HUCH, J H • S A 01/2005
Surgical Hospital, Helsinki University Central Hospital and Department of Surgery, Jorvi Hospital Helsinki University Central Hospital University of Helsinki and Central Hospital of Jyväskylä
HOW TO IMPROVE RESULTS IN RECTAL CANCER SURGERY A CLINICAL STUDY
J V A D
To be presented, with the assent of the Faculty of Medicine, University of Helsinki, for public examination in the Auditorium of Jorvi Hospital, Helsinki University Central Hospital, Turuntie 150, Espoo, on October 28th, 2005, at 12 noon
Supervised by
Docent I K, MD Central Hospital of Jyväskylä Jyväskylä, Finland
Reviewed by
Professor H J, MD Helsinki University Central Hospital Helsinki, Finland Professor J M, MD Oulu University Central Hospital Oulu, Finland
Opponent
L P, MD, PhD, FRCS, FRCS (Glasg) Professor of Surgery Department of Surgery, University Hospital Uppsala, Sweden
Publisher
Hospital District of Helsinki and Uusimaa HUCH, Jorvi Hospital Turuntie • FIN– Espoo • Finland tel + • telefax + http://www.hus.fi/jorvi •
[email protected]
Editorial Board
H A, Editor in chief T B K J T H J K L T ISSN - ISBN --- (paperback) ISBN --- (PDF)
http://www.hus.fi/jorvi/julkaisut • http://ethesis.helsinki.fi Helsinki University Printing House Helsinki
CONTENTS
LIST OF ORIGINAL ARTICLES..................................................................................................4 LIST OF ABBREVIATIONS .........................................................................................................5 ABSTRACT...................................................................................................................................6 INTRODUCTION ........................................................................................................................8 REVIEW OF THE LITERATURE ...............................................................................................10 Colorectal cancer screening .........................................................................................10 Faecal occult blood tests ...............................................................................10 Endoscopic screening ...................................................................................10 Biomarkers of neoplastic transformation....................................................11 Surgical treatment .........................................................................................................11 Anatomical aspects .......................................................................................11 Spread patterns..............................................................................................12 Surgical techniques .......................................................................................12 Complications connected to surgery...........................................................................13 Mortality and morbidity................................................................................13 Anorectal dysfunction...................................................................................14 Sexual and urinary dysfunction ..................................................................15 Local recurrence and survival ......................................................................................16 Elderly patients – special considerations ....................................................................17 e role of adjuvant therapies ......................................................................................17 Preoperative radiotherapy and chemoradiotherapy ..................................17 Tumour response ..........................................................................................18 Quality of life after rectal cancer surgery.....................................................................19 AIMS OF THE STUDY...............................................................................................................20 PATIENTS AND METHODS.....................................................................................................21 RESULTS ....................................................................................................................................25 DISCUSSION .............................................................................................................................32 CONCLUSIONS.........................................................................................................................37 ACKNOWLEDGEMENTS.........................................................................................................38 REFERENCES ............................................................................................................................40 ORIGINAL PUBLICATIONS.....................................................................................................50
LIST OF ORIGINAL ARTICLES
is thesis is based on the following original articles, which are referred to in the text by their Roman numerals: I
V J, K S, A L, K I. A comparison of peanut agglutinin (PNA) -test and immunochemical faecal occult blood test in detecting colorectal neoplasia in symptomatic patients. Scand J Clin Lab Invest ; : –.
II V J, H L, S P, K L, S T, H A, K I. New approaches in the management of rectal carcinoma result in reduced local recurrence rate and improved survival. Eur J Surg ; : –. III V J, S P, H A, K I. Complications and Survival after surgery for rectal cancer in patients younger than and aged or older. Dis Colon Rectum ; : –. IV V J, J M, K M, J I, K I. Tumor regression grading in the evaluation of tumor response after different preoperative radiotherapy treatments for rectal carcinoma. Int J Colorectal Dis ; : –. V V J, K M, K I. Impact of functional results on quality of life after rectal cancer surgery. Dis Colon Rectum (submitted).
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LIST OF ABBREVIATIONS
APR
Abdominoperineal resection
AR
Anterior resection
ASA
American Society of Anaesthesiologists score
CRM
Circumferential resection margin
ERUS
Endorectal ultrasound examination
FOBT
Faecal occult blood test
Gy
Gray (radiation dose)
HAR
High anterior resection
HRQoL
Health related quality of life
LAR
Low anterior resection
PNA
Peanut agglutinin
PRT
Preoperative radiotherapy
QoL
Quality of life
RAND -item Quality of Life questionnaire distributed by RAND corporation RT
Radiotherapy
SF
Short Form (Quality of Life questionnaire)
TME
Total mesorectal excision
TRG
Tumour regression grading
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ABSTRACT
e aim of the present study was to examine possibilities for improvement of the results in rectal cancer surgery from detection of the cancer to outcome in terms of survival and patient satisfaction. In Study I the sensitivity and specificity for detecting colorectal neoplasia of PNArectal mucus test was compared with those of an immunological test for faecal occult blood (Hemolex) in patients examined for colorectal symptoms in the Surgical Hospital of Helsinki University Central Hospital. e sensitivity of the PNA-test and Hemolex for colorectal neoplasia was vs. and specificity vs. (P = .) showing that a single PNA-test is as sensitive indicator of colorectal neoplasia as Hemolex completed over three days, but lacks specificity. Some commonly expressed PNA-binding proteins were identified both in normal mucosa and colorectal cancer, but expression of kD PNA-binding protein was seen almost exclusively in colorectal cancer. Characterization of that cancer-associated antigen may help in developing a more specific PNA-test. e patients treated in the Surgical Hospital for rectal cancer during – (conventional surgery, N = ) and during – (total mesorectal excision, TME, N = ), were included in Studies II and III. e effect of refinement of the surgical technique in complication rate, local recurrence rate and survival was studied, as well as whether elderly patients (≥ years, N = ) can be treated using similar indications as younger patients (N = ) with acceptable perioperative morbidity, mortality and survival. e actuarial local recurrence rate for potentially curative rectal cancer improved from to and the crude -year survival from to between the two study 6
periods (Study II). A significantly lower -year crude survival was seen in the older age group compared to younger patients ( vs. , P = .). However, -year cancer-specific survival ( vs. , P = .) and disease-free -year survival ( vs. , P = .) were similar in both groups. e number of complications ( vs. ) and -day mortality ( vs. ) were similar in both groups. More elderly patients were not operated on at all ( vs. , P = .) compared to patients younger than (Study III). ese studies show that adopting TME-technique and selective use of preoperative radiotherapy leads to improved survival. Furthermore, in selected elderly patients major curative rectal cancer surgery can be done with similar indications, perioperative morbidity and mortality as well as -year cancerspecific and disease-free survival as in younger patients. Patients treated for rectal cancer in the Central Hospital of Jyväskylä during – (N = ) were included in Studies IV and V. e usefulness of histologic tumour regression grading (TRG) in quantifying the effect of preoperative radiotherapy (PRT) or chemoradiation was examined and compared with the downstaging defined as a change in preoperative T stage obtained with endorectal ultrasound examination (uT) and pathologic stage (pT) (Study IV). e histologic tumour regression was more marked after long-term chemoradiation than after short-course radiotherapy (P = .). Complete response (no residual tumour, TRG ) was seen in of the patients and total or major regression (TRG –) in of the patients treated with Gy chemoradiation (N = ). Of those treated with Gy PRT (N = ), showed major tumour regression. When HUCH, Jorvi Hospital Publications • Series A 01/2005
comparing uT with pT, of the tumours were downstaged, but less than half of the dowstaged tumours showed marked response by TRG. In comparison, of the tumours with no downstaging showed marked response by TRG (P = .). In assessing tumour response to preoperative adjuvant therapy TRG seems to offer a more reliable means than uT-downstaging, which did not correlate with TRG results. e impact of surgery-related adverse effects on the quality of life (QoL) was examined using generic RAND- questionnaire and questionnaires assessing urinary, sexual and bowel dysfunction. Results were compared with age and sex-matched Finnish general population (Study V). e
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QoL of rectal cancer patients was not worse than that of general population. Between the treatment groups (sphincter-preserving surgery vs. abdominoperineal resection) there was no significant difference in QoL. Major bowel dysfunction impaired social functioning significantly compared to patients without such symptoms. e QoL of symptomatic patients was similar to that of patients having undergone APR. Urinary dysfunction impaired social functioning and impotence physical and social functioning. In an attempt to improve QoL after rectal cancer surgery, minimizing the incidence of organ dysfunction seems to be at least as important as aiming to sphinctersparing surgery.
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INTRODUCTION
Colorectal cancer is the second leading cause of cancer mortality in Western countries and its incidence and prevalence are increasing. In , a total of new cases were detected in Finland (Finnish Cancer Registry ). Of them ( ) were rectal tumours defined as having the lower edge within cm of the anus. Rectal cancer is the fifth most common cancer in men and tenth most common cancer in women with the incidence of ./ in men and ./ in women. With the population ageing the incidence is rising even if the age-adjusted incidence seems to be stabilizing. Prognosis depends on the extent of the disease at the time of diagnosis. e beneficial effect of early detection on mortality for colorectal cancer has been proved in randomised screening programs (Towler ). Based on an expected reduction of in mortality for colorectal cancer, screening strategies are being evaluated for implementation in several European countries, including Finland. Currently available methods rely on faecal occult blood (FOB) tests and subsequent endoscopic evaluation in the case of positive test. Bleeding, however, is not specific for colorectal neoplasia and may be intermittent in the case of asymptomatic tumours (Ahlquist ). us faecal occult blood tests are hampered by high false positive and false negative rates. erefore, new non-invasive methods to detect colorectal neoplasia at an early, asymptomatic phase are needed. Today, – of patients can be operated on with curative intent. However, a major problem after rectal cancer surgery is local recurrence after which outcome is poor. Local recurrence rates vary considerably between surgeons and institutions ranging from to , suggesting that 8
surgical technique has an important role in the outcome (Holm ; Porter ). Increasing evidence shows that refining and standardizing of surgical techniques decreases local recurrence rates as well as variability of results between individual surgeons (Dahlberg ; e Norwegian Rectal Cancer Group ; Kapiteijn ; Martling ). e technique of total mesorectal excision (TME), first introduced by Heald et al. in (Heald ), has been reported to decrease the local recurrence rates to – and to improve the overall -year survival from – with conventional surgery to (Enker ; MacFarlane ). However, TME surgery seems to be associated more often with potentially dangerous anastomotic leakages than the conventional surgery (Karanjia ). e number of elderly rectal cancer patients is increasing but few studies have addressed the ability of elderly patients, who may have compromised physical capacity, to recover from adverse events that may occur in connection of major rectal surgery. Uncertainty persists, as to whether elderly patients benefit from the same surgical treatment as younger patients (Shankar ). Additional benefits of local control can be obtained with neoadjuvant treatment. It has been shown that preoperative radiotherapy (PRT) or chemoradiotherapy increases the resectability of low and locally advanced tumours (Minsky ) and improves local tumour control and survival (Delaney ; Kapiteijn ; Swedish Rectal Cancer Trial ). However, dosage, timing and optimal combination of radiotherapy and chemotherapy are controversial as well as which patients should receive adjuvant treatment (Simunovic ). Both surgery and adjuvant treatments HUCH, Jorvi Hospital Publications • Series A 01/2005
are connected to adverse effects that may significantly affect a person’s quality of life. Anal sphincter preservation is regarded one of the main goals in rectal cancer surgery to avoid disruption in a patient’s quality of life (QoL) caused by colostomy (Sprangers ). However, anal function may be suboptimal after sphincter-saving surgery, especially after coloanal anastomoses (Lewis ). Also disturbances in sexual and urinary functions are common sequelae (Keating ). e effect of these physical disabilities in quality of life is not well known.
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Improvements in treatment and early detection indicate that more patients will live with the consequences of the disease. Survival and local recurrence rate are important but not the only factors contributing to good outcome results. Long-term functional results have a major impact on quality of life, which has emerged as an important endpoint. With individualized treatment options available, emphasis can be placed also to patient satisfaction and quality of life. It is of major importance to pay attention to details to ensure the best possible outcome after treatment in all perspectives.
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REVIEW OF THE LITERATURE
Colorectal cancer screening ere is evidence that benign adenomatous polyps develop into cancers in the colon. Accumulation of multiple genetic alterations such as mutational activation of oncogenes and inactivation of tumour suppressor genes leads to stepwise progression from normal to hyperproliferative epithelium and adenoma to carcinoma (Bronner ; Fearon ; Leslie ). Removing adenomatous polyps have been shown to reduce the incidence of colorectal cancer (Mandel ; Winawer ). Also, early detection of colorectal cancer by mass screening has been shown to reduce mortality by (RR ., CI . to .) and, when adjusted for screening attendance, by (RR ., CI .–.) (Towler ). However, the best screening method remains controversial. e ideal screening requires high sensitivity and specificity in detecting early stage disease and should be acceptable and safe to patients, inexpensive and feasible in general clinical practise (Winawer ).
Faecal occult blood tests Guaiac tests based on the pseudoperoxidase activity of haemin are the most commonly used tests both in the preliminary assessment of subjects with symptoms of colorectal disease and in screening programs. ese tests involve collection and testing of six samples from three consecutive stools of a patient. A specific diet to minimize the number of false positive results (avoidance of red and white meat, fish, fresh fruit and uncooked vegetables i.e. substances with peroxidase or pseudoperoxidase activity) is recommended before the testing is performed. Stool samples can be tested in either a dehydrated or rehydrated state. 10
Rehydration by a drop of deionized water increases the rate of positive tests from – to – (Mandel ). Rehydration thus increases the sensitivity of a guaiac test, but is generally not recommended as it decreases the specificity leading to high number of false positive results. e sensitivity of guaiac based faecal occult blood test for detecting colorectal neoplasia in asymptomatic patients with an average risk has been reported to be – (Hardcastle ; Kronborg ; Robinson ; omas ) i.e. nearly half of the cancers remain undetected with this test. A detection rate of – has been reported for symptomatic cancers (omas ). Evidence from four randomised controlled trials with Hemoccult II test (Hardcastle ; Jorgensen ; Kewenter ; Kronborg ; Mandel ; Scholefield ) shows that detecting early stage cancers reduces mortality from the disease – in the screened population (Table ). Immunological tests, specific for human haemoglobin, have been shown to be more sensitive for symptomatic colorectal cancer than guaiac-based tests (Robinson ; omas ). However, the specificity is lower; vs. in the asymptomatic population and vs. in symptomatic patients, respectively (Robinson ; omas ). Randomised population based studies have not been performed with immunological tests.
Endoscopic screening Case-control and uncontrolled cohort studies suggest that endoscopic screening with polypectomy reduces the incidence of colorectal cancer by – (iis-Evensen ; Winawer ) and may be even more HUCH, Jorvi Hospital Publications • Series A 01/2005
effective in detecting colorectal neoplasia than FOBT (Segnan ). Furthermore, an increase in the proportion of early cancers (Atkin ) and decrease of – in cancer mortality compared to non-screened patients have been reported (Muller ; Newcomb ; Selby ). However, no results from randomized studies are available so far.
Biomarkers of neoplastic transformation Specific biomarkers of neoplastic transformation in colorectal mucosa, including mutations in APC (adenomatous polyposis coli tumour suppressor gene), K-ras, p and BAT (a marker of microsatellite instability), have potential to be used as new, non-invasive methods to detect colorectal neoplasia (Ahlquist ; Mak ; Sidranski ). Neoplasm-specific altered DNA from tumour cells is released into the bowel lumen more continuously than blood and is stable in stool having thus potential to be used as a screening method. However, colorectal neoplasms are genetically heterogeneous and multiple DNA alterations should be targeted to achieve high sensitivity (Ahlquist ). Besides tumour-derived mutations in genes the new biomarkers isolated from faecal samples or bowel lumen include secretion of abnormally glycosylated carbohydrate structures (e.g. tumour-associated
antigens) (Shamsuddin ) or complex macromolecules (Roseth ). ese antigens can be detected using lectin and antibody immunohistochemistry. Increased binding of the lectin peanut agglutinin (PNA) is a common feature in colorectal carcinoma and hyperplasia (Rhodes ). PNA binds to the disaccharide omsenFriedenreich blood group antigen (galactose-b--N-acetyl-galactosamine), which is an oncofetal antigen commonly expressed in colorectal cancer but concealed by further glycolysation (sialylation and/or fucosylation) in the normal colorectal mucosa (Campbell ). Previous studies have shown that PNA-reactive carbohydrate alterations in rectal mucus have a sensitivity of – in detecting colorectal cancer (Kellokumpu ; Sakamoto ; Shamsuddin ).
Surgical treatment Anatomical aspects Rectum comprises the terminal cm of large bowel. Fatty tissue called mesorectum, containing the terminal branches of the superior rectal vessels and the lymphatic drainage of the rectum, surrounds the rectum and is covered by visceral fascia (fascia propria). Posteriorly rectum is wholly extraperitoneal whereas anteriorly
Table 1. Results of randomised controlled trials of colorectal cancer screening using Hemoccult II test.
Study
Minnesota (Mandel 2000)
Nottingham (Hardcastle 1996)
Funen (Kronborg 1996)
Goteborg (Kewenter 1994)
Population size
46 500
150 000
62 000
68 000
Age group (years)
50–80
45–74
45–75
60–64
Study period (years)
18
12
13
8
Reduction of mortality (%)
33* (21**)
15**
18**
12**
RR (CI)
0.80 (0.70–0.90)
0.85 (0.74–0.99)
0.82 (0.69–0.97)
0.88 (0.69–1.12)
* Annual screen ** Biennial testing
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only the distal third is extraperitoneal and separated from bladder and genital organs by Denonvilliers´ fascia. Posteriorly there is an avascular retrorectal space between parietal and visceral fascia. Parietal fascia thickens over sacrum and coccyx forming a dense Waldeyer´s fascia (Havenga a). e pelvic autonomic nervous system is located between peritoneum and visceral fascia and is intimately related to the rectum. Hypogastric nerves exit bilaterally from the superior hypogastric plexus at the level of the sacral promontory. Caudally they run parallel to ureter and iliac vessels on each side of the pelvis uniting with the pelvic splanchnic nerves to form the inferior hypogastric (pelvic) plexus, which also has connections with sacral roots (S–). e superior hypogastric plexus and hypogastric nerves are mainly sympathetic whereas pelvic splanchnic nerves are parasympathetic. Pelvic plexus is a dense plaque of nerve tissue that sends fibers towards bladder, urethra and genital organs. Lateral mesorectum fuses with this structure from where some fibers enter anterior rectal wall as well. All nerves and vessels are embedded in fat and fibrous tissue resembling a ligament, hence the name lateral ligament (Church ; Havenga a; Maas ).
Spread patterns Tumour spread along the muscle tube beyond cm of the palpable edge of the tumour seems to be uncommon, except in poorly differentiated lesions (Williams ). Instead, tumour growth is more rapid in the transverse than longitudinal axis of the bowel. Subsequently, submucosa and muscle layer of the bowel are invaded allowing the tumour growth enter into the mesorectum. According to modern understanding, distal and proximal tumour spread as microscopic foci within the mesorectum occur frequently (Heald ; Reynolds ). e main route of lymphatic spread is to the chain of glands along the superior hemorrhoidal and inferior mesenteric vessels.
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Lateral lymphatic spread to internal iliac nodes on the pelvic sidewalls may occur especially in case of low rectal cancers in approximately of patients and in up to one third of those with positive mesorectal nodes (Moriya ; Sugihara ; Ueno ).
Surgical techniques Radical surgery aims at removing the tumour with its all extensions, including the area of vascular and lymphatic drainage as well as direct spread to adjacent organs, with adequate margins of clearance. Proximally, the mesorectum is removed to the level of aortic bifurcation including all lymph nodes distal to the origin of the left colic artery. Caudally, the technique of total mesorectal excision (TME) stresses the importance of removing an intact mesorectal envelope from the promontorium down to the anal hiatus in pelvic floor by sharp dissection between the visceral and parietal planes of the pelvic fascia, confirming that none of the mesorectal tissue remains in the pelvis. In case of high tumours, however, mesorectum is transected in -degree angle at least cm below the tumour. Pelvic autonomic nerves are carefully visualized and preserved (Heald ). Figure shows the difference between TME and conventional surgery. With conventional technique there is a tendency to cone the dissection plane towards the rectal wall posteriorly and laterally endangering the radicality. Tumour spread to the lateral resection margin occurs in approximately of patients treated with conventional techniques but in less than of patients treated by TME (Birbeck ; Cawthorn ; Haas-Kock de ; Quirke ; Wibe ). It has been shown that as long as mesorectum is completely removed, the distal mucosal margin can usually be safely reduced to less than cm (Karanjia ; Rullier ). Total mobilization of rectum to the anal hiatus and utilizing modern stapling devices and surgical techniques in
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creating colorectal or coloanal anastomoses ensures that sphincter-sparing surgery can now be performed in – of patients (Enker ; Tytherleigh ). e technique of intersphincteric resection enables sphincter preservation even in patients with carcinomas located at the anorectal junction, if not invading the anal sphincter (Rullier ). Abdominoperineal resection is still necessary for a subset of patients with very low or advanced tumours. After high anterior resection, the bowel continuity is usually re-established by straight end-to-end anastomosis whereas after low or ultralow anterior resection colorectal or coloanal anastomosis can be performed using J-pouch (Lazorthes ; Parc ), side-to-end anastomosis (Huber ) or coloplasty (Z´graggen ) instead to restore the reservoir capacity. e use of colonic pouch may also enhance the healing of the anastomosis compared to straight anastomosis (Hallböök a; Hallböök b).
Complications connected to surgery Mortality and morbidity Overall morbidity after rectal cancer surgery varies between – (Arbman ; Carlsen ; Martling ). In addition to anastomotic dehiscence and acute urinary retention the most common perioperative complications are the same as after any major abdominal surgery (haemorrhage, respiratory-, urinary and wound infections, paralytic ileus and cardiovascular events). Postoperative mortality after elective operations is generally less than after both conventional and TME-surgery (Enker ; Graf ; Heald ; Marijnen ; Martling ). Cardiac complications and anastomotic dehiscence are the most common reasons for postoperative death (Carlsen ; Enker ; Graf ; Marijnen ). e risk for anastomotic dehiscence is greater after low than high anterior resection (Karanjia ; Pakkastie ; Rullier ). TME surgery, resulting in more low
Figure 1. Conventional (a) vs. total mesorectal excision (TME) (b) technique in rectal cancer surgery. a.
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b.
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anastomoses, is associated with leakage rates of up to over compared with that of approximately after conventional surgery (Nesbakken ). e mortality rate associated with anastomotic leakage varies between and (Rullier ). e use of a protective stoma after TME surgery and low anastomosis has been shown to lower the rate of clinically relevant leakages from – to – (Carlsen ; Dehni ; Marijnen ; Marusch ), especially in men (Law ; Poon ; Rullier ), and therefore its routine use has been recommended (Karanjia ). A defunctioning stoma does not necessarily prevent leakage, but reduces the need for reoperations and the risk for permanent stomas. Some favour selective use of stoma only, as complications related directly to stoma have been reported in – of patients (Heald ; Poon ). Preoperative radiotherapy utilizing modern techniques does not seem to increase mortality or the risk of anastomotic leakage (Enker ; Marijnen ; Swedish Rectal Cancer Trial ; Valero ).
Anorectal dysfunction Anterior resection is associated with a variety of specific symptoms like increased bowel function, erratic defecation patterns, urgency, obstructed defecation and impairment of continence (Ortiz ). Diminished rectal capacity and compliance, impaired internal anal sphincter tone and loss of rectoanal inhibitory reflex are the main causing factors (Lee ). e incidence of early postoperative functional disorders has been reported to be as high as – (Dennet ). Functional deficiencies improve over to years (Gamagami ; Ho ; Lee ; Sailer ), but some degree of permanent impairment of sphincter function after anterior resection seems inevitable (Lee ). Functional results are worse the closer the anastomosis is to the anal canal. After high anterior resection some of pa-
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tients have some degree of incontinence compared with – after low anterior resection (Dennet ; Gamagami ; Ortiz ; Rullier ). Ultralow anterior resections, extending to the anorectal junction or more distally into the anal canal, and coloanal anastomosis, have been associated with controversial functional results with – of patients having problems with continence (Gamagami ). Functional results after intersphincteric resections, including removal of internal sphincter, have been reported to be satisfactory with about to of patients having occasional soiling and – suffering from urgency (Rullier ; Saito ; Schiessel ; Tiret ). Erratic defecation patterns have been reported in , urgency in and obstructed defecation in of patients after rectal cancer surgery (Ortiz ). Randomised trials that compared J-pouch anastomosis with straight end-toend anastomosis have shown functional superiority of the J-pouch, especially in the early months after surgery (Hallböök b; Lazorthes ; Ortiz ; Rullier ; Seow-Choen ). Even after one year urgency is more common and the median stool frequency per day higher with straight anastomosis than with a J-pouch (Harris ; Lazorthes ), but may level by two years (Ho ). e majority of patients with a pouch have a daily frequency of less than three bowel movements. In contrast, evacuation difficulties are more common with a pouch occurring in to of patients. e size of the pouch is critical to outcome; a – cm pouch seems to be optimal whereas a larger pouch is associated with incomplete evacuation more often (Dennet ). Functional results comparable to J pouch have been obtained using end-to-side anastomosis (Machado ) or coloplasty (Ho ; Pimentel ; Remzi ). e effect of radiotherapy on anorectal function is not fully known. Irradiated patients recover slower from defecation problems than patients treated with surgery alone (Marijnen ). ere is some
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evidence that sphincter-related symptoms (incontinence and pouch-related specific symptoms such as clustering and incomplete evacuation) may also be more common in irradiated patients than after surgery alone (Gervaz ; Marijnen ).
Sexual and urinary dysfunction Disturbances to bladder and sexual function are well known sequelae of rectal cancer surgery. Damage to the hypogastric nerves or sacral nerves or both, during operation is the most likely cause of sexual dysfunction (Havenga ; Keating ). It has been shown that unilateral sacrifice of inferior hypogastric plexus with its parasympathetic component makes failure of erection highly probable. Bilateral sacrifice makes total impotence certain and often endangers urinary function. Ejaculatory disorders are related to sacrifice of the superior hypogastric plexus (Maas ; Pocard ; Sugihara ). Permanent complete or partial erectile dysfunction has been reported in – of patients, while – of potent patients are not able to ejaculate (Enker ; Havenga ; Maas ; Nesbakken ; Sugihara ). After abdominoperineal resection the risk for permanent impotence seems to be – whereas low anterior resection carries about half the risk of impotence compared to APR (Enker ; Havenga ; Keating ). Inadvertent damage to the pelvic nerves during the perineal phase of operation particularly at the level of prostate may be one of the explanations for that, but the altered anatomy of the pelvic floor caused by division of the perineal muscles may also play a role. Patient age seems to be the single most important factor affecting the risk of sexual dysfunction (Keating ). e risk has been reported to be more than -fold in the patients over years of age compared with patients younger than that (Havenga ). In patients, whose disease is confined to the mesorectum, adopting TME-technique with pelvic nerve preserva-
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tion has lowered the risk for sexual dysfunction but has not completely eliminated it (Keating ; Kim ; Nesbakken ; Pocard ). e dysfunctional outcomes of pelvic nerve damage in women are poorly understood. e likely consequences, impairment of sexual arousal and libido, have been reported to be rare after TME surgery (Havenga b; Nesbakken ; Platell ). Problems related to scarring and changed anatomy (shortness or lack of elasticity of vagina during intercourse, dyspareunia) seem to be more common. Faecal soiling during or after intercourse may also be a problem. Adjuvant radiotherapy may affect on sexual functioning of both male and female patients. In a randomised study comparing Gy preoperative radiotherapy with surgery alone, decrease in erectile function for up to years was noted after PRT (Marijnen ). Ejaculation disorders occurred more frequently too. In female patients, sexual activity and functioning deteriorated significantly more after PRT than surgery alone. e rate of reported urinary dysfunction after surgery for rectal cancer ranges from to (Leveckis ) presenting as various complaints. e most common symptoms are stress incontinence, urgency, elevated frequency of voiding, difficulty emptying the bladder, loss of sensation of fullness of the bladder and overflow incontinence. Since most studies have been retrospective without urodynamic evaluation preoperatively, the incidence of dysfunction attributable to surgery is not known. Many of these symptoms and latent dysfunction are very common in the population of same age as rectal cancer patients (Nuotio ; Pocard ; Schatzl ), whereas urodynamic studies have shown that the incidence of bladder dysfunction as a result of pelvic nerve injury seems to be fairly low, – (Del Rio ; Leveckis ). With TME surgery and nerve preservation, neurogenic bladder requiring catheterisation is rare (Havenga ; Kneist ;
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Maas ), but occurs in – if pelvic autonomic nerves are completely sacrificed (Havenga ; Hojo ). ere does not seem to be any significant correlation between the extent of nerve preservation and minor urinary symptoms reported by the patients (Maas ). Postoperative bladder dysfunction is often temporary (Del Rio ), whereas erectile dysfunction does not seem to improve after – months after surgery (Maas ).
Local recurrence and survival With conventional blunt surgical resection of rectal cancer, local recurrence rates after potentially curative operation are – in reports from special interest centres and up to – in general surgical practice. With TME technique local recurrence rates of below have been reported consistently (Table ). Consequently, five-year survival rates have improved from to (Enker ; MacFarlane ; Wibe a).
Cancer of the low rectum treatable by abdominoperineal resection is associated with more local recurrences and poorer survival than anterior resection. After TME surgery, -year survival rates of after APR compared with that of after sphincter preserving surgery have been reported (Enker ). Similarly, local recurrence rates are higher (– vs. – in midrectal cancers), possibly because cancers of the low rectum often present with more adverse risk factors (positive nodal disease, vascular and perineural invasion) (Enker ). Circumferential resection margin (CRM) involvement has been shown to be a potent predictor of outcome with exponential increase in the rate of local recurrence, metastasis and death with decreasing circumferential margin. As many as of the patients with margin involvement develop a local recurrence (Birbeck ; Nagtegaal ; Quirke ). A disease-free margin of less than – mm carries a – risk of local recurrence compared to – after greater margins (Nagtegaal ; Wibe
Table 2. Local recurrence rate (LR) after surgery before and after adopting TME-surgery. Figures are percents. Study (Period)
Conventional surgery
TME-surgery*
Alone
Alone
With PRT
1. Arbman et al (1984–86 vs. 1990–92)
22
2. Stockholm Study (1980–87 vs. 1994–1997)
30
15
3. Swedish Trial (1987–90)
27
11
4. Dutch Study (1987–90 vs. 1996–99)
With PRT
6 9
1.5
22
9 (11)
2.4 (5.8)
5. Danish Study (1991–93 vs. 1996–98)
30
11
6. Norwegian study (1986–88 vs. 1993–99)
28
8
* Follow-up time since TME-surgery: 1. 4 years (Arbman 1996) 2. 2 years (Martling 2000) 3. (Swedish Rectal Cancer Trial 1997) 4. 2 years (Kapiteijn 2001; Kapiteijn 2002) (5 years(Marr 2005)) 5. 3 years (Bulow 2003) 6. 3 years (Wibe 2003a)
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). About of patients with positive CRM develop metastasis compared with of patients with negative margins (Nagtegaal ; Wibe ). After a curative operation -year survival rate has been reported to be vs. in patients with and without CRM involvement, respectively (Birbeck ).
Elderly patients – special considerations Elderly patients with colorectal cancer have a higher incidence of emergency presentation compared to younger patients (Anderson ; Hessman ; Mulcahy ). Perioperative mortality rates of the elderly in different studies show a large variability from to (Anderson ; Chiappa ; Damhuis ; Fielding ; Hessman ; Kingston ; Mulcahy ); probably partly depending on the proportion of emergency operations in each study. Emergency surgery is more often than elective surgery associated with high perioperative morbidity and mortality (Anderson ; Fielding ; Hessman ; Mäkelä ). After elective surgery for colorectal cancer, the cancer-specific survival seems to be similar to that of younger patients (Shankar ). e number of patients deemed unfit for curative surgery, however, rises with age (Damhuis ; Violi ). e concomitant diseases and fitness rather than the chronological age seem to be the factors affecting the outcome. In some studies American Society of Anaesthesiologists (ASA) score rather than the age was seen to predict morbidity and mortality (Hessman ), whereas others did not find that classification useful. Rectal cancer has many special features with regard to anatomical boundaries and surgical strategies compared to cancer in other parts of the large bowel. Rectal cancer surgery is associated with more frequent complications (e.g. anastomotic leaks) than cancer surgery for other parts of the large bowel (Chiappa ; Hessman ). On
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the other hand emergency presentation is less common in rectal cancer than colon cancer (– vs. ) (Anderson ; Shankar ). However, studies concerning the outcome of elderly patients with rectal cancer are rare. In a retrospective study including patients aged or older and patients younger than that, the complication rate was similar in older and younger age group ( vs. respectively) and mortality rate . vs. . after elective curative rectal cancer surgery (Puig-La Calle ). e selection criteria and number of patients deemed to be unfit for major surgery, however, was not reported.
e role of adjuvant therapies Preoperative radiotherapy and chemoradiotherapy Two European trials of conventional surgery have shown that short-course preoperative radiotherapy ( Gy in five days) reduces local recurrences from – to – (Holm ; Swedish Rectal Cancer Trial ) and improves overall -year survival rate from – to – (Martling ; Swedish Rectal Cancer Trial ). In a randomised trial of standardized TME surgery, a decrease in local recurrence rate from . in non-irradiated patients to . in irradiated patients was seen at two years after surgery (Kapiteijn ). A Swedish study reported similar results; local recurrence rate was vs. . in non-irradiated and irradiated patients, respectively (Martling ) (Table ). Population-based studies have shown that – of rectal cancer patients have primarily nonresectable tumours and only half of them have distant metastases at the time of diagnosis (Påhlman ). Locally advanced tumours requiring downstaging to be converted into mobile and resectable, cannot be effectively treated with × Gy short course preoperative radiotherapy (Marijnen ; Påhlman ). Long course preoperative radiotherapy (– Gy
17
over to weeks) or chemoradiotherapy have been shown to increase the resectability of low and locally advanced tumours (Elsaleh ; Frykholm-Jansson ; Minsky ). In some cases preoperative radiotherapy enables sphincter-saving surgery to be performed in patients, who would have previously required an abdominoperineal resection (Crane ; Francois ; Janjan b; Rullier ; Wagman ). Also, overall survival rates in patients with T low rectal cancers have been reported to improve from to after PRT compared to those who underwent surgery only (Delaney ).
Tumour response Quantification of tumour response is essential in comparing the effectiveness of different multimodality treatments. A commonly used measure is a change in a T stage defined as a difference between endorectal ultrasound (ERUS) finding (uT) and pathologic T stage (pT). After high-dose long-term chemoradiotherapy tumour downstaging has been reported to occur in – of patients when using this criteria (Garcia-Aguilar ; Janjan a; Moore ; Rullier ; eodoropoulos ). Some studies report improved local recurrence rates and cancer-specific survival in responders compared with non-responders (eodoropoulos ) whereas some have not observed significant difference between the groups (Janjan a). Complete pathologic response i.e. sterilization of the tumour is a clearly definable measure for tumour response. e complete response rate seems to be dependent except
on treatment modality, also on interval between preoperative adjuvant therapy and operative treatment (Elsaleh ; Moore ), but the optimal interval is yet to be defined. Complete response has been reported to occur in – of patients and seems to be associated with improved local control and survival (Garcia-Aguilar ; Janjan a; Luna-Perez ; Minsky ; Ruo ; eodoropoulos ) but follow-up times are still fairly short. ree recent studies have reported, after a mean follow-up time of to months, a disease-free survival of – in patients with complete or near-complete response (Garcia-Aguilar ; Ruo ; Wheeler ). In comparison, the disease-free survival was in those with partial or no response (Garcia-Aguilar ). Another study reported the advantages of early survival in complete responders to disappear by – months after treatment (Onaitis ). Besides complete response, also partial radiation-induced histological changes in malignant tumours (necrosis, stromal fibrosis, irradiation vasculopathy, peritumorous inflammatory reactions) have been well documented and can be quantified accurately (Bozzetti ; Bozzetti ; Dworak ; Ruo ; Wheeler ). A pathologic staging system, tumour regression grading (TRG) (Table ) has been suggested (Bozzetti ; Dworak ; Wheeler ) to enable the comparison of partial response as well and thus improve the reliability of outcome comparisons between different combined-modality treatments. is new grading method has not been widely adopted so far.
Table 3. Tumour regression grading (Bozzetti 1996) TRG1 – Complete regression, absence of residual tumour cells TRG2 – Presence of rare residual cancer cells and prominent fibrosis TRG3 – Fibrosis outgrowing residual cancer cells TRG4 – Residual cancer cells outgrowing fibrosis TRG5 – Absence of regression
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Quality of life after rectal cancer surgery It has been assumed that permanent colostomy after rectal cancer surgery impairs health related quality of life (HRQoL) more than sphincter-sparing surgery. A recent Cochrane-analysis did not find support for this assumption (Pachler ). Several of the studies that used validated generic and/or disease-specific quality of life instruments, found that people undergoing APR did not have a poorer QoL than patients undergoing anterior resection (Allal ; Camilleri-Brennan ; Grumann ; Hamashima ) or that stoma only slightly affected the QoL (Jess ). In contrast, a few other studies found a significantly poorer QoL after APR than after AR (Engel ; Grundman ; Kuzu ; Marquis ). Tumor stage and site, level of the anastomosis, surgical technique and adjuvant treatment as well as the follow-up time after surgery varies between the studies (Pachler ), which may partly explain the contradictory results. Longitudinal studies have shown that quality of life improves with time (Engel ; Grumann ), especially after low anterior resection (Engel ). Functional results after HAR are better than after LAR
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(Camilleri-Brennan ) which may contribute to better QoL reported after HAR than LAR (Engel ; Grumann ). After LAR, functional results are better with colonic pouch than with straight end-to-end anastomosis and accordingly, the quality of life of patients having J-pouch or coloplasty has been shown to be better, especially during the early postoperative period (Hallböök b; Remzi ; Sailer ). Urogenital dysfunction after rectal cancer surgery occurs frequently (CamilleriBrennan ). Urinary dysfunction for any reason seems to worsen social functioning (Nuotio ; Rauch ). e effect of sexual dysfunction on quality of life is not very well known, as a high percentage of rectal cancer patients are elderly and often either not sexually active or choose not to answer the questions concerning sexuality (Engel ; Kuzu ; Rauch ). One study showed no difference in sexual dimension of QoL between the treatment groups (Rauch ), whereas another larger study reported lower scores in sexual functioning after APR than HAR or LAR (Engel ). However, patients in the APR group were older, which may affect the results. Based on this scarce data it has been suggested that sexual functioning may not affect overall quality of life (Engel ).
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AIMS OF THE STUDY
e purpose of this study was to evaluate factors, which can be affected in order to improve results of rectal cancer treatment. e specific aims were . to evaluate the usefulness of PNA-test in screening for rectal neoplasia compared with occult faecal blood test. . to find out whether total mesorectal excision (TME) technique alone or combined with preoperative radiotherapy reduces local recurrence rate and improves survival; . to evaluate if elderly patients ( years or older) can be treated using similar indications and treatment strategy as in younger patients without increasing complication risk; . to evaluate the usefulness of tumour regression grading in comparing histopathologic effects of different neoadjuvant treatments in rectal cancer patients; and . to assess the impact of treatment-related adverse effects in quality of life after rectal cancer surgery.
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PATIENTS AND METHODS
Patients is study was carried out at the Surgical Hospital, Helsinki University Central Hospital, and at the Central Hospital of Jyväskylä. e research material in the studies I, II and III consists of patients who were operated on for rectal cancer or examined for colorectal symptoms at the Surgical Hospital, Helsinki University Central Hospital between and . Patients in the studies IV and V were treated for rectal cancer in Central Hospital of Jyväskylä between and (Table ). e data of patients were gathered retrospectively until year and prospectively thereafter. S I From to samples of rectal mucus were obtained from patients undergoing colonoscopy for lower gastrointestinal symptoms (e.g. altered bowel habits, abdominal pain, anaemia, hemorrhagia ex ano). From to , patients also completed Hemolex test over three days prior to the outpatient appointment. ese patients were selected for Study I. Informed consent for obtaining mucus samples for PNA-test was received from all patients and the study was approved by the ethical committee of the hospital.
S II III Between January and December , a total of patients with rectal cancer were admitted ( men, women, mean age years) to the IV Clinic of Surgery, Helsinki University Central Hospital. Of the patients, were admitted during the period – and during –. Major potentially curative operations using a conventional technique were done for of the during –. Between and , major potentially curative resections using the principles of TME-technique were done for of the patients. e patients, who underwent major potentially curative operations during both periods, were included in Study II comparing the outcome between treatment strategies. All patients, of whom patients ( ) were aged or older and younger than years, were enrolled in Study III comparing the treatment strategies and outcome between elderly and young patients. S IV V A total of patients ( men and women, mean age , range –) with rectal cancer were admitted to Jyväskylä Central Hospital between January
Table 4. Number of patients included in the different papers Study
Period
I PNA vs. Hemolex test
1992–94
199
II The effect of treatment strategy
1980–90 1991–97
144 (Conventional surgery) 61 (TME surgery)
III Treatment strategy of the elderly
1980–97
199 (< 75 years) 95 (≥ 75 years)
IV Quality of life
1999–2003
94
V Tumour regression grading
1999–2003
135
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No of patients
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and December . Of them, patients underwent either curative or palliative major resection. Nine patients had an inoperable advanced disease. Patients with high or midrectal tumours penetrating the bowel wall (uT) as judged by endorectal ultrasound received a shortcourse preoperative Gy radiotherapy whereas patients with uT-tumors in proximity to the anal verge necessitating abdominoperineal resection, or with fixed or locally advanced tumours, received a long course preoperative radiotherapy ( Gy over five weeks) combined with weekly infusion of -fluorouracil. Study IV comprises the patients, who underwent either curative or palliative major resection. e histological response of the tumours after different preoperative radiation treatments was evaluated. Of the patients, who underwent curative resection, were alive without any sign of recurrent disease after a minimum follow-up of one year. For Study V they were sent a RAND (SF-) quality of life questionnaire and a specific disease-related questionnaire assessing problems with urinary, sexual or defecation-related functions.
Methods Screening methods of symptomatic patients (Study I) H Hemolex (Orion Diagnostica, Espoo, Finland) is a test based on immunochemical detection of native human haemoglobin with a sensitivity of . mL of blood per g of stool. e test kit includes a latex reagent consisting of polystyrene beads coated with antibodies produced in swine against human haemoglobin. ese agglutinate when haemoglobin is present in the specimen in non-digested form giving visually detectable granular agglutination (Väänänen ). e patients completed Hemolex test over three days prior to the outpatient appointment.
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PNA Samples of rectal mucus, obtained prior to colonoscopy with a cotton stick through a proctoscope from macroscopically normal mucosa, were applied on nitrocellulose filters. e presence of PNAreactive glycoconjugates in rectal mucus was determined by a peroxidase-conjugated PNA-overlay procedure (Kellokumpu ). Two observers unaware of the colonoscopy findings examined PNA-reactivity. PNA-binding profiles of paired normal and malignant colorectal tissue samples taken from cancer patients during surgery were analysed by the PNA-overlay procedure. erefore, tissue samples were ground in a mortar under liquid nitrogen, and detergent-solubilize using TX-, mM Tris (pH .) supplemented with proteinase inhibitors tablets (Complete, mini, Roche Diagnostics Gmbh, Mannheim, Germany). ml of detergent solution was used per mg of frozen tissue, and vortexed on ice for min before clearing with centrifugation ( × g, + °C). A × concentrated SDS sample buffer was added and boiled for min. . microliters (about – microgram of protein) from each sample was subjected to SDS polyacrylamide gel electrophoresis. e samples were then transferred to a nitrocellulose filter. e filter was quenched with BSA (bovine serum albumin, fraction V, Sigma Chemicals) in blotting buffer overnight, and probed with PNA in the same buffer (. microgram / ml of mM Tris/ mM NaCl, . BSA, . Tween). e enhanced chemiluminesence-method (ECL) and exposure onto the Fuji RX film for – min was used for the visualization of the proteins on the filter.
Preoperative evaluation (studies II–V) Tumours were classified as low (≤ cm), mid (– cm) or high (– cm) rectal tumours. e distance of the tumour from the anal verge was assessed with a rigid sigmoidoscope (studies II–III) or colonoscope (studies IV–V) and biopsies were taken. Chest radiography, liver ultrasonography,
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and computed tomography when necessary were used to rule out distant spread. In Study IV endorectal ultrasound (ERUS) staging was done according to Hildebrandt´s criteria (Hildebrandt ) using a ° rotating ∕ MHz endoprobe (type , Bruell & Kjaell Ltg, Sandtoften, Denmark). Magnetic resonance imaging (MRI) and/or computed tomography (CT) were performed as complementary studies in the case of fixed or locally advanced tumours or if ERUS was not successful.
Surgical techniques Conventional surgery (Studies II and III) was defined as sharp dissection and excision of the mesorectum at least cm distally from the lower margin of the tumour. In high and midrectal tumours the mesorectum was divided perpendicularly to the rectum and the lateral ligaments were ligated and divided. Blunt dissection was not used. Since (studies II–V) surgery was performed according to the principles of total mesorectal excision technique (MacFarlane ) except in high (> cm from the anal margin) rectal tumours in which a cm distal margin was considered adequate. Total mesorectal excision was defined as complete removal of the intact mesorectum down to the pelvic floor, preserving pelvic nerve plexuses. For rectal wall, i.e. the muscular tube, a margin of – cm was considered adequate.
Adjuvant treatments Short-course preoperative radiotherapy ( Gy, Gy in five fractions) (Påhlman ) followed by resection within a week was chosen for patients with high (– cm from the anal verge) and midrectal (– cm from the anal verge) uT tumours amenable to anterior resection. External beam radiation therapy was delivered using three or four-field technique. e clinical target volume included the mesorectum and the pelvic sidewalls including the internal iliac lymph nodes.
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High dose preoperative radiotherapy ( Gy over five weeks) combined with radiosensitizing -fluorouracil (-FU mg/m/day once a week as an intravenous bolus) was delivered using three or fourfield technique with the same target volume as in short-course radiotherapy and including pelvic organs infiltrated by the tumour. High dose preoperative chemoradiotherapy was indicated in the case of large, fixed uT / tumours or with low (< cm from the anal verge) uT tumours requiring abdominoperineal resection. All patients were planned to undergo surgical resection within to weeks after completion of PRT. Adjuvant postoperative chemotherapy consisting of -FU ( mg/m/day) as an intravenous bolus in six cycles and low dose leucovorin ( mg/m) (O´Connell ) for five consecutive days every to weeks was prescribed routinely to all patients having tumours with metastatic lymph nodes.
Pathologic evaluation e tumours were classified according to the Turnbull modification of Dukes´ classification during –, and according to the UICC TNM categories (Sobin ) during –. Assessment of the largest tumour diameter as well as manual lymph node harvesting was done in fresh specimens. e operation was considered curative if no visible tumour was left behind and histopathological specimens showed tumourfree distal margins. Lateral margins were not assessed during the period – (Studies II–III). In Study IV the circumferential, radial resection margins were measured in formalin ( ) fixed specimens mounted on macroslides. Tumour response to radiotherapy was quantified using the tumour regression grading (TRG, Table ) (Wheeler ).
Quality of life assessment (study V) Quality of life assessment was done using a validated Finnish version (Aalto ) of
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the RAND -item health survey quality of life questionnaire (Hays ) and a specific disease-related questionnaire assessing problems with urinary, sexual or defecation-related functions. e RAND- consists of items assessing eight dimensions of health from the patient’s viewpoint. ese dimensions measure physical functioning, role limitations because of physical or emotional problems, social functioning, mental health, energy and vitality, body pain and general health perception. e scoring scale ranges from to , with high scores indicating high level of functioning and good quality of life. A sub sample of persons aged – years from a Finnish population study (Aalto ) was used as a population control group in examining the level of health related quality of life (HRQoL) in RAND- subscales among patients. e population
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sample (age – years) was derived from the Finnish population registry.
Statistics Chi-square tests or Fishers exact tests were used to compare the association between categorical variables. Actuarial survival and local recurrence rates were assessed using Kaplan-Meier plots with log-rank analysis (Study II and III). Mann-Whitney U tests were used to compare continuous data and to detect significant differences in health-related quality of life scores between subgroups. Differences in HRQoL between patient and population controls of same age and sex were analysed by ANCOVA (analysis of covariance) adjusting the HRQoL means for sex and age (Study V). A P-value < . was considered statistically significant.
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RESULTS
Study I Details of the clinical findings in the symptomatic patients and the sensitivity for carcinoma of both tests are shown in Table . e sensitivity of the PNA-test and Hemolex for colorectal neoplasia (ad1
2
3
4
Sensitivity = Proportion of diseased subjects, who have a positive test Specificity = Proportion of non-diseased subjects, who yield a negative test result Positive/negative predictive value = Proportion of all individuals with positive/negative tests who do/do not have the disease Accuracy = Proportion of true positive and negative tests of all those who were tested
enomas and carcinomas vs. normal mucosa and hyperplastic polyps) was vs. and specificity vs. (P = .). e positive predictive values of the PNA and Hemolex test were vs. and negative predictive value vs. . e accuracy of the PNA-test and Hemolex was vs. . SDS-PAGE and PNA-overlay showed some commonly expressed PNA-binding proteins both in normal mucosa and colorectal cancer. Instead, expression of kD PNA-binding protein was seen significantly more often (P < .) in colorectal cancer than normal mucosa (Figure ).
Table 5. Test positivity according to clinicopathological characteristics.
Clinicopathological variable
Total N
Positive PNA N ( %)
Positive Hemolex N ( %)
P
Carcinoma
36
30 (83)
26 (72)
0.45
Adenoma
38
21 (55)
18 (50)
0.8
Inflammatory bowel disease
27
14 (52)
13 (48)
1.0
Hyperplastic polyps
21
10 (48)
5 (25)
0.3
Normal/diverticulosis
77
21 (27)
9 (12)
0.3
Figure 2. Peanut agglutinin (PNA)-binding proteins in 12 paired samples of normal colorectal mucosa and colorectal cancer. Notice that both normal (n) and cancer tissues (c) express PNA-reactive proteins. Only the 160 kD band (marked with arrow) appears to be quite specific to colorectal cancer tissues. Numbers on the left denote the molecular size standards used.
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Study II–III
Local recurrence rate and survival
Table shows the patient and tumour characteristics from the two study periods included in studies II and III (– and –) as well as the data from the third study period (–, N = ).
e actuarial local recurrence rate was in the first period utilizing conventional surgery and after adopting TME surgery and selective use of preoperative radiotherapy (P = ., Fig. ). e actuarial crude
Table 6. Details of patients who underwent potentially curative operations during the three study periods (1980–90, 1991–97, 1999–2003). Data are number (%) of patients except were otherwise stated 1980–90 (N = 144)
1991–97 (N = 61)
1999–2003 (N = 113)
Sex (male: female)
69 (48): 75 (52)
22 (36): 39 (64)
78 (69): 35 (31)
Mean age (range)
70 (41–91)
65 (36–82)
68 (41–91)
Dukes´ classification A B C D*
40 (28) 79 (54) 24 (17) 1 (1)
18 (29) 28 (46) 14 (23) 1 (2)
47 (42) 40 (35) 24 (21) 2 (2)
Site of tumour Upper rectum (12–15 cm) Middle rectum (8–11 cm) Lower rectum (≤ 7 cm)
33 (23) 51 (35) 60 (42)
10 (16) 18 (30) 33 (54)
28 (25) 31 (27) 54 (48)
Operation Anterior resection Abdominoperineal resection
76 (53) 68 (47)
43 (71) 18 (29)
73 (65) 40 (35)
Preoperative radiotherapy
0
29 (48)
80 (71)
* Liver metastasis resected later
Figure 3. Actuarial cancer-specific survival (upper curves) and local recurrence rates (lower curves) after major curative surgery during the two study periods.
1980–90 (conventional surgery) 1991–97 (TME surgery)
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-year survival improved from to (P = .) and the cancer-specific survival from to (P = ., Fig. ) between the two study periods. During –, the five-year crude survival was significantly lower in the older age group ( vs. , P = .), but the year cancer-specific survival ( vs. , P = .) (Fig. ) and the disease-free -year survival ( vs. , P = .) were similar in both groups. More patients in the elderly group (/ , ) than in the younger age group (/, ) had a poor physical condition (compromised cardiac and/or respiratory function, symptoms in mild exercise) and underwent local excision (P = .). Ten elderly patients ( ) were not operated on at all in contrast to patients ( ) younger than (P = .).
Complications Overall, of the patients ( ) who underwent major curative surgery during – had complications. After conventional surgery / patients ( ) had postoperative complications compared
Figure 4. Actuarial cancer-specific survival after major curative surgery according to patient age.
75 years or older Below 75 years
with / patients ( ) after TME surgery (P = .). Twenty of the elderly patients ( ) and of the patients ( ) in the younger age group after curative surgery had complications (P = .). e overall incidence of postoperative complications after potentially curative major operations during the all three study periods is shown in Table .
Table 7. Postoperative complications after potentially curative major operations during the three study periods. Data are number ( %) of patients. 1980–1990
1991–1997
1999–2003
Postoperative death
1/144 (1)
0
3/113 (3)
Anastomotic Leak Stenosis
4/76 (5) 1/76 (1)
8/43 (19) 8/43 (19)
4/73 (6) 5/73 (7)
Postoperative bleeding
0
2/61 (3)
1/113 (1)
Infections Abdominal wound Perineal wound Systemic sepsis Pneumonia
2/144 (1) 4/68 (5) 3/144 (2) 4/144 (3)
0 1/18 (6) 1/61 (2) 1/61 (2)
7/113 (6) 8/40 (20) 1/113 (1) 2/113 (2)
Cardiovascular
2/144 (1)
0
3/113 (3)
Urinary
8/144 (6)
4/61 (7)
6/113 (5)
Other
3/144 (2)
1/61 (2)
6/113 (5)
No pts with complications*
32/144 (22)
21/61 (34)
39/113 (35)
* Some patients had more than one complication
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After curative anterior resection / of the patients ( ) during the first period and / ( ) during the second period developed anastomotic leaks (P = .). During –, when all low anastomoses were constructed using J-pouch and usually protected with a temporary stoma, / ( )
patients developed anastomotic leaks. Table shows the incidence of anastomotic leakages in respect to the type of anastomosis and use of protective stoma. After elective operations during –, one elderly patient died due to anastomotic leakage. us operative -day mortality
Table 8. Incidence of anastomotic leakages after curative resection for rectal cancer during the three study periods in respect to the type of operation (HAR = high anterior resection, LAR = low anterior resection). Leakages / total number of patients 1980–90
1991–97
1999–2003
HAR
4 / 76*
1 / 10*
0 / 20**
LAR Straight anastomosis Straight anastomosis + stoma J-pouch J-pouch + stoma
0 0 0 0
5 / 23 0 2/4 0/7
0 0 2/2 2 / 51
Total***
4 / 76 (5 %)
8 / 43 (19 %)
4 / 73 (5 %)
* Straight anastomosis without protective stoma ** Straight anastomosis with (7 patients) or without (13 patients) a protective stoma *** P = 0.02
Table 9. Tumour regression grading (TRG) in different treatment groups. Tumour regression grade a
5
4
3
2
1
Preoperative radiotherapy (number of patients (%))
a b
No radiotherapy (n = 40)
27 (68)
12 (30)
0
1 (2) b
0
25 Gy (n = 42)
12 (29)
21 (50)
8 (19)
1 (2)
0
50 Gy (n = 44)
4 (9)
8 (18)
15 (34)
14 (32)
3 (7)
TRG 1, 2 and 3 correspond to a regression exceeding 50 % of the tumour mass This patient had a small polypoid lesion, which was originally removed endoscopically with snare and electrocoagulation. Only a 7 mm lesion was seen in the resected specimen.
Table 10. Comparison of histopathologic response (TRG) and dowstaging (pT lower than uT stage) in 83 patients, who had a successful endorectal ultrasound (ERUS) examination and received either 25 Gy radiotherapy or 50 Gy chemoradiation preoperatively. TRG classes 1 to 3 are considered `marked response´ regression exceeding 50 % of the tumour mass. TRG Downstaged P = 0.05
28
Marked response
No response
Yes
12
14
No
28
29
40
43
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was (N = ) and after potentially curative conventional and TME surgery, respectively. Consequently, the -day mortality was (N = ) and in the elderly and younger age group. During – the mortality rate was (/ patients); one patient died due to anastomotic leakage.
Study IV
ere was a marked discordance between the two methods in estimating tumour response after Gy radiotherapy or Gy chemoradiation (P = .). Of the tumours, showed marked regression by TRG without any change in T-stage and tumours that showed no response in TRG were downstaged when comparing uT-stage with pT-stage.
Study V
Tumour regression grading Results of TRG of the patients according to treatment group are shown in Table . Complete regression (TRG ) was present in three patients ( ) and tumour regression more than (TRG –; fibrous tissue outgrowing the amount of residual tumour cells) in ( ) of the patients treated with high dose ( Gy) chemoradiation. In those patients treated with short course ( Gy) radiotherapy only ( , P = .) had tumour regression of TRG –. Endorectal ultrasound examination (ERUS) was done in patients. Of them, patients underwent surgery alone. In them, ERUS had an accuracy (uT-stage same as pT-stage) of . e comparison of TRG findings and uT vs. pT change after different treatments is shown in Table .
Quality of life e patient group reported significantly better general health perception and poorer social functioning than population controls of same age and sex (Table ). Between the treatment groups there were no significant differences (Figure ). However, after APR physical functioning tended to be lower (P = .) compared with low anterior resection. Major bowel dysfunction (frequency > bowel movements/day, major incontinence (Jorge ), urgency or constipation (Drossman )) impaired social functioning significantly (P = .) in patients having undergone anterior resection compared with the patients without such problems
Table 11. Health related quality of life according to RAND 36 (SF36) among general population (N=1440) and patients who had curative resection for rectal cancer (N = 71, age < 80 years). The values are adjusted for age and gender. General population
Rectal cancer patients
Mean
(95 % CI)
Mean
(95 % CI)
PF
74.8
73.5–76.0
73.9
67.4–80.2
0.79
RP
62.5
60.4–64.6
54.9
44.2–65.5
0.17
RE
68.7
66.7–70.8
61.9
51.6–72.1
0.20
SF
79.9
78.6–81.2
68.9
62.4–75.4
0.002
MH
73.8
72.8–74.9
77.5
72.9–82.9
0.19
EV
62.7
61.5–64.0
64.0
57.7–70.3
0.70
BP
70.0
68.6–71.4
67.9
60.9–74.8
0.55
HP
55.9
54.8–57.6
63.3
57.7–68.9
0.01
QoL-dimensions*
P-value
* PF = physical functioning; RP = role limitations due to physical problems; RE = role limitations due to emotional problems; SF = social functioning; MH = mental health; EV = energy and vitality; BP = body pain; HP = general health perception.
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(Figure ). Increased bowel frequency (> ) or constipation after low anterior resection did not significantly affect the QoL scores. Incontinence worsened social functioning significantly (P = .). Urgency impaired social functioning (P = .), mental health
(P = .) and general health perception (P = .). e patients without urgency or fecal incontinence had a significantly better physical functioning than the patients, who underwent abdominoperineal resection (P = . and ., respectively), whereas
Figure 5. Quality of life after rectal cancer surgery in different treatment groups (HAR= high anterior resection; LAR = low anterior resection; APR = anterior resection).
PF = physical functioning; RP = role limitations due to physical problems; RE = role limitations due to emotional problems; SF = social functioning; MH = mental health; EV = energy and vitality; P = body pain; HP = general health perception.
Figure 6. Quality of life after anterior resection in patients with (N = 35) or without (N = 18) major bowel dysfunction. In comparison, values of the patients who underwent APR (n=28) are shown.
PF = physical functioning; RP = role limitations due to physical problems; RE = role limitations due to emotional problems; SF = social functioning; MH = mental health; EV = energy and vitality; P = body pain; HP = general health perception.
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the patients having such problems had no statistically significant differences in RAND QoL scores compared with APR patients. Patients with urinary dysfunction had worse social functioning (P = .) and more pain (P = .) than patients with no
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urinary dysfunction. In patients reporting sexual dysfunction only a complete loss of erection was associated with significantly worse physical functioning (P = .) and social functioning (P = .).
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DISCUSSION
Despite the fact that – of patients presenting with colorectal cancer may undergo surgical resection for possible cure and that recent advances in multimodality therapy has improved survival of advanced disease, nearly of patients with cancers of the colon and rectum die from their disease. More effective preventive measures together with further refinement of surgical techniques and adjuvant treatments are clearly warranted to improve the outcome results of this common disease.
Screening Advisory Committee on Cancer Prevention recommends screening for colorectal cancer to be considered in the countries of European Union (Advisory Committee on Cancer Prevention ). Colorectal cancer is a major health problem, which usually develops from benign adenomatous polyp slowly over approximately years providing an opportunity for early detection and removal in pre-cancerous stage or as an early stage cancer (Bronner ; Winawer ). According to recommendation a method of choice for screening is faecal occult blood tests and colonoscopy in positive cases. Current stool guaiac tests, however, appear to be suboptimal in some respects. Many cancers and most adenomas do not bleed and are thus missed (Ahlquist ). e reported sensitivity of serial guaiac based FOBT is only approximately (Hardcastle ; Kronborg ). e positive predictive value has been reported to be – (Hardcastle ; Kronborg ; Winawer ) leading to high number of unnecessary colonoscopies, as bleeding is not specific for neoplasias (Towler ). Despite the recent documentation of a significantly reduced mortality by screening 32
for faecal occult blood (Towler ), there is a need for tests with higher sensitivity and specificity. In our study, we compared the sensitivity and specificity of single PNA-rectal mucus test with those of Hemolex, a test completed over three days and based on immunochemical detection of native human haemoglobin. Immunological tests have been shown to be more sensitive for symptomatic colorectal cancer than guaiac-based tests (Robinson ; omas ). In contrast, lower specificities ( vs. in symptomatic patients and vs. in the asymptomatic population) has been reported using immunological tests than guaiac-tests (Robinson ; omas ). We have found that in symptomatic patients a single PNA-test is as sensitive for colorectal carcinoma as a serial Hemolex ( vs. ). e PNA-test, however, had a lower specificity for colorectal neoplasia than Hemolex ( vs. ), making it less suitable for screening purposes in its present form. e reduced specificity of the PNA-test may result from the fact that some of PNA-reactive proteins (e.g. the kD-band and the diffuse bands at the molecular size between kD and kD) were present both in normal and malignant colorectal tissue. e kD cancer-associated antigen we have identified is under further characterization for development of a more specific PNA-test.
Surgical treatment Local recurrence and survival e concept of TME surgery relies on the observation that tumour deposits may be found to centimetres distal to the main tumour in the lymphovascular mesorectum HUCH, Jorvi Hospital Publications • Series A 01/2005
(Heald ; Wang ). erefore, it has been advocated that all cancers of low or midrectum should be excised with the mesorectum intact. e excellence of this approach is further supported by the findings of Quirke et al. showing that tumour spread to the lateral resection margin occurs in up to of patients treated with conventional techniques but in only – of patients treated by TME (Quirke ). Others have confirmed that the circumferential resection margin involvement is a reliable predictor of local recurrence, distant metastases and survival (Wibe ). Since these observations, surgical and pathological workshop projects have been organized in several countries in Europe to introduce these new methods. National studies have shown that TME surgery improves treatment results in a defined population (Kapiteijn ; Martling ; Påhlman ; Wibe a). In our study, the actuarial risk for developing a local recurrence decreased from to after the introduction of TME surgery, which is in line with the reports from other centres. Accordingly, cancerspecific five-year survival increased from to and disease-free five-year survival from to between the two periods. However, still more than of the patients with Dukes´ C lesions developed locally recurrent disease after TME. As many as of the Dukes´ C carcinomas in the second period were low rectal tumours and four of the five local recurrences occurred after resection of low rectal carcinomas. It has been shown that some of low rectal tumours and of low Dukes´ C tumours spread laterally along the internal iliac vessels (Moriya ), which is outside the dissection area covered by TME and thus may explain the high recurrence rates. Besides lateral lymph node involvement, an inadequate surgical resection despite TMEsurgery might explain some of the treatment failures. Possibly due to tapering of the mesorectum toward levators, circumferential resection margin involvement still occurs
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more frequently after abdominoperineal than anterior resection. Wider surgery including removal of the levator muscles en bloc with anal sphincters might reduce the risk (Marr ; Wibe b). In the future, radioactivity-guided sentinel node mapping may be one option for finding patients with lateral spread and thus greater risk for recurrence (Kitagawa ; Saha ).
Complications e overall complication rate of about in all study periods falls well within the reported range. Also in line with previous reports, the leakage rate was with conventional surgery and in the early phase of TME surgery. Later, when the routine use of protective stoma and J-pouch in low anastomoses was adopted, the clinical leakage rate decreased back to . ere is some proof that colonic J-pouch anastomosis has better blood supply than end-to-end anastomosis and thus may be less prone to leakage (Hallböök a; Hallböök b). Some other studies have found a significant correlation between the absence of stoma and anastomotic dehiscence (Law ; Peeters ). During the TME period between and in our study, of the patients ( ) who had a Jpouch but no protective stoma, developed an anastomotic leak. Of the patients with end-to-end anastomosis, patients ( ) had a leakage. In comparison, only two of the patients (. ) who had a J-pouch and a protective stoma developed a leakage. Our results are in line with others showing leakage rates of and – in patients without and with a protective stoma, respectively (Dehni ; Karanjia ).
Elderly patients An increasing number of rectal cancer patients are elderly and have comorbid medical diseases. A question has been raised whether elderly patients with compromised physical capacity to recover from adverse
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events can be offered similar treatment than younger patients. In the present study, the crude survival was significantly lower ( vs. ) in the elderly but the cancer-specific -year survival rate after curative major surgery for rectal cancer in carefully selected elderly patients was similar to that found in younger patients ( vs. ). e overall postoperative mortality rate including emergency and palliative procedures in our study was . ; . in the elderly group and . in the younger age group. After curative operations, the mortality in the elderly group was compared with in the younger age group. Diligent perioperative care most certainly had an effect on low mortality rates. Furthermore, all possible efforts were made to identify and treat comorbid conditions before surgery. e American Society of Anaesthesiologists (ASA) classification of physical health did not help in assessing the risk of an individual patient. Perioperative mortality was low irrespective of ASA score and also, no statistically significant difference in the number of complications between the ASA groups was noted. According to many reports (Haynes ; Ranta ) there is considerable inter-observer inconsistency of classification making ASA-scoring alone too imprecise an instrument for treatment decisions. Other more reliable scoring systems like POSSUM score are being developed and tested (Senagore ). A considerable number of high-risk patients in our study was not operated on at all ( ) or underwent local excision ( ), which may contribute to acceptable complication and mortality figures, and shows the utmost importance of careful patient selection for major surgery. Preoperative selection is an aspect often excluded from studies in the elderly, even if it is crucial in the evaluation of long-term results of curative surgery. In our study, proportion of elderly patients is consistent with the report of the Finnish Cancer Registry, according to which of all rectal cancer patients
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in Finland were years of age or older in (Finnish Cancer Registry ). Also, tumour site and stage distribution are similar in both groups, old and young. erefore, probably a very realistic picture of the management policy and treatment possibilities of the rectal cancer in the elderly is presented in this study. In future, however, advancements in laparoscopic surgery may increase the number of patients suitable for major surgery. Preliminary experience suggests that laparoscopic resections in the elderly can be performed more safely than standard open surgery (Delgado ; Reissman ).
Adjuvant treatments Several different chemotherapeutic regimens and radiotherapy doses have been used in an effort to increase the percentage of those responding the treatment. e true impact of the adjuvant treatment on outcome has been difficult to assess because of multiple confounding issues such as variability in tumour stage, different techniques employed among studies, variability in the extent of the follow-up and above all, absence of a uniform method to estimate the effect. e most used measures such as changes in tumour size, stage or resectability are all subjective and dependent on the reliability of preoperative evaluation. In the present study, we have shown that assessment of radiation-induced histopathologic changes in tumours is reproducible and easily available method for examining tumour response after preoperative radiotherapy or chemoradiation. After high-dose chemoradiation patients ( ) showed complete regression (TRG ) and marked response (TRG –) was seen in of patients, which is in line with previous studies (Bouzourene ; Bozzetti ; Dworak ; Ruo ). e majority of patients ( ) who received a short course PRT in our study, showed no tumour regression. Non-irradiated patients used as a control group, were all except one classified in TRG –.
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Only of patients with marked response (TRG –) showed actual downstaging according to comparison between uTstage measured by ERUS and pT-stage. On the other hand, just as many ( ) of those with no histological response to PRT (TRG –) seemed to be downstaged. ere was a significant discordance (P = .) between the methods in assessing the effect of PRT. Downstaging defined as a difference between uT stage and pT stage has been considered a precise method to measure tumour response to chemoradiation. However, without preoperative radiotherapy, upstaging is more common than downstaging suggesting that assessment of response to radiation with this method overestimates the rate of tumour downstaging. Furthermore, its accuracy for assessing the rectal wall invasion is highly user-dependent varying from to (Adams ; Akbari ; Kumar ). us, to estimate the accuracy of downstaging based on the change of the T stage, the accuracy of ERUS staging in patients without preoperative radiotherapy should be known, whereas tumour regression grading (TRG) is a measure independent of preoperative evaluation and TNM staging. It has not been shown as to yet, whether histological tumour response translates into improved survival. e follow-up time in our study is too short and number of patients too small to draw any conclusions. A study of patients with T/ tumours, treated preoperatively with . Gy radiotherapy over . weeks and operated on within days, examined correlation of outcome with clinicopathologic variables, one of which was tumour regression grading. In the univariate analysis, absence of tumour regression (grade ) together with N disease, positive resection margin and vascular invasion was correlated with adverse overall survival and local recurrence rate. In the multivariate analysis absence of tumour regression was not an independent prognostic factor (Bouzourene ). In that study, patients with grades – were regarded as responders, whereas we have
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shown that grades – are commonly seen in patients treated without radiotherapy. Comparison of grades – with grades – might have given a more truthful picture of tumour response. A more simplified classification combining grades – into two grades and grades – into one non-responder group has been suggested (Wheeler ). ere are preliminary results showing a trend towards increased survival and decreased local recurrence rate in grade patients when using this three-step classification (Wheeler ). Furthermore, results from several studies suggest that complete response correlates with improved survival (GarciaAguilar ; Ruo ; eodoropoulos ). Considering that, it seems likely that the new tumour regression grading would help in comparing the results of different combined-modality therapies and might help in choosing the most effective neoadjuvant treatment in the future. Studies on molecular biomarkers between responders and non-responders might help in revealing the factors correlating with the tumour sensitivity for chemoradiotherapy.
Quality of life Up until ´s most of the patients with a carcinoma of the middle or low rectum were treated by an abdominoperineal excision, introduced by Sir Ernest Miles in . Today a variety of surgical techniques are available that preserve sphincter function. Maintaining the normal anatomy has become one of the main goals in modern rectal cancer surgery in order to avoid severe disruption of the quality of life. Indeed, a permanent colostomy is rarely necessary provided that all presently available techniques of sphincter salvation and restoration are applied. Tumours extending into anorectal junction or within the anal canal can be treated with ultralow anterior resection or even intersphincteric resection and continuity restored with ultra-low colorectal or coloanal anastomosis using colonic pouch (Tytherleigh ).
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However, sphincter preservation without good function is of questionable benefit. e functional result after low anterior resection may be disappointing because of an increased frequency of defecation, urgency and faecal leakage (Renner ). With the addition of radiation therapy the results may be further compromised (Hallböök b; Marijnen ). In this study, major bowel dysfunction (urgency, frequency, incontinence or constipation) occurred in of patients after high or low anterior resection, which is in line with previous reports (Camilleri-Brennan ). Urogenital dysfunction is also common after surgery for rectal cancer (CamilleriBrennan ). However, with modern operation techniques permanent major urinary dysfunction is rare (Enker ; Maas ). Also in this study, the urinary symptoms were similar to those encountered commonly in general population of same age. No major incontinence or neurogenic bladder requiring catheterization was encountered. e incidence of sexual dysfunction has been reported to be higher after APR than AR (Allal ; Engel ). In line with that, impotence occurred in and after LAR and APR in our study. Overall, the differences in the QoL of patients after sphincter-sacrificing and sphincter-preserving surgery seem to be small (Pachler ). In the present study, no significant difference between the treatment groups in the quality of life was seen.
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Physical functioning tended to be worse after APR than LAR. Of note is that sphinctersaving surgery resulted in significantly better physical functioning in those patients who did not have any major problems with bowel function or continence. e QoL of patients with such problems was similar to that of the patients who had undergone APR. Social functioning was significantly worse in patients with major bowel dysfunction compared with that of patients who did not have such problems. Also urinary dysfunction impaired social functioning and impotence physical and social functioning scores. Consequently, the same age general population scored significantly better in social functioning compared with rectal cancer patients. In other dimensions the QoL of the patient group was not impaired compared with that of general population. In contrast, the patients reported better health perception than the population. According to our results, organ dysfunction is a crucial factor in determining quality of life after rectal cancer surgery. Preoperative information about potential side effects is mandatory to make a patient’s expectations realistic, and to help to cope with the consequences. Refining surgical techniques to minimize the incidence of treatment-related adverse effects is probably at least as important as aiming to sphincter-sparing surgery in an attempt to improve the quality of life after rectal cancer surgery.
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CONCLUSIONS
On the basis of the present study, the following conclusions can be drawn: . A single PNA-test in its present form is as sensitive indicator of colorectal neoplasia as Hemolex completed over three days but lacks specificity, making it less suitable for screening purposes. e kD cancer-associated antigen under further characterization might help in developing a more specific PNA-test. . Total mesorectal excision technique (TME) technique in low and midrectal cancers results in improved survival and decreased local recurrence rate compared with conventional surgery. Despite an increased number of anastomotic complications TME technique is safe. e use of covering stoma and colonic J-pouch seems to reduce the incidence and severity of anastomotic complications. . Identification and treatment of comorbid conditions before surgery for rectal cancer is mandatory to keep morbidity and mortality rates acceptable. In carefully selected elderly patients similar survival rates to those found in younger patients are obtained. . In assessing tumour response to preoperative adjuvant therapy, histologic tumour regression grading (TRG) seems to offer a more accurate means than uT-downstaging, which did not correlate with TRG results. . Bowel and urinary dysfunction and impotence have a major adverse impact on the quality of life after rectal cancer surgery. ese adverse effects need to be discussed with the patient and preoperative function needs to be taken into account when choosing between treatment options. Refining surgical techniques to minimize the incidence of treatment-related adverse effects is probably at least as important as aiming to sphinctersparing surgery in an attempt to improve the quality of life after rectal cancer surgery.
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ACKNOWLEDGEMENTS
e present study was carried out at the Fourth Department of Surgery, the Helsinki University Central Hospital and the Jyväskylä Central Hospital. Analyzing the data and writing the papers were done while I was working at the Jorvi Hospital. I wish to thank Professor Krister Höckerstedt, MD, and the late Professor Juhani Ahonen, MD, and all the colleagues with whom I have worked at the Fourth Department of Surgery. e stimulating conversations and fine attitude towards both clinical and scientific work created the ground for this thesis. Above all, I wish to express my deepest gratitude to my supervisor, docent Ilmo Kellokumpu, MD, whose skills as a surgeon and researcher I highly respect. He guided me to the world of science and provided resources and subjects for this study. I could not have imagined having a better advisor and mentor and without his knowledge and perceptiveness I might have never finished this work. His commitment to good quality work will always inspire me. I owe sincere thanks to all my co-authors of the published manuscripts for their important contribution. Especially I wish to express my gratitude to docent Leena Halme, MD, whose patience and determination in solving problems connected to computers and statistics was of great help during the early phases of this work. Gratefully acknowledged is also Peter Sainio, MD, PhD, who showed me the importance of preciseness in scientific work. Docent Matti Kairaluoma, MD, Matti Juhola, MD, and Sakari Kellokumpu, PhD, are sincerely thanked for collecting data, for examining histopathologic samples and for laboratory analyses in PNA-tests, respectively. My sincere thanks are due to the reviewers, Professor Heikki Järvinen, MD, and 38
Professor Jyrki Mäkelä, MD, for their constructive comments in accomplishing the manuscript to its final form. e colleagues at the Jorvi Hospital have a special place in my heart as well. Above all, I am deeply indebted to Jorma Nieminen, MD, the Surgeon-in-Chief, for his encouraging, trusting and supporting attitude that helped enormously in bringing this thesis to its conclusion. Also, I am very grateful to the wonderful staff at the Day Surgery Unit, who had to put up with me in good and bad days during this process. I owe thanks to the staff at the patient archives of the Surgical Hospital, the Helsinki University Central Hospital and the Jyväskylä Central Hospital, for their prompt assistance and positive attitude when I was collecting data from patient files. Many warm thanks go also to Mrs Tuula Boström for her always so helpful attitude in literature haunt, to Mr Jari Simonen for handling the lay-out of this thesis, and to Mrs Sari Karesvuori and Mrs Eila Karonen for their invaluable help in organizing practical things for the dissertation. My special thanks go to my cousin and very dear friend Mrs Tarja Sarvi for helping me with the English language. My warmest thanks go also to Mrs Jutta Gröhn with whom I shared hilarious moments in the miraculous world of science, and her husband Mr Heikki Pikkarainen as well as Mrs and Mr Helle and Erkki Päiviö, who all took a great interest in the study. anks are due to my dear colleague and friend Pia Nordström who was a great source of strength all through this work. Collectively, I am deeply grateful to all my dear friends and relatives for their caring, support and always so refreshing company. Special thanks are due to each one of them who kept asking me all these years: ”Have you finished your HUCH, Jorvi Hospital Publications • Series A 01/2005
thesis yet?” Silencing that question was a prime motivation when other interests in life enticed. I wish to thank my dear mother Maria for always believing in me. My warmest thanks go also to my wonderful children Eveliina and Aleksi for their patience and interest in what I was doing throughout this work. Finally, I owe my most loving thanks to my husband Pekka who so often during many lonely hours spent at the computer nourished me with a hot cup of tea and lov-
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ing attitude to keep me going. is work is dedicated to them all. is study was financially supported by the Jorvi Hospital scientific foundation, the University of Helsinki, the Finnish Medical Society Duodecim and the Finnish Research Foundation of Gastroenterology, which I gratefully acknowledge. Looking forward to new challenges Jaana Vironen Espoo, th September
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