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 stud-ies 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 be-tween and (Table ). e data of patients were gathered retrospectively until year and prospectively thereafter.
S I From to samples of rec-tal mucus were obtained from patients undergoing colonoscopy for lower gastroin-testinal symptoms (e.g. altered bowel habits, abdominal pain, anaemia, hemorrhagia ex ano). From to , patients also completed Hemolex test over three days pri-or 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 com-mittee 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 opera-tions 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 dur-ing 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 strate-gies 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 No of patients
I PNA vs. Hemolex test 1992–94 199
II The effect of treatment strategy 1980–90
1991–97 144
61 (Conventional surgery) (TME surgery) III Treatment strategy of the elderly 1980–97 199
95
(< 75 years) (≥ 75 years)
IV Quality of life 1999–2003 94
V Tumour regression grading 1999–2003 135
and December . Of them,
patients underwent either curative or pal-liative 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 short-course preoperative Gy radiotherapy whereas patients with uT-tumors in proximity to the anal verge necessitating ab-dominoperineal 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 ma-jor resection. e histological response of the tumours after different preoperative ra-diation 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-RAND-) 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 im-munochemical 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.
PNA Samples of rectal mucus, obtained prior to colonoscopy with a cotton stick through a proctoscope from macroscopi-cally normal mucosa, were applied on nitrocellulose filters. e presence of PNA-reactive glycoconjugates in rectal mucus was determined by a peroxidase-conju-gated PNA-overlay procedure (Kellokumpu
). Two observers unaware of the colonoscopy findings examined PNA-re-activity.
PNA-binding profiles of paired normal and malignant colorectal tissue samples taken from cancer patients during surgery were analysed by the PNA-overlay proce-dure. erefore, tissue samples were ground in a mortar under liquid nitrogen, and de-tergent-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 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 chemilumines-ence-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 sig-moidoscope (studies II–III) or colonoscope (studies IV–V) and biopsies were taken.
Chest radiography, liver ultrasonography,
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 tu-mours 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 di-vided perpendicularly to the rectum and the lateral ligaments were ligated and divided.
Blunt dissection was not used.
Since (studies II–V) surgery was per-formed 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 mesorec-tum 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 ra-diation 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.
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 four-field technique with the same target volume as in short-course radiotherapy and includ-ing 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´ clas-sification during –, and according to the UICC TNM categories (Sobin ) during –. Assessment of the larg-est 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 his-topathological specimens showed tumour-free distal margins. Lateral margins were not assessed during the period –
(Studies II–III). In Study IV the circumfer-ential, radial resection margins were mea-sured 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
the RAND -item health survey quality of life questionnaire (Hays ) and a specific disease-related questionnaire assessing problems with urinary, sexual or defeca-tion-related functions.
e RAND- consists of items as-sessing eight dimensions of health from the patient’s viewpoint. ese dimensions mea-sure 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 con-trol group in examining the level of health related quality of life (HRQoL) in RAND-
subscales among patients. e population
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.
RESULTS
Study I
Details of the clinical findings in the
symptomatic patients and the sensitiv-ity for carcinoma of both tests are shown in Table . e sensitivity of the PNA-test and Hemolex for colorectal neoplasia
(ad-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-bind-ing proteins both in normal mucosa and colorectal cancer. Instead, expression of
kD PNA-binding protein was seen sig-nificantly more often (P < .) in colorectal cancer than normal mucosa (Figure ).
1 Sensitivity = Proportion of diseased subjects, who have a positive test
2 Specificity = Proportion of non-diseased subjects, who yield a negative test result
3 Positive/negative predictive value = Proportion of all individuals with positive/negative tests who do/do not have the disease
4 Accuracy = Proportion of true positive and negative tests of all those who were tested
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 colorec-tal mucosa and coloreccolorec-tal 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 stan-dards used.
Study II–III
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 = ).
Local recurrence rate and survival
e actuarial local recurrence rate was in the first period utilizing conventional surgery and after adopting TME surgery and selective use of preoperative radiother-apy (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)
-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 conven-tional surgery / patients ( ) had postoperative complications compared
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 .
Figure 4. Actuarial cancer-specific survival after major curative surgery according to patient age.
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
75 years or older Below 75 years
After curative anterior resection / of the patients ( ) during the first period and
/ ( ) during the second period devel-oped anastomotic leaks (P = .). During
–, when all low anastomoses were constructed using J-pouch and usually pro-tected with a temporary stoma, / ( )
patients developed anastomotic leaks. Table
shows the incidence of anastomotic leak-ages 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 9. Tumour regression grading (TRG) in different treatment groups.
Tumour regression grade a 5 4 3 2 1
Preoperative radiotherapy (number of patients (%))
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)
a TRG 1, 2 and 3 correspond to a regression exceeding 50 % of the tumour mass
b 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 Marked response No response
Downstaged Yes 12 14
No 28 29
P = 0.05 40 43
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 11. Health related quality of life according to RAND 36 (SF36) among general popula-tion (N=1440) and patients who had curative resecpopula-tion for rectal cancer (N = 71, age < 80 years). The values are adjusted for age and gender.
QoL-dimensions* General population Rectal cancer patients
P-value
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
* 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.
was (N = ) and after potentially cura-tive conventional and TME surgery, respec-tively. Consequently, the -day mortal-ity 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
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 .
ere was a marked discordance between the two methods in estimating tumour response after Gy radiotherapy or Gy chemoradiation (P = .). Of the tu-mours, 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
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 inconti-nence (Jorge ), urgency or constipation (Drossman )) impaired social function-ing significantly (P = .) in patients hav-ing undergone anterior resection compared with the patients without such problems
(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
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.
Figure 5. Quality of life after rectal cancer surgery in different treatment groups (HAR=
high anterior resection; LAR = low anterior resection; APR = anterior resection).
(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
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
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 = .).
DISCUSSION
Despite the fact that – of patients presenting with colorectal cancer may un-dergo 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 dis-ease. 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
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