significantly more chemoradiotherapy was given after 2005: 27 of 30 versus six of 10 before 2005 (P = 0⋅031). Chemoradiotherapy resulted in downstaging of the T category in 43 (52 per cent) of 82 patients, compared with four (31 per cent) of 13 who had radiotherapy or no neoadjuvant treatment (P = 0⋅147). A significantly higher proportion of women underwent exenteration at CHE (32 of 55 versus 15 of 40 at RPA), probably explaining the higher percentage of PPEs performed at CHE. More TPEs were carried out at RPA. The R0 resection rate did not differ between the institutions (both 87 per cent). Neoadjuvant treatment and downstaging were not related to an R0 margin (P = 0⋅564 and P = 0⋅511 respectively). Lymph node status was not influenced by which neoadjuvant treatment was given © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Local and distant recurrence Overall, 11 patients developed a local recurrence (5-year local recurrence rate 17 per cent). No factors were significantly associated with local recurrence in univariable analysis (Table 4). The 5-year distant metastasis rate was 16 per cent among patients without previously metastasized disease. Univariable analysis identified no factors significantly associated with distant recurrence.
Survival The overall 5-year survival rate was 62 per cent. The only risk factor for death identified by univariable analysis was the omission of postoperative chemotherapy (Table 4). Patients who had adjuvant chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 53 per cent in those without chemotherapy (P = 0⋅016) (Fig. 1). The effect of adjuvant chemotherapy was even more pronounced in the elderly: patients older than 70 years who had chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 39 per cent of elderly patients who had no chemotherapy (P = 0⋅019). In patients www.bjs.co.uk
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Table 4
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Univariable Cox regression analysis of factors affecting recurrence and survival Local recurrence Hazard ratio
Age (years) < 70 ≥70 Sex M F Preoperative treatment Chemoradiotherapy None/radiotherapy Type of surgery Bladder retained (PPE) Bladder removed (TPE/SLE) Intraoperative radiotherapy Yes No Any downstaging Yes No Node category N0 N+ Metastasis category M0 M1 Surgical margin R0 R1/R2 Postoperative chemotherapy Yes No
Distant metastasis P
Hazard ratio
Cancer-specific survival P
0⋅151
Hazard ratio
0⋅805
1⋅00 (reference) 2⋅42 (0⋅73, 8⋅07)
1⋅00 (reference) 1⋅17 (0⋅35, 3⋅91) 0⋅202 1⋅00 (reference) 0⋅43 (0⋅13, 1⋅47) 0⋅428 1⋅00 (reference) 2⋅08 (0⋅26, 16⋅66) 0⋅297
0⋅324
0⋅378
1⋅00 (reference) n.c. 0⋅917
0⋅528
1⋅00 (reference) 0⋅93 (0⋅30, 2⋅90) 0⋅733
0⋅427
1⋅00 (reference) 1⋅88 (0⋅59, 5⋅98)
0⋅290 1⋅00 (reference) n.c.
0⋅769 1⋅00 (reference) 1⋅15 (0⋅45, 2⋅94)
0⋅288
1⋅00 (reference) 1⋅24 (0⋅36, 4⋅35)
0⋅995 1⋅00 (reference) 1⋅00 (0⋅48, 2⋅08)
1⋅00 (reference) n.c. 0⋅895
1⋅00 (reference) 1⋅06 (0⋅32, 3⋅53)
0⋅408 1⋅00 (reference) 0⋅59 (0⋅17, 2⋅05)
1⋅00 (reference) 1⋅36 (0⋅53, 3⋅51) 0⋅507
1⋅00 (reference) 2⋅25 (0⋅45, 11⋅29)
0⋅921 1⋅00 (reference) 1⋅04 (0⋅51, 2⋅13)
1⋅00 (reference) 0⋅40 (0⋅05, 3⋅09)
1⋅00 (reference) 2⋅68 (0⋅78, 9⋅21)
0⋅101
0⋅799
0⋅117
1⋅00 (reference) 0⋅49 (0⋅13, 1⋅89)
0⋅604 1⋅00 (reference) 1⋅21 (0⋅59, 2⋅49)
0⋅050 1⋅00 (reference) 2⋅59 (1⋅00, 6⋅70)
0⋅667
0⋅669 1⋅00 (reference) 1⋅18 (0⋅56, 2⋅49)
0⋅078
1⋅00 (reference) n.c.
–
–
0⋅464
1⋅00 (reference) 4⋅01 (0⋅86, 18⋅70)
0⋅198
1⋅00 (reference) 1⋅79 (0⋅38, 8⋅49)
1⋅00 (reference) 2⋅39 (0⋅64, 8⋅95) 0⋅474 1⋅00 (reference) 1⋅17 (0⋅32, 4⋅31)
0⋅277 1⋅00 (reference) 2⋅27 (0⋅52, 9⋅94)
0⋅173 1⋅00 (reference) 2⋅20 (0⋅71, 6⋅85)
0⋅818
1⋅00 (reference) 1⋅63 (0⋅43, 6⋅15)
0⋅345 1⋅00 (reference) 1⋅60 (0⋅60, 4⋅26)
0⋅209 1⋅00 (reference) 2⋅15 (0⋅65, 7⋅09)
P
1⋅00 (reference) 1⋅91 (0⋅88, 4⋅16)
1⋅00 (reference) 0⋅89 (0⋅35, 2⋅27) 0⋅490
1⋅00 (reference) n.c.
Hazard ratio
0⋅194 1⋅00 (reference) 1⋅90 (0⋅72, 5⋅02)
0⋅181
1⋅00 (reference) 2⋅41 (0⋅62, 9⋅29)
P
Overall survival
0⋅018 1⋅00 (reference) 3⋅40 (1⋅23, 9⋅40)
Values in parentheses are 95 per cent c.i. n.c., Not calculable because the number of events in each group was too small for reliable analysis. PPE, posterior pelvic exenteration; TPE, total pelvic exenteration; SLE, supralevator exenteration.
up to 69 years of age the effect of adjuvant chemotherapy on survival was also evident, but not significant (P = 0⋅085). The overall cancer-specific survival rate was 72 per cent after 5 years. In univariable analysis factors associated with death from cancer were lymph node positivity and M1 status. Neither of these factors remained significant in the multivariable model (P = 0⋅115 and P = 0⋅180 respectively).
1·0
Survival
0·8
0·6
0·4 Adjuvant chemotherapy
Discussion
No adjuvant chemotherapy 0·2
0
24
12
36
48
60
Time after surgery (months) No. at risk Chemotherapy No chemotherapy
31 64
31 48
23 31
18 22
12 18
Overall survival in patients who did, or did not receive adjuvant chemotherapy. P = 0⋅016 (log rank test)
Fig. 1
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10 14
This was a pooled analysis of 95 patients who underwent exenterative surgery for locally advanced T4 tumours in two tertiary referral centres, representing 18 per cent of 528 curatively treated T4 tumours. The overall results showed successful treatment, with 87 per cent clear margins and a local recurrence rate of 17 per cent after 5 years. The overall survival rate was 62 per cent after 5 years, which is comparable to, or even better than, rates among patients with colorectal cancer in general in www.bjs.co.uk
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M. Kusters, K. K. S. Austin, M. J. Solomon, P. J. Lee, G. A. P. Nieuwenhuijzen and H. J. T. Rutten
two population-based studies from Australia, Canada and Europe14,15 . The first of these studies14 reported an overall 5-year survival rate of between 45⋅7 and 66⋅4 per cent for colorectal cancer between 1995 and 2007, depending on the country and period, with an average of 57⋅8 per cent. For rectal cancer alone in Europe the 5-year survival rates were worse: 52⋅1 per cent for patients operated on between 1999 and 2001, and 57⋅6 per cent between 2005 and 200715 . Based on the present data, if referral to expert centres with a subspecialized multidisciplinary approach to exenteration surgery occurred, patients who in the past were treated palliatively could be offered long-term cure and a good quality of life8 . In the present study, the main factor that improved overall survival was the administration of adjuvant chemotherapy. Patients who had adjuvant chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 53 per cent in patients without chemotherapy. That this factor is significant even after multivariable analysis in this relatively small group of patients is striking. The results of this study, however, should be interpreted with caution, as patient numbers are small and there may be a selection bias resulting from the oncologists selecting physically more fit patients for chemotherapy. It should also be noted that use of adjuvant chemotherapy did not affect cancer-specific survival. Although it should be borne in mind that these are subgroup analyses, the fact that the effect of adjuvant chemotherapy was even more pronounced in patients aged over 70 years suggests that any elderly patient who is considered fit for this extensive surgery should also be strongly considered for adjuvant chemotherapy, despite their age. In the literature there is increasing evidence that chemotherapy can improve survival10,16 and local recurrence17 rates, at least in a selected group of patients with rectal cancer. In the absence of randomized trial data, the results of this study at least reinforce the need to consider adjuvant chemotherapy in physically fit patients with advanced primary rectal cancer. The definitions of pelvic exenteration vary in the literature, and many studies also included exenterations for locally recurrent rectal cancer or other pelvic cancers in their outcome data. This makes it difficult to compare morbidity and postoperative mortality rates. A recent review9 described a perioperative mortality rate ranging from 0 to 25 per cent (another 0–12 per cent died after the first 30 days) and a complication rate of 37–100 per cent in 19 studies. In the present cohort, the 30-day (and 90-day) mortality rate was 4 per cent. The main major complications were bleeding, wound dehiscence, and anastomotic and urinary leakage.
In recent decades preoperative imaging has improved with the introduction of MRI to determine the exact extent of invasion of T4 rectal cancers18 . Although in the early years of this study the surgeons could rely only on rectal examination and endoanal ultrasonography or CT, interestingly this had no influence on the radicality of resection, as the R0 rate was exactly the same in the two intervals (up to 2005 versus after 2005). The higher rate of bladder-resecting surgery after 2005 suggests that more confidence had been gained that such large resections would be curative and that the centres were becoming better at managing the complications. This study analysed a subgroup of patients with locally advanced tumours treated by exenterative surgery from a total of more than 500 T4 tumours. However, the number of patients was still too small to reach statistical significance in some analyses where clinically significant differences were apparent. It cannot be concluded from this study whether there is a quantitative effect of IORT in the treatment of locally advanced T4 rectal cancer. The present data suggest that patients with advanced T4 primary rectal cancers necessitating pelvic exenteration have survival rates comparable to those of all patients with colorectal cancer if they are treated in tertiary referral centres specialized in this type of surgery. Adjuvant chemotherapy might possibly play a role in improving survival, even in the elderly.
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Acknowledgements
At the time of this study M.K. was supported by a Clinical Fellowship Grant from the Dutch Cancer Society and worked as a Colorectal Fellow at the Royal Prince Alfred Hospital. Disclosure: The authors declare no conflict of interest. References 1 Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1986; 1: 1479–1482. 2 Sebag-Montefiore D, Glynne-Jones R, Falk S, Meadows HM, Maughan T. A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group (CCOG) study. Br J Cancer 2005; 93: 993–998. 3 Wong RK, Tandan V, De Silva S, Figueredo A. Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst Rev 2007; (2)CD002102. 4 Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R et al. Preoperative versus postoperative
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9
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