Erik Carlsen

A national strategic change in treatment policy for rectal cancer--implementation of total mesorectal excision as routine treatment in Norway. A national audit.

AbstractINTRODUCTION: Rectal cancer surgery has been characterized by a high incidence of local recurrence, an occurrence which influences survival negatively. In Norway there was a growing recognition that local recurrence rates were related to surgeon performance and that surgeons applying a standardized surgical technique in the form of total mesorectal excision could achieve better results. This contrasts with the prevailing argument voiced by many opinion leaders that local recurrence rates and possibly survival rates can only be improved by adjuvant or neoadjuvant treatment strategies. The Norwegian Rectal Cancer Project—initiated in 1993—aimed at improving the outcome of patients with rectal cancer by implementing total mesorectal excision as the standard rectal resection technique. METHODS: This observational national cohort study covers all new patients (3,319) with rectal cancer from a population of 4.5 million treated between November 1993 and August 1997. The main outcome measures were local recurrence, survival, and postoperative mortality and morbidity rates. The technique of total mesorectal excision was compared with conventional surgery. RESULTS: The proportion of patients undergoing total mesorectal excision was 78 percent in 1994, increasing to 92 percent in 1997. The observed local recurrence rate for patients undergoing a curative resection was 6 percent in the group treated by total mesorectal excision and 12 percent in the conventional surgery group. Four-year survival rate was 73 percent after total mesorectal excision and 60 percent after conventional surgery. Postoperative mortality rate was 3 percent and the anastomotic dehiscence rate was 10 percent. Radiotherapy was given to 5 percent and chemotherapy to 3 percent of the patients in the curative resection group. CONCLUSION: A refinement of the surgical resection technique for rectal cancer can be achieved on a national level, the technique of total mesorectal excision can be widely distributed, and surgery alone can give good results.

LATE SIDE EFFECTS AND QUALITY OF LIFE AFTER RADIOTHERAPY FOR RECTAL CANCER

PURPOSE There is little knowledge on long-term morbidity after radiotherapy (50 Gy) and total mesorectal excision for rectal cancer. Therefore, late effects on bowel, anorectal, and urinary function, and health-related quality of life (QoL), were studied in a national cohort (n = 535). METHODS AND MATERIALS All Norwegian patients who received pre- or postoperative (chemo-)radiotherapy for rectal cancer from 1993 to 2003 were identified. Patients treated with surgery alone served as controls. Patients were without recurrence or metastases. Bowel and urinary function was scored with the LENT SOMA scale and the St. Marks Score for fecal incontinence and QoL with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). RESULTS Median time since surgery was 4.8 years. Radiation-treated (RT+) patients (n = 199) had increased bowel frequency compared with non-radiation-treated (RT-) patients (n = 336); 19% vs. 6% had more than eight daily bowel movements (p < 0.001). In patients without stoma, a higher proportion of RT+ (n = 69) compared with RT- patients (n = 240), were incontinent for liquid stools (49% vs. 15%, p < 0.001), needed a sanitary pad (52% vs. 13%, p < 0.001), and lacked the ability to defer defecation (44% vs. 16%, p < 0.001). Daily urinary incontinence occurred more frequently after radiotherapy (9% vs. 2%, p = 0.001). Radiation-treated patients had worse social function than RT- patients, and patients with fecal or urinary incontinence had impaired scores for global quality of life and social function (p < 0.001). CONCLUSIONS Radiotherapy for rectal cancer is associated with considerable long-term effects on anorectal function, especially in terms of bowel frequency and fecal incontinence. RT+ patients have worse social function, and fecal incontinence has a negative impact on QoL.

Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis

Background:Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation.Methods:We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy.Results:EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (⩾40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55).Conclusion:Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.

Design, organization and management of a controlled population screening study for detection of colorectal neoplasia: Attendance rates in the NORCCAP study (Norwegian Colorectal Cancer Prevention)

Background: In the past three decades, the incidence of colorectal cancer (CRC) in Norway has doubled, surpassing all other Nordic countries for both men and women to become the most frequently diagnosed cancer. A small-scale, randomized study on flexible sigmoidoscopy (FS) screening in Telemark, Norway, has shown a reduction in accumulated CRC incidence after 13 years. The aim of our study was to evaluate the effect on CRC mortality and morbidity by screen detection of CRC and removal of precursor lesions (polypectomy), and to test out the management and organization mimicking a countrywide screening service. A total of 13,823 men and women (1:1), age 55-64 years, were drawn randomly from the population registries in Oslo (urban) and the county of Telemark (mixed urban and rural) and invited to have a screening examination. The rest of the relevant age cohorts constituted the control groups. In the screening group, 535 individuals were excluded according to exclusion criteria, rendering 13,288 individuals eligible for screening examination. Methods: A once only screening model was used. In the screening group, individuals were randomized to have a once only FS or a combination of FS and faecal occult blood test (FOBT). Results: The overall attendance rate was 8,849 out of 13,288 (67%); 73% in Telemark and 60% in Oslo. Attendance for FS only was 68% and 65% for combined FS&FOBT. Conclusions: The present FS/FS&FOBT screening study obtained a high acceptance rate for both screening modalities. The attendance rate was stable throughout the trial, suggesting an acceptable model for management of future countrywide screening.

Sexual Function in Males After Radiotherapy for Rectal Cancer

PURPOSE Knowledge of sexual problems after pre- or postoperative radiotherapy (RT) with 50 Gy for rectal cancer is limited. In this study, we aimed to compare self-rated sexual functioning in irradiated (RT+) and nonirradiated (RT-) male patients at least 2 years after surgery for rectal cancer. METHODS AND MATERIALS Patients diagnosed with rectal cancer from 1993 to 2003 were identified from the Norwegian Rectal Cancer Registry. Male patients without recurrence at the time of the study. The International Index of Erectile Function, a self-rated instrument, was used to assess sexual functioning, and serum levels of serum testosterone were measured. RESULTS Questionnaires were returned from 241 patients a median of 4.5 years after surgery. The median age was 67 years at survey. RT+ patients (n = 108) had significantly poorer scores for erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction with sex life compared with RT- patients (n = 133). In multiple age-adjusted analysis, the odds ratio for moderate-severe erectile dysfunction in RT+ patients was 7.3 compared with RT- patients (p <0.001). Furthermore, erectile dysfunction of this degree was associated with low serum testosterone (p = 0.01). CONCLUSION RT for rectal cancer is associated with significant long-term effects on sexual function in males.

Nationwide quality assurance of rectal cancer treatment

Objective  The purpose of this prospective study was to examine the influence of the efforts for nationwide quality assurance of rectal cancer treatment. The study focuses on local recurrence and overall survival.

Sexual function in females after radiotherapy for rectal cancer

Abstract Background. Knowledge about female sexual problems after pre- or postoperative (chemo-)radiotherapy and radical resection of rectal cancer is limited. The aim of this study was to compare self-rated sexual functioning in women treated with or without radiotherapy (RT+ vs. RT−), at least two years after surgery for rectal cancer. Methods and materials. Female patients diagnosed from 1993 to 2003 were identified from a national database, the Norwegian Rectal Cancer Registry. Eligible patients were without recurrence or metastases at the time of the study. The Sexual function and Vaginal Changes Questionnaire (SVQ) was used to measure sexual functioning. Results. Questionnaires were returned from 172 of 332 invited and eligible women (52%). The mean age was 65 years (range 42–79) and the time since surgery for rectal cancer was 4.5 years (range 2.6–12.4). Sexual interest was not significantly impaired in RT+ (n=62) compared to RT− (n=110) women. RT+ women reported more vaginal problems in terms of vaginal dryness (50% vs. 24%), dyspareunia (35% vs. 11%) and reduced vaginal dimension (35% vs. 6%) compared with RT− patients; however, they did not have significantly more worries about their sex life. Conclusion. An increased risk of dyspareunia and vaginal dryness was observed in women following surgery combined with (chemo-)radiotherapy compared with women treated with surgery alone. Further research is required to determine the effect of adjuvant therapy on female sexual function.

Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group

Background. The recommendation of adjuvant chemotherapy for colon cancer with lymph node metastases, based on two studies from USA, was reluctantly accepted by Norwegian medical doctors. It was therefore decided to assess the role of adjuvant therapy with 5fluorouracil (5-FU) combined with levamisole (Lev) in a confirmatory randomised study. Material and methods. Four hundred and twenty five patients with operable colon and rectum cancer, Stage II and III (Dukes’ stage B and C), were from January 1993 to October 1996, included in a randomised multicentre trial in Norway. The age limits were 18–75 years. Therapy started with a loading course of bolus i.v. 5-FU (450 mg/m2) daily for 5 days and p.o. doses of Lev (50 mg x 3) for 3 days. From day 28 a weekly i.v. 5-FU dose (450 mg/m2) were administered for 48 weeks. From day 28 also p.o. doses of Lev (50 mg x 3) for 3 days were given every 14 days. In total 214 patients were randomised to 5FU/Lev and 211 were included in the control group with surgery alone. Some did not comply with the inclusion and exclusion criteria, thus leaving 206 evaluable patients in each group. Results. There was no significant survival difference between the two groups at 5 years: Disease-free survival (DFS) was 73% after chemotherapy, 68% (p=0.24) in the control group, and corresponding cancer specific survival (CSS) 75% and 71%, respectively (p=0.69). There was no difference between the two groups when analysed for colon and rectum separately. However, the subgroup of colon cancer with stage III exhibited a statistically significant difference both for DFS, 58% vs. 37% (p=0.012) and CSS, 65% vs. 47% (p=0.032) in favour of adjuvant chemotherapy. The benefit was further statistically significant for women but not for men. Toxicity was generally mild and acceptable with no drug related fatalities. Conclusions. Colon cancer patients with lymph node metastases benefit from adjuvant chemotherapy with 5-FU/Lev with acceptable toxicity. In a subgroup analysis females did better than males. Rectal cancer does not benefit from this regimen.

Loop Ileostomy: technical aspects and complications

OBJECTIVE To study the incidence of complications of construction and closure of loop ileostomies and the final outcome for the patients. DESIGN Retrospective study. SETTING University hospital, Norway. SUBJECTS 100 patients with 103 loop ileostomies, operated on between 1980 and 1990. MAIN OUTCOME MEASURES Number of complications after ileostomy construction and closure. RESULTS 7 required re-operation after construction of the loop ileostomy and 11 after its closure. The most common cause was small intestinal obstruction (4 after construction and 6 after closure). 2 developed stomal necrosis. The mean duration of hospital stay was 13 and 10 days for primary and secondary loop ileostomy, respectively, and the mean time before closure was 31 weeks. After closure another 6 developed leaks from the ileal anastomosis that required further operation. Patients with secondary loop ileostomies had their stomas significantly longer than those with primary loop ileostomies (21 compared with 43 weeks, p = 0.00005). CONCLUSION Despite the number of complications, we think that faecal diversion is still justified in complex pelvic surgery and we should try to reduce the complication rate further.

Radiotherapy for Rectal Cancer Is Associated With Reduced Serum Testosterone and Increased FSH and LH

PURPOSE It is known that scattered radiation to the testes during pelvic radiotherapy can affect fertility, but there is little knowledge on its effects on male sex hormones. The aim of this study was to determine whether radiotherapy for rectal cancer affects testosterone production. METHODS AND MATERIALS All male patients who had received adjuvant radiotherapy for rectal cancer from 1993 to 2003 were identified from the Norwegian Rectal Cancer Registry. Patients treated with surgery alone were randomly selected from the same registry as control subjects. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sex hormone binding globulin (SHBG) were analyzed, and free testosterone was calculated (N = 290). Information about the radiotherapy treatment was collected from the patient hospital charts. RESULTS Serum FSH was 3 times higher in the radiotherapy group than in the control group (median, 18.8 vs. 6.3 IU/L, p <0.001), and serum LH was 1.7 times higher (median, 7.5 vs. 4.5 IU/l, p <0.001). In the radiotherapy group, 27% of patients had testosterone levels below the reference range (8-35 nmol/L), compared with 10% of the nonirradiated patients (p <0.001). Irradiated patients had lower serum testosterone (mean, 11.1 vs. 13.4 nmol/L, p <0.001) and lower calculated free testosterone (mean, 214 vs. 235 pmol/L, p <0.05) than control subjects. Total testosterone, calculated free testosterone, and gonadotropins were related to the distance from the bony pelvic structures to the caudal field edge. CONCLUSIONS Increased serum levels of gonadotropins and subnormal serum levels of testosterone indicate that curative radiotherapy for rectal cancer can result in permanent testicular dysfunction.